Wireless audio and haptic devices and systems for neural stimulation and methods of using the same

Abstract

Devices, systems, and methods of the present disclosure are directed to devices, systems, and methods for administering a non-invasive stimulus to a subject, wherein the non-invasive stimulus comprises a gamma frequency. The devices and systems can include auditory and haptic devices such as wireless headphones, wireless earphones, wireless bone conduction headphones, or wireless in-ear phones configured to emit a neural, an auditory, or a haptic stimulus to a subject. In some cases, devices, systems and methods disclosed herein may be useful for the treatment of cognitive dysfunction.

Description

WIRELESS AUDIO AND HAPTIC DEVICES AND SYSTEMS FOR NEURAL STIMULATION AND METHODS OF USING THE SAME CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 678,157 filed August 01, 2024, which is incorporated herein by reference for all purposes in its entirety.BACKGROUND

[0002] Neural oscillation occurs in humans or animals and includes rhythmic or repetitive neural activity in the central nervous system. Neural tissue can generate oscillatory activity by mechanisms within individual neurons or by interactions between neurons. Oscillations can appear as either oscillations in membrane potential or as rhythmic patterns of action potentials, which can produce oscillatory activation of post-synaptic neurons. Synchronized activity of a group of neurons can give rise to macroscopic oscillations, which can be observed by electroencephalography (“EEG”). Neural oscillations can be characterized by their frequency, amplitude, and phase. Neural oscillations can give rise to electrical impulses that form a brainwave. These signal properties can be observed from neural recordings using time-frequency analysis. System and methods can be employed to synchronize neural oscillations within a brain region, including the use of systems and methods designed to direct neural oscillations via neural, visual, auditory, or haptic stimulation. The audio devices and systems may comprise wireless headphones, wireless earphones, or wireless in-earphones. The haptic devices and systems may comprise wireless bone conduction headphones, wireless bone conduction protheses, and / or wireless bone conduction hearing aid devices.

[0003] The systems and methods can include the use of devices such as wireless headphones, wireless earphones, wireless in-earphones, wireless bone conduction headphones, wireless bone conduction protheses, and / or wireless bone conduction hearing aid devices configured to provide wireless non-invasive neural, auditory, or haptic stimulation. In some cases, systems and methods can include configuring the devices to deliver wireless non-invasive neural, auditory, or haptic stimulation to treat and / or mitigate a disease or condition, e.g., dementia or Alzheimer’s disease.SUMMARY

[0004] In one aspect, disclosed herein is a wireless device configured to administer a non- invasive stimulus to a subject, wherein the non-invasive stimulus comprises a gamma frequency and wherein the administration of the non-invasive stimulus induces gamma oscillations within at least one brain region of the subject.

[0005] In some embodiments, the gamma frequency comprises about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0006] In some embodiments, the non-invasive stimulus comprises a visual stimulus, an auditory stimulus, or a haptic stimulus. In some embodiments, the haptic stimulus comprises vibration.

[0007] In some embodiments, the wireless device comprises a wireless non-invasive visual device configured to administer the visual stimulus. In some embodiments, the wireless non- invasive visual device comprises wireless glasses.

[0008] In some embodiments, the wireless device comprises a wireless non-invasive audio device configured to administer the auditory stimulus. In some embodiments, the wireless non- invasive audio device comprises wireless headphones. In some embodiments, the wireless headphones comprise wireless over-ear headphones or wireless in-ear headphones.

[0009] In some embodiments, the visual stimulus comprises a gamma frequency. In some embodiments, the gamma frequency comprises about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0010] In some embodiments, the visual stimulus comprises a pulse. In some embodiments, the visual stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second. In some embodiments, the visual stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second. In some embodiments, the visual stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second. In some embodiments, the visual stimulus comprises a pulse frequency of about 40 pulses per second.

[0011] In some embodiments, the auditory stimulus comprises a gamma frequency. In some embodiments, the gamma frequency comprises about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0012] In some embodiments, the auditory stimulus comprises a pulse. In some embodiments, the auditory stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second. In some embodiments, the auditory stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second. In some embodiments, the auditory stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second. In some embodiments, the auditory stimulus comprises a pulse frequency of about 40 pulses per second.

[0013] In some embodiments, the wireless device comprises a wireless non-invasive haptic device configured to deliver the vibration. In some embodiments, the vibration comprises a gamma frequency. In some embodiments, the gamma frequency comprises about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0014] In some embodiments, the haptic stimulus comprises a pulse. In some embodiments, the haptic stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second. In some embodiments, the haptic stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second. In some embodiments, the haptic stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second. In some embodiments, the haptic stimulus comprises a pulse frequency of about 40 pulses per second.

[0015] In a further aspect, disclosed herein is a wireless device configured to administer a non- invasive stimulus to a subject, the wireless device comprising: a signal emitter, wherein the signal emitter is configured to administer the non-invasive stimulus to the subject based on a signal generated by the wireless device; a feedback component; and a memory for storing processor executable instructions and at least one processor communicatively connected to the wireless non-invasive audio device and the at least one memory; wherein the non-invasive stimulus comprises a gamma frequency. In some embodiments, the wireless device further comprises a microphone. In some embodiments, the gamma frequency comprises about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0016] In some embodiments, the non-invasive stimulus comprises a visual stimulus, auditory stimulus and / or a haptic stimulus. In some embodiments, the haptic stimulus comprises vibration. In some embodiments, the wireless device comprises a wireless non-invasive audio device configured to administer the auditory stimulus. In some embodiments, the wireless non-invasive audio device comprises wireless headphones. In some embodiments, the wireless headphones comprise wireless over-ear headphones or wireless in-ear headphones. In some embodiments, the auditory stimulus comprises a gamma frequency. In some embodiments, the auditory stimulus comprises a frequency of about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0017] In some embodiments, the signal emitter comprises a speaker.

[0018] In some embodiments, the wireless device comprises a wireless non-invasive haptic device configured to deliver the vibration. In some embodiments, the vibration comprises a gamma frequency. In some embodiments, the vibration comprises a frequency of about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, or about 35 Hz to about 45 Hz.

[0019] In some embodiments, the vibration comprises a pulse. In some embodiments, the vibration comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second. In some embodiments, the vibration comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second. In some embodiments, the vibration comprises a pulsefrequency of about 35 pulses per second to about 45 pulses per second. In some embodiments, the vibration comprises a pulse frequency of about 40 pulses per second.

[0020] In some embodiments, the signal emitter comprises a vibrator.

[0021] In some embodiments, the wireless device further comprises a processor configured to receive an indication of a physiological, cognitive, neural, or physical assessment of the subject wearing the wireless device.

[0022] In some embodiments, when the processor receives the indication of the physiological, cognitive, neural, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive auditory, or haptic stimulus.

[0023] In some embodiments, the physical assessment of the subject comprises ascertaining at least one of the subject's: compliance with proper use and positioning of the system, eye status, alert or sleep status, or environment and surroundings. In some embodiments, the physical assessment of the subject is performed to determine hearing of the subject.

[0024] In some embodiments, the cognitive assessment of the subject is obtained through questions posed to the subject, activities and tasks performed by the subject in response to a prompt, or behaviors exhibited by the subject.

[0025] In some embodiments, the processor further instructs the device to lengthen or shorten the duration of stimulation in response to the indication of the physiological, cognitive, neural, or physical assessment.

[0026] In some embodiments, the indication of the physiological, cognitive, neural, or physical assessment of the subject comprises a biosignal. In some embodiments, the biosignal comprises an electroencephalography (EEG).

[0027] In some embodiments, a device and / or system as disclosed herein is used to treat, prevent, or mitigate cognitive dysfunction in a subject. In some embodiments, a device and / or system as disclosed herein is used to treat prevent or mitigate a disease or condition in a subject in need thereof, the disease or condition comprises dementia. In some embodiments, the dementia comprises Alzheimer’s disease, vascular dementia, Lewy body dementia, Pick's disease, frontotemporal dementia (FTD), AIDS dementia, age-related cognitive impairments, and age-related memory impairments. In some embodiments, the disease or condition comprises Parkinson’s disease.

[0028] In a further aspect, disclosed herein is a method comprising: stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby inducing gamma oscillations in at least one brain region of the subject. In some embodiments, the induced gamma oscillations comprise synchronized gamma oscillations.

[0029] In some embodiments, the at least one brain region comprises an entorhinal cortex, a hippocampus, a cerebral cortex, a visual association cortex, an auditory association cortex, a cingulate lobe, an amygdala, a thalamic nucleus, a cingulate lobe, a pons, a brainstem, a cerebellum, a lateral ventricle, an occipital lobe, a parietal lobe, a temporal lobe, a midbrain, a striatum, a basal ganglia, a globus pallidus, a substantia nigra, or any combination thereof.

[0030] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby maintaining, or reducing a level of tau phosphorylation in at least one brain region of the subject. In some embodiments, the maintaining or reducing tau phosphorylation including maintaining or reducing punctate localization of phosphorylated tau protein in the at least one brain region of the subject. In some embodiments, the maintaining or reducing tau phosphorylation including maintaining or reducing cell body localization of phosphorylated tau protein in the auditory cortex of the subject.

[0031] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby maintaining, or improving cognitive function in the subject. In some embodiments, the maintaining or improving cognitive function comprises maintaining or improving recognition, discrimination, spatial memory, working memory, attention, or a combination thereof.

[0032] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby maintaining, or reducing an amount of amyloid-P (A P) peptide in at least one brain region of the subject. In some embodiments, maintaining or reducing an amount of amyloid-P (AP) peptide in at least one brain region comprises reducing production of Ap peptide in the at least one brain region of the subject.

[0033] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby maintaining, or reducing an amount of at least one of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in at least one brain region of the subject.

[0034] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby maintaining, or reducing cleavage of APP into CTFs and NTFs by at least one of P- secretase (BACE1) and y-secretase in at least one brain region of the subject.

[0035] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby maintaining or reducing a number of endosomes in at least one brain region of the subject.

[0036] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby promoting clearance of Ap peptide in at least one brain region of the subject.

[0037] In a further aspect, disclosed herein is a method comprising stimulating a subject with a wireless non-invasive stimulus generated by a wireless device and / or system as disclosed herein, thereby increasing uptake of Ap peptide by microglia in the at least one brain region of the subject.

[0038] In some embodiments, a method as disclosed herein comprises inducing a change in microglial cells in at least one brain region of a subject. In some embodiments, inducing the change in microglial cells in at least one brain region of a subject improves the cognitive function of the subject, or prevents, reduces, or treats cognitive decline in the subject.

[0039] In some embodiments, the non-invasive stimulus is administered to a subject for about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, or more than about 1 hour per day.

[0040] In some embodiments, the non-invasive stimulus is administered to the subject at least once, twice, three times, or more than three times per day.

[0041] In some embodiments, the subject comprises a mammal. In some embodiments, the mammal comprises a non-human primate. In some embodiments, the mammal comprises a human.

[0042] In a further aspect, disclosed herein is a system comprising a wireless device as disclosed herein, further comprising a signal emitter; a feedback component; at least one memory for storing processor executable instructions; and at least one processor communicatively connected to the wireless device and the at least one memory; wherein the system is configured to implement the methods described and disclosed herein.INCORPORATION BY REFERENCE

[0043] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0044] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of which:

[0045] FIG. 1 shows a computer system that is programmed or otherwise configured to implement methods provided herein.

[0046] FIG. 2 is an example efficacy summary chart for a modified intent to treat (mITT) population, including hypothesized p-values, difference, confidence intervals (CI), and a hypothesized standardized estimate of efficacy based on the values.

[0047] FIG. 3 shows an example separate means analysis, on the left, and the linear model analysis, on the right, of a hypothesized Alzheimer's Disease composite score (ADCOMS) as optimized for mid and moderate Alzheimer's Disease (MADCOMS) for the sham and active treatment groups.

[0048] FIG. 4 shows an example separate means analysis, on the left, and a linear model analysis, on the right, of hypothesized Alzheimer's Disease Assessment Scale-Cognitive Subscale 14 (ADAS-Cogl4) values for the sham and active treatment groups.

[0049] FIG. 5 shows an example separate means analysis, on the left, and a linear model analysis, on the right, of hypothesized Clinical Dementia Rating Sale Sum of Boxes (CDR-SB) values for the sham and active treatment groups.

[0050] FIG. 6 shows an example separate means analysis, on the left, and a linear model analysis, on the right, of hypothesized Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL) scores for the sham and active treatment groups.

[0051] FIG. 7 shows an example linear model analysis of a hypothesized Mini-Mental State Examination (MMSE) score, as measured after six months of neuromodulation treatment (i.e., at the last time point).

[0052] FIG. 8 shows an example linear model analysis of hypothesized magnetic resonance imaging (MRI) results of whole brain volume value, on the left, and hippocampal volume, on the right, after six months of neuromodulation treatment.

[0053] FIG. 9 is a table depicting a summary of efficacy findings resulting from the human clinical trial, including p-values, treatment differences, Cl values and the percentage of slowing of brain atrophy.

[0054] FIG. 10 depicts an embodiment of a wireless non-invasive device. The device can be configured to include wireless visual, auditory, and haptic stimulation so that the patient can engage in routine daily activities during use. The wireless-non-invasive device can include accessibility updates, wireless and Bluetooth connectivity capabilities.DETAILED DESCRIPTION

[0055] While various embodiments of the invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed.

[0056] Devices, systems, and methods of the present disclosure are directed to wireless non- invasive stimulation via neural, visual, auditory, or haptic stimulation. Neural, visual, auditory, or haptic stimulation, including neural, visual, auditory, or haptic signals, can affect frequencies of neural oscillations. The neural, visual, auditory, or haptic stimulation can elicit brainwave effects or stimulation via modulated neural, auditory, or haptic input. The neural, visual, auditory, or haptic stimulation can adjust, control, or otherwise manage the frequency of the neural oscillations to provide beneficial effects to one or more cognitive states or cognitive functions of the brain or the immune system, while mitigating or preventing adverse consequences of a cognitive state or cognitive function. For example, devices, systems, and methods of the present technology can treat, prevent, protect against, or otherwise affect diseases or conditions such as dementia and / or Alzheimer's Disease.

[0057] External signals, such as visual signals, audio signals and / or haptic signals, can be observed or perceived by the brain. The brain can observe or perceive the visual, audio and / or haptic signals. The brain, in response to perceiving the visual, audio and / or haptic signals, can adjust, manage, or control the frequency of neural oscillations within a region or regions of the brain. This stimulation can result in repeated activation of portions of the brain which are known to process input, such as the auditory cortex. For example, visual, audio and / or haptic signals having a predetermined modulation frequency and perceived by the auditory cortex or other brain regions can trigger neural activity in the brain to cause a predetermined or resulting frequency of neural oscillations. The frequency of neural oscillations can be affected by or correspond to the modulation frequency of the visual, audio and / or haptic signals. Thus, devices, systems, and methods of the present disclosure can induce brainwave oscillations via visual, auditory and / or haptic stimulation.

[0058] Devices, systems, and methods of the present disclosure can induce brainwave oscillations using an external stimulus, such as a visual, auditory and / or haptic stimulus, including stimuli such as audio and / or haptic signals forming acoustic and / or vibratory pulses emitted at a predetermined modulation frequency to synchronize electrical activity among groups of neurons based on the modulation frequency of the visual, audio and / or haptic signals. Brainwave oscillations can be observed based on the aggregate frequency of oscillations produced by the synchronous electrical activity in ensembles of cortical neurons which the visual, acoustic and / or haptic vibratory pulses can adjust to synchronize with frequency of the visual, acoustic and / or haptic vibratory pulses.

[0059] The present disclosure provides devices, and systems for wireless non-invasive stimulation via visual, auditory and / or haptic stimulation. The visual and audio devices and systems may comprise wireless glasses, headphones, wireless earphones, or wireless inearphones, or a combination thereof. The haptic devices and systems may comprise wireless bone conduction headphones, wireless bone conduction protheses, and / or wireless bone conduction hearing aid devices. Wireless devices and / or systems as disclosed herein may comprise a combination of wireless visual, auditory, and haptic devices or systems as described herein.

[0060] The wireless systems may be configured to emit a neural, visual, auditory, or haptic stimulus. In some embodiments, the stimulus comprises a gamma frequency. In some cases, the gamma frequency is about 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz.

[0061] In some embodiments, the wireless glasses, headphones, wireless earphones, wireless inearphones, or wireless bone conduction headphones as disclosed herein are configured to emit a neural, auditory, or haptic stimulus of about 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz.

[0062] In some embodiments, the devices, and systems for wireless non-invasive stimulation as disclosed herein are configured to emit a non-invasive stimulus with a pulse. In some embodiments, the non-invasive stimulus comprises from about 20 pulses per second to about 60 pulses per second. In some embodiments, the non-invasive stimulus comprises from about 35 pulses per second to about 45 pulses per second. In some embodiments, the non-invasive stimulus comprises about 40 pulses per second.

[0063] In some embodiments, the wireless glasses, headphones, wireless earphones, or wireless in-earphones as disclosed herein may be configured to emit the neural, auditory, or haptic stimulus in conjunction with other sounds (e.g., music, podcasts, or other audio) playing on thewireless headphones, wireless earphones, wireless in-earphones, or wireless bone conduction headphones.Wireless Devices

[0064] In some embodiments, a wireless device as disclosed herein includes any wireless device that can deliver a wireless non-invasive visual, auditory and / or haptic stimulus to a subject.(i) Wireless Non- Invasive Audio Devices

[0065] By way of example, a wireless non-invasive audio device may comprise wireless headphones worn about the head of a subject. The wireless headphones may comprise wireless over-ear headphones or wireless in-ear headphones suitable for delivering a wireless non- invasive auditory gamma stimulus to the subject.

[0066] In some embodiments, wireless headphones can include, for example, circumaural headphones (e.g., full size / over-ear headphones) that include circular or ellipsoid earpads that are designed and constructed to seal against the head to attenuate external noise. Circumaural headphones can facilitate providing an immersive auditory brainwave wave stimulation experience, while reducing external distractions. In some embodiments, headphones can include supra-aural headphones, which include pads that press against the ears rather than around them. Supra-aural headphones may provide less attenuation of external noise.

[0067] Both circumaural headphones and supra-aural headphones can have an open back, closed back, or semi-open back. An open back may leak more sound and allow more ambient sounds to enter but may provide a more natural or speaker-like sound. Closed back headphones may block more of the ambient noise as compared to open back headphones, thus providing a more immersive auditory brainwave stimulation experience while reducing external distractions.

[0068] In some embodiments, headphones include ear-fitting headphones, such as earphones or in-ear headphones. Earphones (or earbuds) can refer to small headphones that are fitted directly in the outer ear, facing but not inserted in the ear canal. In-ear headphones (or in-ear monitors or canalphones) can refer to small headphones that can be designed and constructed for insertion into the ear canal. In-ear headphones engage the ear canal and can block out more ambient noise as compared to earphones, thus providing a more immersive auditory brainwave stimulation experience. In-ear headphones can include ear canal plugs made or formed from one or more material, such as silicone rubber, elastomer, or foam. In some embodiments, in-ear headphones can include custom-made castings of the ear canal to create custom-molded plugs that provide added comfort and noise isolation to the subject, thereby further improving the immersion of a subject.(1) Auditory Stimulus

[0069] In some embodiments, a wireless non-invasive audio device is configured to generate a wireless non-invasive auditory stimulus such as an audio tone, a beep, a click, or a similar audio stimulus. In some cases, the wireless non-invasive auditory stimulus comprises a sound with amplitude or intensity, a frequency, a pulse rate, a tone, a signal delay, an offset, a duration, a sinusoidal grating, a dynamic sound, a perceived direction of motion, or any combination thereof.

[0070] In some cases, the wireless non-invasive auditory stimulus comprises one or more acoustic waves. In some cases, the sound comprises an ultrasound or an infrasound. In some cases, the sound comprises a tone or frequency perceptible to the subject. In some cases, the sound comprises a tone or frequency imperceptible to the subject. In some cases, the sound comprises an acoustic frequency from about 0 Hz to about 50 kHz. In some cases, the sound comprises an acoustic frequency from about 20 Hz to about 20 kHz. In some cases, the sound comprises an acoustic frequency from about 8 Hz to about 12 kHz. In some cases, the sound comprises an acoustic frequency of 10 kHz.

[0071] In some cases, the dynamic sound comprises a tone or acoustic frequency perceptible to the subject. In some cases, the dynamic sound comprises a tone or acoustic frequency imperceptible to the subject. In some cases, the dynamic sound comprises an acoustic frequency from about 20 Hz to about 20 kHz. In some cases, the wireless non-invasive auditory stimulus comprises an acoustic frequency capable of modulating a gamma waveform in the subject. In some cases, the acoustic frequency capable of modulating a gamma waveform in the subject comprises an acoustic waveform of .1 Hz, 1 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45 Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz, 4,000 Hz, 5000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.

[0072] The wireless non-invasive auditory stimulus can be turned on and off based on a predetermined or fixed pulse rate interval, such as every 0.025 seconds, to provide a pulse repetition frequency of 40 Hz. The audio source can be turned on and off to provide a pulse repetition frequency in the range of about 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz, in accordance with methods disclosed herein.

[0073] In some embodiments, the auditory stimulus comprises a frequency from about 0.001 pulses / sec to about 50,000 pulses / sec. In some embodiments, the visual stimulus comprises a frequency from about 0.001 pulses / sec to about 2,000 pulses / sec, from about 0.01 pulses / sec to about 1,000 pulses / sec, from about 0.1 pulses / sec to about 1,000 pulses / sec, from about 5pulses / sec to about 100 pulses / sec, from about 10 pulses / sec to about 100 pulses / sec, from about 20 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 70 pulses / sec, from about 20 pulses / sec to about 60 pulses / sec, from about 20 pulses / sec to about 50 pulses / sec, from about 30 pulses / sec to about 80 pulses / sec, from about 30 pulses / sec to about 70 pulses / sec, from about 30 pulses / sec to about 60 pulses / sec, from about 30 pulses / sec to about 50 pulses / sec, or from about 35 pulses / sec to about 45 pulses / sec. In some cases, the visual stimulus comprises a frequency of about 40 pulses / sec. In some cases, the visual stimulus comprises a gamma frequency. A gamma frequency can comprise a visual stimulus frequency of from about 20 pulses / sec to about 100 pulses / sec, from about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec.

[0074] In some embodiments, the auditory stimulus comprises a pulse. In some embodiments the pulse comprises from about 20 pulses per second to about 60 pulses per second. In some embodiments, the pulse comprises from about 35 pulses per second to about 45 pulses per second. In some embodiments, the pulse comprises from 40 pulses per second.

[0075] In some embodiments, the auditory stimulus comprises a frequency configured to modulate a neural response, preferably a gamma waveform, in a brain region of the subject. In some embodiments, the auditory stimulus comprises a frequency capable of modulating a neural response (e.g., gamma waveform) in a brain region of the subject. In some embodiments, the frequency configured to modulate said neural response (e.g., gamma waveform) in the subject comprises a waveform of from about 1 pulses / sec to about 150 pulses / sec, from about 10 pulses / sec to about 150 pulses / sec, from about 10 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 70 pulses / sec, from about 20 pulses / sec to about 60 pulses / sec, from about 20 pulses / sec to about 50 pulses / sec, from about 30 pulses / sec to about 80 pulses / sec, from about 30 pulses / sec to about 70 pulses / sec, from about 30 pulses / sec to about 60 pulses / sec, from about 30 pulses / sec to about 50 pulses / sec, or from about 35 pulses / sec to about 45 pulses / sec. In some embodiments, the frequency capable of modulating a neural response (e.g., a gamma waveform) in the subject comprises a waveform of about 40 pulses / sec. In some cases, the frequency is configured to modulate a gamma waveform in a brain region of the subject. In some cases, the frequency is configured to be adjusted by the visual source of the system visual stimulus-emitting device.

[0076] In some embodiments, the frequency capable of modulating a gamma waveform in the subject comprises a waveform of .1 Hz, 1 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45 Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz,300 Hz, 400 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 3,000 Hz, 4,000 Hz, 5,000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.(2) Signal Emitter

[0077] In some embodiments, a wireless non-invasive audio device comprises a signal emitter. In some embodiments, a signal emitter includes a speaker, wherein the speaker can include one or more types of speaker hardware, components, or technology to generate a wireless non-invasive auditory stimulus such as the audio tone, beep, or click disclosed herein.

[0078] The speaker can include a diaphragm to produce sound. The speaker can include a moving-iron loudspeaker that uses a stationary coil to vibrate a magnetized piece of metal. The speaker can include a piezoelectric speaker. A piezoelectric speaker can use the piezoelectric effect to generate sound by applying a voltage to a piezoelectric material to generate motion, which is converted into audible sound using diaphragms and resonators.

[0079] The speaker can include various other types of hardware or technology, such as magnetostatic loudspeakers, magnetostrictive speakers, electrostatic loudspeakers, a ribbon speaker, planar magnetic loudspeakers, bending wave loudspeakers, coaxial drivers, horn loudspeakers, Heil air motion transducers, or transparent ionic conductions speaker.

[0080] In some cases, the speaker may not include a diaphragm. For example, the speaker can be a plasma arc speaker that uses electrical plasma as a radiating element. The speaker can be a thermoacoustic speakers that uses carbon nanotube thin film. The speaker can be a rotary woofer that includes a fan with blades that constantly change their pitch.(3) Microphone

[0081] In some embodiments, the wireless non-invasive audio device comprises one or more microphones. The microphones can be used to detect sound. A microphone can be integrated with a speaker. The microphone can provide feedback information to a wireless non-invasive audio device or system as disclosed herein. The microphone can provide feedback to a component of the speaker to cause the speaker to adjust a parameter of a wireless non-invasive auditory stimulus.

[0082] The microphone can include a transducer that converts sound into an electrical signal. The microphone can use electromagnetic induction, capacitance change, or piezoelectricity to produce the electrical signal from air pressure variations. In some cases, the microphone can include or be connected to a pre-amplifier to amplify the signal before it is recorded or processed. The microphone can include one or more type of microphone, including, for example, a condenser microphone, RF condenser microphone, electret condenser, dynamic microphone, moving-coil microphone, ribbon microphone, carbon microphone, piezoelectric microphone,crystal microphone, fiber optic microphone, laser microphone, liquid or water microphone, microelectromechanical systems (“MEMS”) microphone, or speakers as microphones.(4) Feedback Component

[0083] In some embodiments, a wireless non-invasive audio device comprises one or more feedback components. The feedback component can include or interface with the microphone to obtain, identify, or receive sound. The feedback component can obtain ambient noise. The feedback component can obtain sound from the speakers to facilitate the wireless non-invasive audio device adjusting a characteristic of the wireless non-invasive auditory stimulus generated by the speaker. The microphone can receive voice input from a subject, such as audio commands, instructions, requests, feedback information, or responses to survey questions.(5) Processor and Memory Device

[0084] In some embodiments, a wireless non-invasive audio device also includes at least one memory for storing processor executable instructions and at least one processor communicatively connected to the wireless non-invasive audio device and the at least one memory. The instructions can comprise administering any one of the methods as described herein. For instance, upon execution of the processor executable instructions, the at least one processor may control the wireless non-invasive audio device such that device emits the wireless non-invasive auditory stimulus at a frequency that activates neural oscillations, e.g., gamma oscillations, in at least one brain region of the subject corresponding to the audio frequency generated by the wireless non-invasive audio device. In some embodiments, the at least one processor may control the wireless non-invasive audio device such that the device actuates the wireless non-invasive auditory stimulus at the frequency that activates neural oscillations, e.g., gamma oscillations, in at least one of the auditory cortex and the hippocampus at the frequency corresponding to the audio frequency generated by the wireless non-invasive audio device.

[0085] In some embodiments, the wireless non-invasive audio device includes a data interface that enables data communication between the wireless non-invasive audio device and an external control device or system. The external device may be external device such as a fitting system, PDA, computer, mobile phone, or any other suitable device. Preferably, the interface allows two- way or bidirectional communication. That is, interface data may be sent from both the wireless non-invasive audio device and the external device. For example, in one embodiment, the interface may be adapted to receive control signals from the external device for generating a wireless non-invasive auditory stimulus at predetermined frequencies and receive control settings for the wireless non-invasive audio device for storing in the memory unit. In some embodiments,however, the interface is a one-way interface, allowing only data to be forwarded from the external device to the wireless non-invasive audio device. In other embodiments, communication is a one-way interface with data being forwarded from the wireless non-invasive audio device to any type of receiving device. The data may include measured control signals or any type of status information or other suitable data. This information may be used to merely monitor the wireless non-invasive audio device or be used with a control device that may be a separate device or be integrated into the wireless non-invasive audio device or be any other suitable device.

[0086] In some cases, the processor is configured to receive an indication of a physiological, cognitive, neural, or physical assessment of the subject wearing the wireless non-invasive audio device. In some cases, when the processor receives the indication of the physiological, cognitive, neural, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive auditory stimulus. In some cases, the physical assessment of the subject comprises ascertaining at least one of the subject's: compliance with proper use and positioning of the system, eye status, alert or sleep status, or environment and surroundings. In some cases, the physical assessment of the subject is performed to determine hearing of the subject, the indication of the physiological, cognitive, neural, or physical assessment of the subject comprises a biosignal. In some cases, the biosignal comprises an electroencephalography (EEG).

[0087] In some cases, the cognitive assessment of the subject is obtained through questions posed to the subject, activities and tasks performed by the subject in response to a prompt, or behaviors exhibited by the subject.

[0088] In some embodiments, a wireless non-invasive audio device as disclosed herein is provided with and / or operatively connected to a computer system as disclosed herein. The computer system 101 can communicate with one or more remote computer systems through the network 130. For instance, the computer system 101 can communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 101 via the network 130. In some cases, the computer systems are programmed to implement the function of a wireless non-invasive audio device, such as implementing a wireless non-invasive auditory stimulus delivered to a subject by the wireless non-invasive audio device as described herein. Any of the computer systems as described herein can carry out any of the methods as described herein.

[0089] Any of the devices as described herein can be used in conjunction with a mobile application. The mobile application may be used to modulate one or more parameters of a visual,auditory, or haptic stimulus as described herein. The mobile application may be used to monitor a response in the subject administered the one or more gamma oscillations. In view of the disclosure provided herein, a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications are written in several languages. Suitable programming languages include, by way of non-limiting examples, C, C++, C#, Objective-C, Java™, JavaScript, Pascal, Object Pascal, Python™, Ruby, Rails, VB.NET, WML, and XHTML / HTML with or without CSS, or combinations thereof.

[0090] Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator®, Celsius, Bedrock, Elash Lite, .NET Compact Eramework, Rhomobile, and WorkLight Mobile Platform. Other development environments are available without cost including, by way of non-limiting examples, Lazarus, MobiElex, MoSync, and Phonegap. Also, mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK, BlackBerry® SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, and Windows® Mobile SDK.

[0091] Those of skill in the art will recognize that several commercial forums are available for distribution of mobile applications including, by way of non-limiting examples, Apple® App Store, Google® Play, Chrome WebStore, BlackBerry® App World, App Store for Palm devices, App Catalog for webOS, Windows® Marketplace for Mobile, Ovi Store for Nokia® devices, Samsung® Apps, and Nintendo® DSi Shop.(ii) Wireless Non- Invasive Haptic Devices

[0092] In a fully functional human hearing anatomy, the outer ear comprises an auricle and an ear canal. A sound wave or acoustic pressure is collected by the auricle and channeled into and through the ear canal. Disposed across the distal end of the ear canal is a tympanic membrane which vibrates in response to acoustic wave. This vibration is coupled to the oval window or fenestra ovalis through three bones of middle ear, collectively referred to as the ossicles and comprising the malleus, the incus, and the stapes. The ossicles of the middle ear serve to filter and amplify an acoustic wave, causing the oval window to vibrate. Such vibration sets up waves of fluid motion within the cochlea. Such fluid motion, in turn, activates hair cells that line the inside of cochlea. Activation of the hair cells causes appropriate nerve impulses to be transferred through the spiral ganglion cells and auditory nerve to the brain, where they are perceived as sound. In some cases, such as in damaged or dysfunctional hearing, this process is disrupted. Awireless non-invasive haptic device, such as a wireless bone conduction device, works by transmitting vibrations through the bones of the skull to the inner ear's cochlea, bypassing the outer and middle ear. In some cases, a wireless non-invasive haptic device can improve hearing perception, such as in damaged or dysfunctional hearing and can be useful in activating neural oscillations, e.g., gamma oscillations, in at least one brain region of a subject corresponding to the haptic frequency generated by the wireless non-invasive haptic device.

[0093] By way of example, a wireless non-invasive haptic device may comprise wireless headphones worn about the head of a subject. The wireless headphones may comprise wireless bone conduction headphones suitable for delivering a wireless non-invasive haptic vibration gamma stimulus to the subject. The wireless bone conduction headphones can include, for example, circumaural headphones (e.g., full size / over-ear headphones) designed to sit above the ear of a user.

[0094] In some embodiments, bone conduction headphones include ear- fitting headphones, such as earphones or in-ear headphones. Earphones (or earbuds) can refer to small headphones that are fitted directly in the outer ear, facing but not inserted in the ear canal. In-ear headphones (or in- ear monitors or canalphones) can refer to small headphones that can be designed and constructed for insertion into the ear canal. In-ear headphones engage the ear canal and can block out more ambient noise as compared to earphones, thus providing a more immersive auditory brainwave stimulation experience. In-ear headphones can include ear canal plugs made or formed from one or more material, such as silicone rubber, elastomer, or foam. In some embodiments, in-ear headphones can include custom-made castings of the ear canal to create custom-molded plugs that provide added comfort and noise isolation to the subject, thereby further improving the immersion of a subject during the non-invasive stimulation.

[0095] In some embodiments, the wireless non-invasive haptic device may include an implanted bone conduction prosthesis, and / or a bone conduction hearing aid device.(1) Haptic Stimulus

[0096] In some embodiments, a wireless non-invasive haptic device is configured to generate a wireless non-invasive haptic stimulus such as a vibration, or a similar haptic stimulus. In some cases, the haptic stimulus can include any means that induces the perception of vibration through touch. In some cases, a haptic stimulus can be any stimulus that activates the somatosensory system.

[0097] In some cases, the frequency of the wireless non-invasive haptic stimulus comprises an wireless non-invasive haptic stimulus of 1 Hz, 1 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz, 4,000 Hz, 5000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.

[0098] In some cases, the wireless non-invasive haptic stimulus can be turned on and off based on a predetermined or fixed pulse rate interval, such as every 0.025 seconds, to provide a pulse repetition frequency of 40 Hz. The haptic source can be turned on and off to provide a pulse repetition frequency in the range of 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz, in accordance with methods disclosed herein.

[0099] In some embodiments, the haptic stimulus comprises a frequency from about 0.001 pulses / sec to about 50,000 pulses / sec. In some embodiments, the visual stimulus comprises a frequency from about 0.001 pulses / sec to about 2,000 pulses / sec, from about 0.01 pulses / sec to about 1,000 pulses / sec, from about 0.1 pulses / sec to about 1,000 pulses / sec, from about 5 pulses / sec to about 100 pulses / sec, from about 10 pulses / sec to about 100 pulses / sec, from about 20 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 70 pulses / sec, from about 20 pulses / sec to about 60 pulses / sec, from about 20 pulses / sec to about 50 pulses / sec, from about 30 pulses / sec to about 80 pulses / sec, from about 30 pulses / sec to about 70 pulses / sec, from about 30 pulses / sec to about 60 pulses / sec, from about 30 pulses / sec to about 50 pulses / sec, or from about 35 pulses / sec to about 45 pulses / sec. In some cases, the visual stimulus comprises a frequency of about 40 pulses / sec. In some cases, the visual stimulus comprises a gamma frequency. A gamma frequency can comprise a visual stimulus frequency of from about 20 pulses / sec to about 100 pulses / sec, from about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec.

[0100] In some embodiments, the haptic stimulus comprises a pulse. In some embodiments the pulse comprises from about 20 pulses per second to about 60 pulses per second. In some embodiments, the pulse comprises from about 35 pulses per second to about 45 pulses per second. In some embodiments, the pulse comprises from 40 pulses per second.

[0101] In some embodiments, the haptic stimulus comprises a frequency configured to modulate a neural response, preferably a gamma waveform, in a brain region of the subject. In some embodiments, the haptic stimulus comprises a frequency capable of modulating a neural response (e.g., gamma waveform) in a brain region of the subject. In some embodiments, the frequency configured to modulate said neural response (e.g., gamma waveform) in the subject comprises a waveform of from about 1 pulses / sec to about 150 pulses / sec, from about 10 pulses / sec to about 150 pulses / sec, from about 10 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec toabout 80 pulses / sec, from about 20 pulses / sec to about 70 pulses / sec, from about 20 pulses / sec to about 60 pulses / sec, from about 20 pulses / sec to about 50 pulses / sec, from about 30 pulses / sec to about 80 pulses / sec, from about 30 pulses / sec to about 70 pulses / sec, from about 30 pulses / sec to about 60 pulses / sec, from about 30 pulses / sec to about 50 pulses / sec, or from about 35 pulses / sec to about 45 pulses / sec. In some embodiments, the frequency capable of modulating a neural response (e.g., a gamma waveform) in the subject comprises a waveform of about 40 pulses / sec. In some cases, the frequency is configured to modulate a gamma waveform in a brain region of the subject. In some cases, the frequency is configured to be adjusted by the visual source of the system visual stimulus-emitting device.

[0102] In some embodiments, the frequency capable of modulating a gamma waveform in the subject comprises a waveform of .1 Hz, 1 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45 Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz, 300 Hz, 400 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 3,000 Hz, 4,000 Hz, 5,000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.(2) Signal Emitter

[0103] In some embodiments, a wireless non-invasive haptic device comprises a signal emitter. In some embodiments, a signal emitter includes a vibrator, wherein the vibrator can include one or more types of vibrator hardware, components, or technology to generate a non-invasive haptic stimulus such as the vibration disclosed herein.(3) Microphone

[0104] In some embodiments, the wireless non-invasive haptic device comprises one or more microphones. The microphones can be used to detect sound. A microphone can be integrated with a vibrator. The microphone can provide feedback information to a wireless non-invasive haptic device or system as disclosed herein. The microphone can provide feedback to a component of the vibrator to cause the vibrator to adjust a parameter of a wireless non-invasive haptic stimulus.

[0105] The microphone can include a transducer that converts sound into an electrical signal. The microphone can use electromagnetic induction, capacitance change, or piezoelectricity to produce the electrical signal from air pressure variations. In some cases, the microphone can include or be connected to a pre-amplifier to amplify the signal before it is recorded or processed. The microphone can include one or more type of microphone, including, for example, a condenser microphone, RF condenser microphone, electret condenser, dynamic microphone,moving-coil microphone, ribbon microphone, carbon microphone, piezoelectric microphone, crystal microphone, fiber optic microphone, laser microphone, liquid or water microphone, microelectromechanical systems (“MEMS”) microphone, or vibrators as microphones.(4) Feedback Component

[0106] In some embodiments, a wireless non-invasive haptic device comprises one or more feedback components. The feedback component can include or interface with the microphone to obtain, identify, or receive sound. The feedback component can obtain ambient noise. The feedback component can obtain sound from the vibrators to facilitate the wireless non-invasive haptic device adjusting a characteristic of the stimulus generated by the vibrator. The microphone can receive voice input from a subject, such as haptic commands, instructions, requests, feedback information, or responses to survey questions.(5) Processor and Memory Device

[0107] In some embodiments, a wireless non-invasive haptic device also includes at least one memory for storing processor executable instructions and at least one processor communicatively connected to the wireless non-invasive haptic device and the at least one memory. Upon execution of the processor executable instructions, the at least one processor may control the wireless non-invasive haptic device such that device emits the wireless non-invasive haptic stimulus at a frequency that activates neural oscillations, e.g., gamma oscillations, in at least one brain region of the subject corresponding to the haptic frequency generated by the wireless non- invasive haptic device. In some embodiments, the at least one processor may control the wireless non-invasive haptic device such that the device actuates the wireless non-invasive haptic stimulus at the frequency that activates neural oscillations, e.g., gamma oscillations, in at least one of the auditory cortex and the hippocampus at the frequency corresponding to the haptic frequency generated by the wireless non-invasive haptic device.

[0108] In some cases, the processor is configured to receive an indication of a physiological, cognitive, neural, or physical assessment of the subject wearing the wireless non-invasive haptic device. In some cases, when the processor receives the indication of the physiological, cognitive, neural, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive auditory, or haptic stimulus. In some cases, the physical assessment of the subject comprises ascertaining at least one of the subject's: compliance with proper use and positioning of the system, eye status, alert or sleep status, or environment and surroundings. In some cases, the physical assessment of the subject is performed to determine hearing of the subject, the indication of the physiological, cognitive, neural, or physical assessment of thesubject comprises a biosignal. In some cases, the biosignal comprises an electroencephalography (EEG).

[0109] In some cases, the cognitive assessment of the subject is obtained through questions posed to the subject, activities and tasks performed by the subject in response to a prompt, or behaviors exhibited by the subject.

[0110] In some embodiments, a wireless non-invasive haptic device as disclosed herein is provided with and / or operatively connected to a computer system as disclosed herein. The computer system 101 can communicate with one or more remote computer systems through the network 130. For instance, the computer system 101 can communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 101 via the network 130. In some cases, the computer systems are programmed to implement the function of a wireless non-invasive haptic device, such as implementing an auditory stimulus delivered to a subject by the wireless non- invasive haptic device as described herein.(iii) Wireless Non-invasive Visual Devices

[0111] By way of example, a wireless non-invasive visual device may comprise a visual source worn about the head of a subject, wherein the visual source is suitable for delivering a wireless non-invasive visual stimulus to the subject.

[0112] In some embodiments, said visual source comprises a pair of glasses worn by the subject with a visual source capable of providing a visual stimulus. The visual source can comprise a lens, e.g., a translucent lens. In some embodiments, a visual source as disclosed herein provides a visual stimulus to a subject using a visual source with an opaque or transparent lens. In some embodiments, the glasses comprise one or more lenses. In some embodiments, the lenses comprise transparent lenses. In some embodiments, a lens comprises a transmittance of about 0% to about 100%. In some embodiments, the visual source is operatively coupled to one or more processors. In some embodiments a wireless non-invasive visual device is operatively connected to wireless non-invasive haptic device and / or a wireless non-invasive audio device.

[0113] In some embodiments, a visual device comprises a frame that can be designed and constructed to be placed or positioned on a subject’s head. The frame can be configured to be worn by the person. The frame can be designed and constructed to stay in place. The frame can be configured to be worn and stay in place as a person sits, stands, walks, runs, or lays down flat. In some embodiments, a visual source comprises a visual source operatively connected to one ormore processors that can be configured on the frame to project light pulses towards the person’s eyes in various positions. In some embodiments, the visual source can be configured to project light pulses towards the person’s eyes if their eyelids are closed such that the light pulse penetrates the eyelid to be perceived by the retina. The frame can include a bridge. The frame can include one or more eye wires coupled to the bridge. The bridge can be positioned in between the eye wires. The frame can include one or more temples extending from the one or more eye wires. In some embodiments, the visual source can include or hold a lens. In some embodiments, the visual source can include or hold a solid material or cover. The lens, solid material, or cover can be transparent, semi-transparent, opaque, or completely block out external light.

[0114] One or more visual sources can be positioned on or adjacent to the eye wire, lens or other solid material, or bridge. For example, a visual source can be positioned in the middle of the eye wire on a solid material in order to transmit light pulses into the direct visual field. In some embodiments, a visual source can be positioned at a corner of the eye wire, such as a comer of the eye wire coupled to the temple, in order to transmit light pulses towards a peripheral field.

[0115] The visual source can perform visual stimulation via a single eye or both eyes. For example, the visual source can direct light pulses to a single eye or both eyes. The visual signaling component can include a single visual source configured and positioned to direct light pulses to a first eye. The visual signaling component can further include a light blocking component that keeps out or blocks the light pulses generated from the visual source from entering a second eye. The visual signaling component can block or prevent light from entering the second eye during the brain stimulation process.

[0116] In some embodiments, the visual source can alternatively transmit or direct light pulses to the first eye and the second eye. For example, the visual source can direct light pulses to the first eye for a first-time interval. The visual source can direct light pulses to the second eye for a second time interval. The first-time interval and the second time interval can be a same time interval, overlapping time intervals, mutually exclusive time intervals, or subsequent time intervals.

[0117] The lens can include electrochromic glass or plastic. Electrochromic glass or plastic can change from light to dark (e.g., clear to opaque) in response to an electrical voltage or current. Electrochromic glass or plastic can include metal-oxide coatings that are deposited on the glass or plastic, multiple layers, and lithium ions that travel between two electrodes between a layer to lighten or darken the lens.

[0118] In some embodiments, a visual source can include a tablet computing visual source or other computing visual source having a display screen.

[0119] In some embodiments, the visual source can display a pattern of light. The light can flicker, toggle or switch between two or more patterns to generate flashes of light or light pulses. Patterns can include, for example, alternating checkerboard patterns. The pattern can include symbols, characters, or images that can be toggled or adjusted from one state to another state. For example, the color of a character or text relative to a background color can be inverted to cause a switch between a first state and a second state. Inverting a foreground color and background color at a predetermined frequency can generate light pulses by way of indicating visual changes that can facilitate adjusting or managing a frequency of neural oscillations.

[0120] In some embodiments, the visual source can instruct or cause a visual stimulus to flicker, toggle, or switch between images configured to stimulate specific or predetermined portions of the brain or a specific cortex. The presentation, form, color, motion and other aspects of the light or an image based stimuli can dictate which cortex or cortices are recruited to process the stimuli. The visual source can stimulate discrete portions of the cortex by modulating the presentation of the stimuli to target specific or general regions of interest. The relative position in the field of view, the color of the input, or the motion and speed of the light stimuli can dictate which region of the cortex is stimulated. For example, the brain can include at least two portions that process predetermined types of visual stimuli: the primary visual cortex on the left side of the brain, and the calcarine fissure on the right side of the brain. Each of these two portions can have one or more multiple sub-portions that process predetermined types of visual stimuli. For example, the calcarine fissure can include a sub-portion referred to as area V5 that can include neurons that respond strongly to motion but cannot register stationary objects. Subjects with damage to area V5 can have motion blindness, but otherwise normal vision. In another example, the primary visual cortex can include a sub-portion referred to as area V4 that can include neurons that are specialized for color perception. Subjects with damage to area V4 can have color blindness and only perceive objects in shades of gray. In another example, the primary visual cortex can include a sub-portion referred to as area V 1 that includes neurons that respond strongly to contrast edges and helps segment the image into separate objects. Thus, the visual source can instruct or cause a visual stimulus to form a type of still image or video, or generate a flicker, or toggle between images that configured to stimulate specific or predetermined portions of the brain or a specific cortex. For example, the visual source can generate images of human faces to stimulate a fusiform face area, which can facilitate brain stimulation for subjects having prosopagnosia or face blindness. In some embodiments, the visual source can generate images of faces flickering to target this area of the subject’s brain. In another example, the visual source cangenerate images that include edges or line drawings to stimulate neurons of the primary visual cortex that respond strongly to contrast edges.

[0121] The visual source can include, access, interface with, or otherwise communicate with at least one visual source. The visual source can be designed and constructed to measure or verify an environmental variable (e.g., light intensity, timing, incident light, ambient light, eye lid status, etc.) to adjust a parameter associated with the visual signal, such as a frequency, amplitude, wavelength, intensity pattern or other parameter of the visual signal, or any combination thereof. The visual source can automatically vary a parameter of the visual signal based on profile information or feedback. The visual source can receive the feedback information from a feedback monitor. The visual source can receive instructions or information from a side effects management module. The visual source can receive profile information from a profile manager. The visual source can include an LED.

[0122] The visual source can include, access, interface with, or otherwise communicate with at least one unwanted frequency filtering module. The unwanted frequency filtering module can be designed and constructed to block, mitigate, reduce, or otherwise filter out frequencies of visual signals that are undesired to prevent or reduce an amount of such visual signals from being perceived by the brain. The unwanted frequency filtering module can interface, instruct, control, or otherwise communicate with a filtering component to cause the filtering component to block, attenuate, or otherwise reduce the effect of the unwanted frequency on the neural oscillations.

[0123] The visual source can include, access, interface with, or otherwise communicate with at least one profile manager. The profile manager can be designed or constructed to store, update, retrieve or otherwise manage information associated with one or more subjects associated with the . Profile information can include, for example, historical treatment information, historical brain stimulation information, dosing information, parameters of light waves, feedback, physiological information, environmental information, or other data associated with the systems and methods of brain stimulation.

[0124] The visual source can include, access, interface with, or otherwise communicate with at least one side effects management module. The side effects management module can be designed and constructed to provide information to the visual source to change one or more parameter of the visual signal in order to reduce a side effect. Side effects can include, for example, nausea, migraines, fatigue, seizures, eye strain, or loss of sight.

[0125] The side effects management module can automatically instruct a component of the visual source to alter or change a parameter of the visual signal. The side effects management module can be configured with predetermined thresholds to reduce side effects. For example, the sideeffects management module can be configured with a maximum duration of a pulse train, maximum intensity of light waves, maximum amplitude, maximum duty cycle of a pulse train (e.g., the pulse width multiplied by the frequency of the pulse train), maximum number of treatments for brainwave stimulation in a time period (e.g., 1 hour, 2 hours, 12 hours, or 24 hours).

[0126] The side effects management module can cause a change in the parameter of the visual signal in response to feedback information. The side effect management module can receive feedback from the feedback monitor. The side effects management module can determine to adjust a parameter of the visual signal based on the feedback. The side effects management module can compare the feedback with a threshold to determine to adjust the parameter of the visual signal.

[0127] The side effects management module can be configured with or include a policy engine that applies a policy or a rule to the current visual signal and feedback to determine an adjustment to the visual signal. For example, if feedback indicates that a patient receiving visual signals has a heart rate or pulse rate above a threshold, the side effects management module can turn off the pulse train until the pulse rate stabilizes to a value below the threshold, or below a second threshold that is lower than the threshold.

[0128] The visual source can include, access, interface with, or otherwise communicate with at least one feedback monitor. The feedback monitor can be designed and constructed to receive feedback information from a feedback component. The feedback component can include, for example, a feedback sensor such as a temperature sensor, heart or pulse rate monitor, physiological sensor, ambient light sensor, ambient temperature sensor, sleep status via actigraphy, blood pressure monitor, respiratory rate monitor, brain wave sensor, EEG probe, electrooculography (“EOG”) probes configured to measure the comeo-retinal standing potential that exists between the front and the back of the human eye, accelerometer, gyroscope, motion detector, proximity sensor, camera, microphone, or photo detector, or any combination thereof.

[0129] In some embodiments, a computing visual source can include the feedback component or feedback sensor. For example, the feedback sensor can be placed on a tablet and can include a front-facing camera that can capture images of a person viewing the visual source.

[0130] The feedback sensor can interact with or communicate with visual source. For example, the feedback sensor can provide detected feedback information or data to the visual source. The feedback sensor can provide data to the visual source in real-time, for example as the feedback sensor detects or senses or information. The feedback sensor can provide the feedback information to the visual source based on a time interval, such as 1 minute, 2 minutes, 5 minutes,10 minutes, hourly, 2 hours, 4 hours, 12 hours, or 24 hours. The feedback sensor can provide the feedback information to the visual source responsive to a condition or event, such as a feedback measurement exceeding a threshold or falling below a threshold. The feedback sensor can provide feedback information responsive to a change in a feedback parameter. In some embodiments, the visual source can ping, query, or send a request to the feedback sensor for information, and the feedback sensor can provide the feedback information in response to the ping, request, or query. Feedback sensors can include, for example, EEG probes that detect brain wave activity.

[0131] The feedback monitor can detect, receive, obtain, or otherwise identify feedback information from the one or more feedback sensors . The feedback monitor can provide the feedback information to one or more component of the visual source for further processing or storage. For example, the profile manager can update profile data structure stored in data repository with the feedback information. Profile manager can associate the feedback information with an identifier of the patient or person undergoing the visual brain stimulation, as well as a time stamp and date stamp corresponding to receipt or detection of the feedback information. The identifier can be indicative of an activity of a subject, a physiological or physical condition of a subject, or a mental condition of a subject. The identifier can also be indicative of a disease, disorder, or condition.

[0132] The feedback monitor can detect symptoms of a neurological disease or disorder. For the example, the feedback monitor can be used to evaluate changes in fine motor skills over time or changes in voice pitch or tone. The profile manager can update profile data structure with the feedback information. The profile data structure can be used to assess whether a person is at risk of developing a neurological disorder, whether a person has a neurological disorder, or progression of symptoms of a neurological disorder.

[0133] The feedback monitor can determine a level of attention. The level of attention can refer to the focus provided to the light pulses used for brain stimulation. The feedback monitor can determine the level of attention using various hardware and software techniques. The feedback monitor can assign a score to the level of attention (e.g., 1 to 10 with 1 being low attention and 10 being high attention, or vice versa, 1 to 100 with 1 being low attention and 100 being high attention, or vice versa, 0 to 1 with 0 being low attention and 1 being high attention, or vice versa), categorize the level of attention (e.g., low, medium, high), grade the attention (e.g., A, B, C, D, or F), or otherwise provide an indication of a level of attention.

[0134] In some cases, the feedback monitor can track a person’s eye movement to identify a level of attention. The feedback monitor can interface with a feedback component that includesan eye-tracker. The feedback monitor can detect and record eye movement of the person and analyze the recorded eye movement to determine an attention span or level of attention. The feedback monitor can measure eye gaze which can indicate or provide information related to covert attention. For example, the feedback monitor can be configured with electro-oculography (“EOG”) to measure the skin electric potential around the eye, which can indicate a direction the eye faces relative to the head. In some embodiments, the EOG can include a system or visual source to stabilize the head so it cannot move in order to determine the direction of the eye relative to the head. In some embodiments, the EOG can include or interface with a head tracker system to determine the position of the heads, and then determine the direction of the eye relative to the head.

[0135] In some embodiments, the feedback monitor and feedback component can determine or track the direction of the eye or eye movement using video detection of the pupil or corneal reflection. For example, the feedback component can include one or more camera or video camera. The feedback component can include an infra-red source that sends light pulses towards the eyes. The light can be reflected by the eye. The feedback component can detect the position of the reflection. The feedback component can capture or record the position of the reflection. The feedback component can perform image processing on the reflection to determine or compute the direction of the eye or gaze direction of the eye.

[0136] The feedback monitor can compare the eye direction or movement to historical eye direction or movement of the same person, nominal eye movement, or other historical eye movement information to determine a level of attention. For example, if the eye is focused on the light pulses during the pulse train, then the feedback monitor can determine that the level of attention is high. If the feedback monitor determines that the eye moved away from the pulse train for 25% of the pulse train, then the feedback monitor can determine that the level of attention is medium. If the feedback monitor determines that the eye movement occurred for more than 50% of the pulse train or the eye was not focused on the pulse train for greater than 50%, then the feedback monitor can determine that the level of attention is low.

[0137] In some embodiments, the visual source can include a filter to control the spectral range of the light emitted from the visual source. In some embodiments, the visual source includes a light reactive material affecting the light emitted, such as a polarizer, filter, prism or a photochromic material, or electrochromic glass or plastic. The filtering component can receive instructions from the unwanted frequency filtering module to block or attenuate one or more frequencies of light.- l-

[0138] The filtering component can include an optical filter that can selectively transmit light in a particular range of wavelengths or colors, while blocking one or more other ranges of wavelengths or colors. The optical filter can modify the magnitude or phase of the incoming light wave for a range of wavelengths. The optical filter can include an absorptive filter, or an interference or dichroic filter. An absorptive filter can take energy of a photon to transform the electromagnetic energy of a light wave into internal energy of the absorber (e.g., thermal energy). The reduction in intensity of a light wave propagating through a medium by absorption of a part of its photons can be referred to as attenuation.

[0139] An interference filter or dichroic filter can include an optical filter that reflects one or more spectral bands of light, while transmitting other spectral bands of light. An interference filter or dichroic filter can have a nearly zero coefficient of absorption for one or more wavelengths. Interference filters can be high-pass, low-pass, bandpass, or band-rejection. An interference filter can include one or more thin layers of a dielectric material or metallic material having different refractive indices.(1) Visual Stimulus

[0140] In some embodiments, a visual source is configured to generate a visual stimulus such as such as a light pulse or flash of light. In some embodiments, the visual stimulus comprises a light pulse or flash of light with amplitude or intensity, a frequency, a pulse rate, a tone, a signal delay, an offset, a duration, or any combination thereof. In some embodiments, the visual source comprises a light emitting diode (LED) capable of producing a light pulse or flash of light.

[0141] In some embodiments, the visual stimulus comprises one or more light waves. In some embodiments, the visual stimulus is perceptible to the subject. In some embodiments, the visual stimulus is imperceptible to the subject. In some embodiments, the visual stimulus comprises a frequency from about 0 Hz to about 50 kHz. In some embodiments, the visual stimulus comprises a frequency from about 20 Hz to about 20 kHz.

[0142] In some embodiments, the visual stimulus comprises a frequency capable of modulating a gamma waveform in a brain region of the subject. In some embodiments, the frequency capable of modulating a gamma waveform in the subject comprises a waveform of .1 Hz, 1 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45 Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz, 4,000 Hz, 5000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.

[0143] The visual stimulus can be turned on and off based on a predetermined or fixed pulse rate interval, such as every 0.025 seconds, to provide a pulse repetition frequency of 40 Hz. Thevisual source can be turned on and off to provide a pulse repetition frequency in the range of about 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz, in accordance with methods disclosed herein.

[0144] In some embodiments, the visual stimulus comprises a pulse. In some embodiments the pulse comprises from about 20 pulses per second to about 60 pulses per second. In some embodiments, the pulse comprises from about 35 pulses per second to about 45 pulses per second. In some embodiments, the pulse comprises from 40 pulses per second.

[0145] In some embodiments, the present disclosure describes systems and devices for providing a gamma-oscillation inducing waveform that is imperceptible to a subject. In some cases, a display device can be configured to output the gamma oscillation inducing waveform. In some cases, a stimulation source can be configured to be operatively configured to another device, such that the stimulation source outputs the gamma oscillation inducing waveform in association with the output of the device. In some cases, a device can comprise a filter, wherein the filter is capable of masking one or more waveforms of a waveform source such that a subject using the filter receives a gamma oscillation inducing waveform. In some cases, a device can comprise a cover, wherein the cover is configured to add a gamma-oscillation inducing waveform to one or more waveforms of a waveform source such that a subject using the cover receives a gamma oscillation inducing waveform.

[0146] In some embodiments, the visual stimulus comprises one or more light waves. In some embodiments, the visual stimulus is perceptible to the subject. In some embodiments, the visual stimulus is imperceptible to the subject. In some embodiments, the visual stimulus comprises a frequency from about 0.001 pulses / sec to about 50,000 pulses / sec. In some embodiments, the visual stimulus comprises a frequency from about 0.001 pulses / sec to about 2,000 pulses / sec, from about 0.01 pulses / sec to about 1,000 pulses / sec, from about 0.1 pulses / sec to about 1,000 pulses / sec, from about 5 pulses / sec to about 100 pulses / sec, from about 10 pulses / sec to about 100 pulses / sec, from about 20 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 70 pulses / sec, from about 20 pulses / sec to about 60 pulses / sec, from about 20 pulses / sec to about 50 pulses / sec, from about 30 pulses / sec to about 80 pulses / sec, from about 30 pulses / sec to about 70 pulses / sec, from about 30 pulses / sec to about 60 pulses / sec, from about 30 pulses / sec to about 50 pulses / sec, or from about 35 pulses / sec to about 45 pulses / sec. In some cases, the visual stimulus comprises a frequency of about 40 pulses / sec. In some cases, the visual stimulus comprises a gamma frequency. A gamma frequency can comprise a visual stimulus frequency of from about 20 pulses / sec to about 100 pulses / sec, from about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec.

[0147] In some embodiments, the one or more light waves comprise light waves having a wavelength of from about 300 nm to about 2000 nm, from about 300 nm to about 1000 nm, from about 300 nm to about 850 nm, from about 300 nm to about 450 nm, from about 300 nm to about 550 nm, from about 300 nm to about 650 nm, from about 300 nm to about 750 nm, from about 450 nm to about 850 nm, from about 450 nm to about 750 nm, from about 450 nm to about 650 nm, from about 450 nm to about 550 nm, from about 500 nm to about 850 nm, from about 500 nm to about 750 nm, from about 500 nm to about 650 nm, or from about 650 nm to about 850 nm.

[0148] In some embodiments, the visual stimulus comprises a frequency configured to modulate a neural response, preferably a gamma waveform, in a brain region of the subject. In some embodiments, the visual stimulus comprises a frequency capable of modulating a neural response (e.g., gamma waveform) in a brain region of the subject. In some embodiments, the frequency configured to modulate said neural response (e.g., gamma waveform) in the subject comprises a waveform of from about 1 pulses / sec to about 150 pulses / sec, from about 10 pulses / sec to about 150 pulses / sec, from about 10 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 80 pulses / sec, from about 20 pulses / sec to about 70 pulses / sec, from about 20 pulses / sec to about 60 pulses / sec, from about 20 pulses / sec to about 50 pulses / sec, from about 30 pulses / sec to about 80 pulses / sec, from about 30 pulses / sec to about 70 pulses / sec, from about 30 pulses / sec to about 60 pulses / sec, from about 30 pulses / sec to about 50 pulses / sec, or from about 35 pulses / sec to about 45 pulses / sec. In some embodiments, the frequency capable of modulating a neural response (e.g., a gamma waveform) in the subject comprises a waveform of about 40 pulses / sec. In some cases, the frequency is configured to modulate a gamma waveform in a brain region of the subject. In some cases, the frequency is configured to be adjusted by the visual source of the system visual stimulus-emitting device.

[0149] In some embodiments, the frequency capable of modulating a gamma waveform in the subject comprises a waveform of .1 Hz, 1 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45 Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz, 300 Hz, 400 Hz, 500 Hz, 1,000 Hz, 2,000 Hz, 3,000 Hz, 4,000 Hz, 5,000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.

[0150] In some embodiments, the visual stimulus can be turned on and off based on a predetermined or fixed pulse rate interval, such as every 0.025 seconds, to provide a pulse repetition frequency of 40 pulses / sec. In some cases, the predetermined or fixed pulse rate interval is from about 0.001 seconds to about 0.5 seconds, from about 0.01 seconds to about 0.5seconds, from about 0.0125 seconds to about 0.1 seconds, from about 0.02 to about 0.05 seconds, or from about 0.033 seconds to about 0.022 seconds. In some cases, the predetermined or fixed pulse rate interval is about 0.025 seconds.

[0151] In some embodiments, the visual source can be turned on and off to provide a pulse repetition frequency in the range of about 20 Hertz (pulses / sec) to about 140 pulses / sec, about 30 pulses / sec to about 60 pulses / sec, about 40 pulses / sec to about 60 pulses / sec, about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec, in accordance with the systems, devices, and methods disclosed herein. In some cases, the visual source flashes the visual stimulus to provide a pulse repetition frequency in the range of about 20 Hertz (pulses / sec) to about 140 pulses / sec, about 30 pulses / sec to about 60 pulses / sec, about 40 pulses / sec to about 60 pulses / sec, about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec, in accordance with the systems, devices, and methods disclosed herein.

[0152] In some embodiments, the visual source can transmit or direct a first plurality of light pulses to a first eye, a second eye, or both eyes of a subject. In some embodiments, the visual source can transmit or direct a second plurality of light pulses to a first eye, a second eye, or both eyes of a subject. In some cases, visual source can transmit or direct light pulses comprising a first plurality of light pulses and a second plurality of light pulses to a first eye, a second eye, or both eyes of a subject. In some embodiments, the first plurality of light pulses is transmitted to a first eye, a second eye, or both eyes of a subject before the second plurality of light pulses is transmitted to a first eye, a second eye, or both eyes of a subject. In some embodiments, the first plurality of light pulses is transmitted to a first eye, a second eye, or both eyes of a subject after the second plurality of light pulses is transmitted to a first eye, a second eye, or both eyes of a subject. For example, the brain can include at least two portions that process predetermined types of visual stimuli: the primary visual cortex on the left side of the brain, and the calcarine fissure on the right side of the brain. Each of these two portions can have one or more multiple subportions that process predetermined types of visual stimuli. For example, the calcarine fissure can include a sub-portion referred to as area V5 that can include neurons that respond strongly to motion but may not register stationary objects. Subjects with damage to area V5 may have motion blindness, but otherwise normal vision. In another example, the primary visual cortex can include a sub-portion referred to as area V4 that can include neurons that are specialized for color perception. Subjects with damage to area V4 may have color blindness and only perceive objects in shades of gray. In another example, the primary visual cortex can include a sub-portion referred to as area V 1 that includes neurons that respond strongly to contrast edges and helps segment the image into separate objects.(2) Signal Emitter

[0153] In some embodiments, a wireless non-invasive visual device comprises a signal emitter. In some embodiments, a signal emitter includes a visual source as disclosed herein. In some embodiments, a visual signal emitter is configured to generate a visual stimulus such as such as a light pulse or flash of light. In some embodiments, the visual stimulus comprises a light pulse or flash of light with amplitude or intensity, a frequency, a pulse rate, a tone, a signal delay, an offset, a duration, or any combination thereof.(3) Microphone

[0154] In some embodiments, the wireless non-invasive visual device comprises one or more microphones. The microphones can be used to detect sound. A microphone can be integrated with a speaker. The microphone can provide feedback information to a wireless non-invasive visual device or system as disclosed herein.

[0155] The microphone can include a transducer that converts sound into an electrical signal. The microphone can use electromagnetic induction, capacitance change, or piezoelectricity to produce the electrical signal from air pressure variations. In some cases, the microphone can include or be connected to a pre-amplifier to amplify the signal before it is recorded or processed. The microphone can include one or more type of microphone, including, for example, a condenser microphone, RF condenser microphone, electret condenser, dynamic microphone, moving-coil microphone, ribbon microphone, carbon microphone, piezoelectric microphone, crystal microphone, fiber optic microphone, laser microphone, liquid or water microphone, microelectromechanical systems (“MEMS”) microphone, or speakers as microphones. The microphone can receive voice input from a subject, such as audio commands, instructions, requests, feedback information, or responses to survey questions.(4) Feedback Component

[0156] In some embodiments, a wireless non-invasive visual device comprises one or more feedback components. The feedback component can include or interface with the visual source to obtain, identify, or receive light. The feedback component can obtain ambient light. The feedback component can obtain a visual stimulus from the visual source to facilitate the wireless non-invasive audio visual adjusting a characteristic of the wireless non-invasive visual stimulus generated by the visual source.(5) Processor and Memory Device

[0157] In some embodiments, a wireless non-invasive visual device also includes at least one memory for storing processor executable instructions and at least one processor communicatively connected to the wireless non-invasive visual device and the at least one memory. Theinstructions can comprise administering any one of the methods as described herein. For instance, upon execution of the processor executable instructions, the at least one processor may control the wireless non-invasive visual device such that device emits the wireless non-invasive visual stimulus at a frequency that activates neural oscillations, e.g., gamma oscillations, in at least one brain region of the subject corresponding to the visual frequency generated by the wireless non-invasive visual device. In some embodiments, the at least one processor may control the wireless non-invasive visual device such that the device actuates the wireless non- invasive visual stimulus at the frequency that activates neural oscillations, e.g., gamma oscillations, in at least one of the visual cortex and / or the hippocampus at the frequency corresponding to the visual frequency generated by the wireless non-invasive visual device.

[0158] In some embodiments, the wireless non-invasive visual device includes a data interface that enables data communication between the wireless non-invasive visual device and an external control device or system. The external device may be external device such as a fitting system, PDA, computer, mobile phone, or any other suitable device. In some embodiments, the interface allows two-way or bidirectional communication. That is, interface data may be sent from both the wireless non-invasive visual device and the external device. For example, in one embodiment, the interface may be adapted to receive control signals from the external device for generating a wireless non-invasive visual stimulus at predetermined frequencies and receive control settings for the wireless non-invasive visual device for storing in the memory unit. In some embodiments, however, the interface is a one-way interface, allowing only data to be forwarded from the external device to the wireless non-invasive visual device. In other embodiments, communication is a one-way interface with data being forwarded from the wireless non-invasive visual device to any type of receiving device. The data may include measured control signals or any type of status information or other suitable data. This information may be used to merely monitor the wireless non-invasive visual device or be used with a control device that may be a separate device or be integrated into the wireless non-invasive visual device or be any other suitable device.

[0159] In some cases, the processor is configured to receive an indication of a physiological, cognitive, neural, or physical assessment of the subject wearing the wireless non-invasive visual device. In some cases, when the processor receives the indication of the physiological, cognitive, neural, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive visual stimulus. In some cases, the physical assessment of the subject comprises ascertaining at least one of the subject's: compliance with proper use and positioning of the system, eye status, alert or sleep status, or environment and surroundings. In some cases, the physical assessment of the subject is performed to determine hearing of the subject, theindication of the physiological, cognitive, neural, or physical assessment of the subject comprises a biosignal. In some cases, the biosignal comprises an electroencephalography (EEG).

[0160] In some cases, the cognitive assessment of the subject is obtained through questions posed to the subject, activities and tasks performed by the subject in response to a prompt, or behaviors exhibited by the subject.

[0161] In some embodiments, a wireless non-invasive visual device as disclosed herein is provided with and / or operatively connected to a computer system as disclosed herein. The computer system 101 can communicate with one or more remote computer systems through the network 130. For instance, the computer system 101 can communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones, Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 101 via the network 130. In some cases, the computer systems are programmed to implement the function of a wireless non-invasive visual device, such as implementing a wireless non-invasive visual stimulus delivered to a subject by the wireless non-invasive visual device as described herein. Any of the computer systems as described herein can carry out any of the methods as described herein.

[0162] Any of the devices as described herein can be used in conjunction with a mobile application. The mobile application may be used to modulate one or more parameters of a visual, auditory, or haptic stimulus as described herein. The mobile application may be used to monitor a response in the subject administered the one or more gamma oscillations. In view of the disclosure provided herein, a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications are written in several languages. Suitable programming languages include, by way of non-limiting examples, C, C++, C#, Objective-C, Java™, JavaScript, Pascal, Object Pascal, Python™, Ruby, Rails, VB.NET, WML, and XHTML / HTML with or without CSS, or combinations thereof.

[0163] Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator®, Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments are available without cost including, by way of non-limiting examples, Lazarus, MobiFlex, MoSync, and Phonegap. Also, mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK, BlackBerry®SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, and Windows® Mobile SDK.

[0164] Those of skill in the art will recognize that several commercial forums are available for distribution of mobile applications including, by way of non-limiting examples, Apple® App Store, Google® Play, Chrome WebStore, BlackBerry® App World, App Store for Palm devices, App Catalog for webOS, Windows® Marketplace for Mobile, Ovi Store for Nokia® devices, Samsung® Apps, and Nintendo® DSi Shop.(iv) Combined Wireless Non-Invasive Audio, Visual, and Haptic Devices

[0165] In some embodiments, a wireless device as disclosed herein comprises a wireless audio, visual, or haptic device as described herein, or a combination thereof. For example, in some embodiments, a wireless device as disclosed herein comprises a combined wireless audio, visual, and haptic device, or a combined wireless audio and visual device as described herein.Wireless Systems

[0166] In some embodiments, provided herein are systems for administering a wireless non- invasive stimulus to a subject via wireless non-invasive visual, auditory and haptic stimulation.

[0167] A system for wireless non-invasive visual, auditory and / or haptic stimulation can include one or more signal emitters. The system can include one or more microphones. In some embodiments, the system can include both signal emitters and microphones. In some embodiments, the system includes signal emitters and may not include microphones. In some embodiments, the system includes microphones and may not include speakers.

[0168] In some embodiments, a wireless non-invasive visual system comprises a visual signaling component. The visual signaling component can include a single visual source configured and positioned to direct light pulses to a first eye. The visual signaling component can further include a light blocking component that keeps out or blocks the light pulses generated from the visual source from entering a second eye. The visual signaling component can block or prevent light from entering the second eye during the brain stimulation process. In some embodiments, a visual signaling component comprises a visual signal emitter. In some embodiments, a visual signal emitter comprises a light-emitting diode.

[0169] In some embodiments, a wireless non-invasive audio system comprises an audio signaling component. A signal emitter, such as a speaker can be integrated with the audio signaling component. The audio signaling component can include speakers. The speakers can interact or communicate with the audio signaling component. For example, the audio signaling component can instruct the speaker to generate sound.

[0170] In some embodiments, a wireless haptic system comprises a haptic signaling component. A signal emitter, such as a vibrator can be integrated with the haptic signaling component. The haptic signaling component can include vibrators. The vibrators can interact or communicate with the haptic signaling component. For example, the haptic signaling component can instruct the vibrator to generate vibration.

[0171] The microphones can be integrated with a feedback component. The feedback component can include microphones. The microphones can interact or communicate with feedback component. For example, the feedback component can receive information, data, or signals from microphone.

[0172] In some embodiments, the wireless non-invasive visual, audio and / or haptic system can include a single signal emitter positioned at one of the eyes of the subject (for the visual system) ears of the subject (for the audio system) or at one of the skull bones of the subject (for the haptic system), or a combination thereof. In some embodiments, the system can include two signal emitters. For the wireless non-invasive audio device, a first signal emitter can be positioned at a first ear, and the second signal emitter can be positioned at the second ear. For the wireless non- invasive haptic device, a first signal emitter can be positioned at a first skull bone, and the second signal emitter can be positioned at a second skull bone, e.g., at a first skull bone located on a first side of a subject’s head and at a second skull bone located on a second side of the subject’s head.

[0173] The signal emitter can include a speaker configured to produce sound from an electrical signal and / or a vibrator configured to produce vibration from an electrical signal. The signal emitter can include a full-range driver to produce acoustic and / or haptic waves with frequencies over some or all of the audible and / or haptic range (e.g., about 60 Hz to about 20,000 Hz). The signal emitter can include a driver to produce acoustic and / or haptic waves with frequencies of about 0 Hz to about 60 Hz, or in the range such as about 20 kHz to about 4 GHz.

[0174] The signal emitter can include or be integrated into various types of headphones. For example, the headphones can include, for example, circumaural headphones (e.g., full size headphones) that include circular or ellipsoid earpads that are designed and constructed to seal against the head to attenuate external noise. Circumaural headphones can facilitate providing an immersive auditory brainwave wave stimulation experience, while reducing external distractions. In some embodiments, headphones can include supra-aural headphones, which include pads that press against the ears rather than around them. Supra-aural headphones may provide less attenuation of external noise.

[0175] Both circumaural headphones and supra-aural headphones can have an open back, closed back, or semi open back. An open back leaks more sound and allows more ambient sounds toenter, but provides a more natural or speaker-like sound. Closed back headphones block more of the ambient noise as compared to open back headphones, thus providing a more immersive auditory brainwave stimulation experience while reducing external distractions.

[0176] In some embodiments, headphones can include ear-fitting headphones, such as earphones or in-ear headphones. Earphones (or earbuds) can refer to small headphones that are fitted directly in the outer ear, facing but not inserted in the ear canal. Earphones, however, provide minimal acoustic isolation and allow ambient noise to enter. In-ear headphones (or in-ear monitors or canalphones) can refer to small headphones that can be designed and constructed for insertion into the ear canal. In-ear headphones engage the ear canal and can block out more ambient noise as compared to earphones, thus providing a more immersive auditory brainwave stimulation experience. In-ear headphones can include ear canal plugs made or formed from one or more material, such as silicone rubber, elastomer, or foam. In some embodiments, in-ear headphones can include custom-made castings of the ear canal to create custom-molded plugs that provide added comfort and noise isolation to the subject, thereby further improving the immersion of a subject during the wireless non-invasive auditory stimulation.

[0177] In some embodiments, signal emitter can include or be integrated into bone conduction headphones, and / or bone conduction prothesis or bone conduction hearing aid devices.

[0178] In some embodiments, the system microphone can include a transducer that converts sound into an electrical signal. The microphone can use electromagnetic induction, capacitance change, or piezoelectricity to produce the electrical signal from air pressure variations. In some cases, the microphone can include or be connected to a pre-amplifier to amplify the signal before it is recorded or processed. The microphone can include one or more type of microphone, including, for example, a condenser microphone, RF condenser microphone, electret condenser, dynamic microphone, moving-coil microphone, ribbon microphone, carbon microphone, piezoelectric microphone, crystal microphone, fiber optic microphone, laser microphone, liquid or water microphone, microelectromechanical systems (“MEMS”) microphone, or speakers as microphones.

[0179] The system feedback component can include or interface with the microphone to obtain, identify, or receive sound. The feedback component can obtain ambient noise. The feedback component can obtain sound from the signal emitter to facilitate adjusting a characteristic of the audio and / or haptic signal generated by the signal emitter. The microphone can receive voice input from the subject, such as audio commands, instructions, requests, feedback information, or responses to survey questions.

[0180] In some embodiments, the system can use a binaural beats technique to provide different wireless non-invasive visual, auditory and / or haptic signals to a first and second signal emitter that, when perceived by the brain, is combined to have the desired stimulation frequency, e.g., a pulse repetition frequency in the range of 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz, in accordance with methods disclosed herein.

[0181] In some embodiments, the system can adjust for any latency between first and second signal emitters such that the brain perceives the audio and / or haptic signals at the same or substantially same time (e.g., within 1 milliseconds, 2 milliseconds, 5 milliseconds, or 10 milliseconds). The system can buffer the audio and / or haptic signals to account for latency such that audio and / or haptic signals are transmitted from the signal emitters at the same time.

[0182] In some embodiments, the system can receive a musical track from a digital music repository. The system can manipulate or modify the musical track to embed acoustic and / or haptic pulses in accordance with the desired pulse rate interval (PRI). The system can then provide the modified musical track to provide a modified audio signal to the signal emitter.

[0183] In some embodiments, the system comprises an active noise cancellation component that can receive ambient noise information from the microphone, identify unwanted frequencies or noise, and generate an inverted phase waveform to cancel out or attenuate the unwanted waveforms. In some embodiments, the system can include an additional signal emitter that generates the noise canceling waveform provided by the noise cancellation component. The noise cancellation component can include the additional signal emitter.

[0184] The feedback component of the system can detect feedback information, such as environmental parameters or physiological conditions. The feedback component can provide the feedback information to the system. The system can adjust or change the wireless non-invasive auditory and / or haptic signal based on the feedback information. For example, the system can determine that a pulse rate of the subject exceeds a predetermined threshold, and then lower the volume of the wireless non-invasive auditory or the intensity of the haptic signal. The system can detect that the volume of the wireless non-invasive auditory signal and / or the intensity of the wireless non-invasive haptic signal exceeds a threshold, and decrease the amplitude. The system can determine that the pulse rate interval is below a threshold, which can indicate that a subject is losing focus or not paying a satisfactory level of attention to the wireless non-invasive auditory and / or wireless non-invasive haptic signal, and the system can increase the amplitude of the wireless non-invasive auditory and / or wireless non-invasive haptic signal or change the tone or music track. In some embodiments, the system can vary the vibration or the tone or the musictrack based on a time interval. Varying the vibration, tone, or the music track can cause the subject to pay a greater level of attention to the wireless non-invasive auditory and / or wireless non-invasive haptic stimulation, which can facilitate oscillations of the desired frequency in at least one brain region of the subject.

[0185] In some embodiments, the system can receive neural oscillation information from EEG probes, and adjust the wireless non-invasive auditory and / or wireless non-invasive haptic stimulation based on the EEG information. For example, the system can determine, from the probe information, that neurons are oscillating at an undesired frequency. The system can then identify the corresponding undesired frequency in ambient noise using the microphone. The system can then instruct the active noise cancellation component to cancel out the waveforms corresponding to the ambient noise having the undesired frequency.

[0186] In some embodiments, the system can enable a passive noise filter. A passive noise filter can include a circuit having one or more or a resistor, capacitor or an inductor that filters out undesired frequencies of noise. In some cases, a passive filter can include a sound insulating material, sound proofing material, or sound absorbing material.

[0187] In some embodiments, the feedback component can comprise feedback sensors placed or positioned at, on, or near a subject’s or user’s head. Feedback sensors can include, for example, EEG probes that detect brain wave activity.

[0188] In some embodiments, a feedback monitor can detect, receive, obtain, or otherwise identify feedback information from the one or more feedback sensors. The feedback monitor can provide the feedback information to one or more components of the system, such as the memory and / or processor, for further processing or storage. In some embodiments, the system comprises a profile manager that can update a profile data structure stored in a data repository with the feedback information. The profile manager can associate the feedback information with an identifier of the patient or person undergoing the wireless non-invasive auditory and / or wireless non-invasive haptic stimulation, as well as a time stamp and date stamp corresponding to receipt or detection of the feedback information.

[0189] The feedback monitor can determine a level of attention. The level of attention can refer to the focus provided to the acoustic and / or haptic pulses used for stimulation. The feedback monitor can determine the level of attention using various hardware and software techniques. The feedback monitor can assign a score to the level of attention (e.g., 1 to 10 with 1 being low attention and 10 being high attention, or vice versa, 1 to 100 with 1 being low attention and 100 being high attention, or vice versa, 0 to 1 with 0 being low attention and 1 being high attention,or vice versa), categorize the level of attention (e.g., low, medium, high), grade the attention (e.g., A, B, C, D, or F), or otherwise provide an indication of a level of attention.

[0190] In some cases, the feedback monitor can track a person's eye movement to identify a level of attention. The feedback monitor can interface with a feedback component that includes an eyetracker. The feedback monitor can detect and record eye movement of the person and analyze the recorded eye movement to determine an attention span or level of attention. The feedback monitor can measure eye gaze which can indicate or provide information related to covert attention. For example, the feedback monitor can be configured with electro-oculography (“EOG”) to measure the skin electric potential around the eye, which can indicate a direction the eye faces relative to the head. In some embodiments, the EOG can include a system or device to stabilize the head so it cannot move in order to determine the direction of the eye relative to the head. In some embodiments, the EOG can include or interface with a head tracker system to determine the position of the heads, and then determine the direction of the eye relative to the head.

[0191] In some embodiments, the feedback monitor and feedback component can determine a level of attention the subject is paying to the auditory and / or haptic stimulation based on eye movement. For example, increased eye movement may indicate that the subject is focusing on visual stimuli, as opposed to the auditory and / or haptic stimulation. To determine the level of attention the subject is paying to visual stimuli as opposed to the auditory and / or haptic stimulation, the feedback monitor and feedback component can determine or track the direction of the eye or eye movement using video detection of the pupil or corneal reflection. For example, the feedback component can include one or more camera or video camera. The feedback component can include an infra-red source that sends light pulses towards the eyes. The light can be reflected by the eye. The feedback component can detect the position of the reflection. The feedback component can capture or record the position of the reflection. The feedback component can perform image processing on the reflection to determine or compute the direction of the eye or gaze direction of the eye.

[0192] The feedback monitor can compare the eye direction or movement to historical eye direction or movement of the same person, nominal eye movement, or other historical eye movement information to determine a level of attention. For example, the feedback monitor can determine a historical amount of eye movement during historical wireless non-invasive auditory and / or wireless non-invasive haptic stimulation sessions. The feedback monitor can compare the current eye movement with the historical eye movement to identify a deviation. The system can determine, based on the comparison, an increase in eye movement and further determine that thesubject is paying less attention to the current wireless non-invasive auditory and / or wireless non- invasive haptic stimulation based on the increase in eye movement. In response to detecting the decrease in attention, the feedback monitor can instruct an audio and / or haptic adjustment module to change a parameter of the wireless non-invasive auditory and / or wireless non-invasive haptic signal to capture the subject's attention. The audio adjustment module can change the volume, tone, pitch, or music track to capture the subject's attention or increase the level of attention the subject is paying to the auditory stimulation. The haptic adjustment module can change the amplitude and / or intensity of the haptic vibration. Upon changing the audio and / or haptic signal, the system can continue to monitor the level of attention. For example, upon changing the wireless non-invasive auditory and / or wireless non-invasive haptic signal, the system can detect a decrease in eye movement which can indicate an increase in a level of attention provided to the wireless non-invasive auditory and / or wireless non-invasive haptic signal.

[0193] In some embodiments, the feedback sensor can interact with or communicate with the system. For example, a feedback sensor can provide detected feedback information or data to the system. The feedback sensor can provide data to the system in real-time, for example as the feedback sensor detects or senses or information. The feedback sensor can provide the feedback information to the system based on a time interval, such as 1 minute, 2 minutes, 5 minutes, 10 minutes, hourly, 2 hours, 4 hours, 12 hours, or 24 hours. The feedback sensor can provide the feedback information to the system responsive to a condition or event, such as a feedback measurement exceeding a threshold or falling below a threshold. The feedback sensor can provide feedback information responsive to a change in a feedback parameter. In some embodiments, the system can ping, query, or send a request to the feedback sensor for information, and the feedback sensor can provide the feedback information in response to the ping, request, or query.Computing Devices and Systems

[0194] The present disclosure provides computer systems that can be used with any of the devices or systems as described herein, or that can be programmed to implement methods of the disclosure. FIG. 1 shows a computer system 101 that is programmed or otherwise configured to implement methods of the disclosure. The computer system 101 can be an electronic device of a user or a computer system that is remotely located with respect to the electronic device. The electronic device can be a mobile electronic device.

[0195] The computer system 101 includes a central processing unit (CPU, also “processor” and “computer processor” herein) 105, which can be a single core or multi core processor, or aplurality of processors for parallel processing. The computer system 101 also includes memory or memory location 110 (e.g., random-access memory, read-only memory, flash memory), electronic storage unit 115 (e.g., hard disk), communication interface 120 (e.g., network adapter) for communicating with one or more other systems, and peripheral devices 125, such as cache, other memory, data storage and / or electronic display adapters. The memory 110, storage unit 115, interface 120 and peripheral devices 125 are in communication with the CPU 105 through a communication bus (solid lines), such as a motherboard. The storage unit 115 can be a data storage unit (or data repository) for storing data. The computer system 101 can be operatively coupled to a computer network (“network”) 130 with the aid of the communication interface 120. The network 130 can be the Internet, an internet and / or extranet, or an intranet and / or extranet that is in communication with the Internet. The network 130 in some cases is a telecommunication and / or data network. The network 130 can include one or more computer servers, which can enable distributed computing, such as cloud computing. The network 130, in some cases with the aid of the computer system 101, can implement a peer-to-peer network, which may enable devices coupled to the computer system 101 to behave as a client or a server.

[0196] The CPU 105 can execute a sequence of machine -readable instructions, which can be embodied in a program or software. The instructions may be stored in a memory location, such as the memory 110. The instructions can be directed to the CPU 105, which can subsequently program or otherwise configure the CPU 105 to implement methods of the present disclosure. Examples of operations performed by the CPU 105 can include fetch, decode, execute, and writeback.

[0197] The CPU 105 can be part of a circuit, such as an integrated circuit. One or more other components of the system 101 can be included in the circuit. In some cases, the circuit is an application specific integrated circuit (ASIC).

[0198] The storage unit 115 can store files, such as drivers, libraries, and saved programs. The storage unit 115 can store user data, e.g., user preferences and user programs. The computer system 101 in some cases can include one or more additional data storage units that are external to the computer system 101, such as located on a remote server that is in communication with the computer system 101 through an intranet or the Internet.

[0199] The computer system 101 can communicate with one or more remote computer systems through the network 130. For instance, the computer system 101 can communicate with a remote computer system of a user. Examples of remote computer systems include personal computers (e.g., portable PC), slate or tablet PC’s (e.g., Apple® iPad, Samsung® Galaxy Tab), telephones,Smart phones (e.g., Apple® iPhone, Android-enabled device, Blackberry®), or personal digital assistants. The user can access the computer system 101 via the network 130.

[0200] Methods as described herein can be implemented by way of machine (e.g., computer processor) executable code stored on an electronic storage location of the computer system 101, such as, for example, on the memory 110 or electronic storage unit 115. The machine executable or machine -readable code can be provided in the form of software. During use, the code can be executed by the processor 105. In some cases, the code can be retrieved from the storage unit 115 and stored on the memory 110 for ready access by the processor 105. In some situations, the electronic storage unit 115 can be precluded, and machine-executable instructions are stored on memory 110.

[0201] The code can be pre-compiled and configured for use with a machine having a processer adapted to execute the code or can be compiled during runtime. The code can be supplied in a programming language that can be selected to enable the code to execute in a pre-compiled or as- compiled fashion.

[0202] Aspects of the systems and methods provided herein, such as the computer system 101, can be embodied in programming. Various aspects of the technology may be thought of as “products” or “articles of manufacture” typically in the form of machine (or processor) executable code and / or associated data that is carried on or embodied in a type of machine readable medium. Machine-executable code can be stored on an electronic storage unit, such as memory (e.g., read-only memory, random- access memory, flash memory) or a hard disk. “Storage” type media can include any or all of the tangible memory of the computers, processors or the like, or associated modules thereof, such as various semiconductor memories, tape drives, disk drives and the like, which may provide non-transitory storage at any time for the software programming. All or portions of the software may at times be communicated through the Internet or various other telecommunication networks. Such communications, for example, may enable loading of the software from one computer or processor into another, for example, from a management server or host computer into the computer platform of an application server. Thus, another type of media that may bear the software elements includes optical, electrical and electromagnetic waves, such as used across physical interfaces between local devices, through wired and optical landline networks and over various air-links. The physical elements that carry such waves, such as wired or wireless links, optical links or the like, also may be considered as media bearing the software. As used herein, unless restricted to non-transitory, tangible “storage” media, terms such as computer or machine “readable medium” refer to any medium that participates in providing instructions to a processor for execution.

[0203] Hence, a machine readable medium, such as computer-executable code, may take many forms, including but not limited to, a tangible storage medium, a carrier wave medium or physical transmission medium. Non-volatile storage media include, for example, optical or magnetic disks, such as any of the storage devices in any computer(s) or the like, such as may be used to implement the databases, etc. shown in the drawings. Volatile storage media include dynamic memory, such as main memory of such a computer platform. Tangible transmission media include coaxial cables; copper wire and fiber optics, including the wires that comprise a bus within a computer system. Carrier-wave transmission media may take the form of electric or electromagnetic signals, or acoustic or light waves such as those generated during radio frequency (RF) and infrared (IR) data communications. Common forms of computer-readable media therefore include for example: a floppy disk, a flexible disk, hard disk, magnetic tape, any other magnetic medium, a CD-ROM, DVD or DVD-ROM, any other optical medium, punch cards paper tape, any other physical storage medium with patterns of holes, a RAM, a ROM, a PROM and EPROM, a FLASH-EPROM, any other memory chip or cartridge, a carrier wave transporting data or instructions, cables or links transporting such a carrier wave, or any other medium from which a computer may read programming code and / or data. Many of these forms of computer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.

[0204] The computer system 101 can include or be in communication with an electronic display 135 that comprises a user interface (UI) 140. Examples of UI’s include, without limitation, a graphical user interface (GUI) and web-based user interface.

[0205] Methods and systems of the present disclosure can be implemented by way of one or more algorithms. An algorithm can be implemented by way of software upon execution by the central processing unit 105.

[0206] Any of the computer systems as described herein can carry out any of the methods as described herein.

[0207] Any of the devices as described herein can be used in conjunction with a mobile application. The mobile application may be used to modulate one or more parameters of a visual, auditory, or haptic stimulus as described herein. The mobile application may be used to monitor a response in the subject administered the one or more gamma oscillations. In view of the disclosure provided herein, a mobile application is created by techniques known to those of skill in the art using hardware, languages, and development environments known to the art. Those of skill in the art will recognize that mobile applications are written in several languages. Suitable programming languages include, by way of non-limiting examples, C, C++, C#, Objective-C,Java™, JavaScript, Pascal, Object Pascal, Python™, Ruby, Rails, VB.NET, WML, and XHTML / HTML with or without CSS, or combinations thereof.

[0208] Suitable mobile application development environments are available from several sources. Commercially available development environments include, by way of non-limiting examples, AirplaySDK, alcheMo, Appcelerator®, Celsius, Bedrock, Flash Lite, .NET Compact Framework, Rhomobile, and WorkLight Mobile Platform. Other development environments are available without cost including, by way of non-limiting examples, Lazarus, MobiFlex, MoSync, and Phonegap. Also, mobile device manufacturers distribute software developer kits including, by way of non-limiting examples, iPhone and iPad (iOS) SDK, Android™ SDK, BlackBerry® SDK, BREW SDK, Palm® OS SDK, Symbian SDK, webOS SDK, and Windows® Mobile SDK.

[0209] Those of skill in the art will recognize that several commercial forums are available for distribution of mobile applications including, by way of non-limiting examples, Apple® App Store, Google® Play, Chrome WebStore, BlackBerry® App World, App Store for Palm devices, App Catalog for webOS, Windows® Marketplace for Mobile, Ovi Store for Nokia® devices, Samsung® Apps, and Nintendo® DSi Shop.Methods of Using the Wireless Devices and Systems Herein

[0210] In some embodiments, methods of using a wireless non-invasive auditory and / or haptic device and / or system as disclosed herein are provided below.

[0211] In some cases, the method comprises administering to a subject a wireless non-invasive auditory and / or wireless non-invasive haptic stimulus generated by a wireless device and / or system as disclosed herein. In some cases, the non-invasive stimulation induces neural oscillations in at least one brain region of the subject, wherein the frequency of the induced neural oscillations corresponds to the frequency of the non-invasive auditory and / or haptic stimulus that is administered to the subject.

[0212] In some cases, the wireless non-invasive auditory and / or wireless non-invasive haptic stimulus is administered at a frequency of 1 Hz, 2 Hz, 5 Hz, 10 Hz, 20 Hz, 25 Hz, 30 Hz, 31 Hz, 32 Hz, 33 Hz, 34 Hz, 35 Hz, 36 Hz, 37 Hz, 38 Hz, 39 Hz, 40 Hz, 41 Hz, 42 Hz, 43 Hz, 44 Hz, 45 Hz, 46 Hz, 47 Hz, 48 Hz, 49 Hz, 50 Hz, 60 Hz, 70 Hz, 80 Hz, 90 Hz, 100 Hz, 150 Hz, 200 Hz, 250 Hz, 300 Hz, 400 Hz, 500 Hz, 1000 Hz, 2000 Hz, 3000 Hz, 4,000 Hz, 5000 Hz, 6,000 Hz, 7,000 Hz, 8,000 Hz, 9,000 Hz, or 10,000 Hz.

[0213] In some cases, the wireless non-invasive auditory and / or wireless non-invasive haptic stimulus is administered at a frequency of about 20 Hertz (Hz) to about 140 Hz, about 30 Hz to about 60 Hz, about 40 Hz to about 60 Hz, about 35 Hz to about 45 Hz, or about 40 Hz. In somecases, the non-invasive auditory and / or haptic stimulus is administered at a gamma frequency. In some embodiments, administration of the gamma frequency results in the induction of synchronized gamma oscillations within the at least one brain region of the subject.(i) Stimulus Exposure, Session duration, Session frequency, and Regimen

[0214] In some cases, administering the wireless non-invasive auditory and / or wireless non- invasive haptic stimulus comprises a stimulus exposure. In some cases, the stimulus exposure comprises a session duration, a session frequency, a regimen duration, or a combination thereof. In some cases, the stimulus exposure may comprise more than one regimen duration. In some cases, administering may be performed continuously for a session duration. In some cases, the session duration may be between 10 minutes and 2 hours. In some cases, the session duration may be at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. In some cases, the session duration may be at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some cases, the session duration may be at least 1, 2, 3, 4, 5, 6, or 7 days. In some cases, the session duration may be at most 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 minutes. In some cases, the session duration may be at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some cases, the session duration may be at most 1, 2, 3, 4, 5, 6, or 7 days.

[0215] In some cases, the session frequency may occur at least once, at least twice, at least 3 times, at least 4 times, or at least 5 times per day. In some cases, the session frequency may occur at least once, at least twice, at least 3 times, at least 4 times, at least 5 times, at least 6 times, or at least 7 times per week. In some cases, the session frequency may occur at least once, at least twice, at least 3 times, at least 4 times, or at least 5 times, at least 8 times, at least 10 times, at least 20 times, at least 28 times, at least 30 times, or at least 31 times per month. In some cases, the session frequency may occur at least once, at least twice, at least 3 times, at least 4 times, or at least 5 times, at least 10 times, at least 20 times, at least 30 times, at least 50 times, at least 100 times, at least 150 times, at least 200 times, at least 300 times, at least 365 times, at least 400 times, at least 500 times, at least 600 times, at least 700 times, at least 800 times, at least 900 times, or at least one thousand times per year.

[0216] The regimen duration refers to the length of time over which all session durations and session frequencies for the administering of the non-invasive stimulus occur. For example, a regimen duration can refer to a total length of an experimental study period, a total length of a therapeutic treatment, or a total length of a diagnostic period. In some cases, the regimen duration comprises at least one day, at least one week, at least one month, at least 3 months, at least 4months, at least 5 months, at least 6 months, at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least one year, at least 2 years, at least 3 years, at least 4 years, at least 5 years, at least 10 years, at least 15 years, or at least 20 years. In some cases, the regimen duration comprises the reminder of the life expectancy of the subject. In some cases, the regimen duration comprises the remainder of the subject’s life.

[0217] In some cases, the regimen duration and session frequency comprises about once a day for 6 months. In some cases, the regimen duration and session frequency comprises at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day. In some cases, the regimen duration and session frequency comprises at most about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 times a day.(ii) Methods of Verifying Administration of a Non-Invasive Stimulus

[0218] In some cases, the administration of a wireless non-invasive auditory and / or wireless non- invasive haptic stimulus to a subject is confirmed or verified within the subject by evaluating and measuring the wireless non-invasive auditory and / or wireless non-invasive haptic stimulus. In some cases, the wireless non-invasive auditory and / or wireless non-invasive haptic stimulus is measured in the brain of the subject. In some cases, wireless non-invasive auditory and / or wireless non-invasive haptic stimulus is measured in at least one, at least two, at least three, at least 4, at least 5, at least 8, at least 10, at least 15, at least 20 specific brain regions of the subject. In some cases, wireless non-invasive auditory and / or wireless non-invasive haptic stimulus is measured simultaneously in at least one, at least two, at least three, at least 4, at least 5, at least 8, at least 10, at least 15, at least 20 specific brain regions of the subject.

[0219] In some cases, the measuring comprises analyzing the brain or a specific brain region of the subject. In some cases, the measuring comprises analyzing the wireless non-invasive auditory and / or wireless non-invasive haptic stimulus in the brain or a specific brain region of the subject.

[0220] In some cases, the specific brain region comprises an entorhinal cortex, a hippocampus, a cerebral cortex, a visual association cortex, an auditory association cortex, a cingulate lobe, an amygdala, a thalamic nucleus, a cingulate lobe, a pons, a brainstem, a cerebellum, a lateral ventricle, an occipital lobe, a parietal lobe, a temporal lobe, a midbrain, a striatum, a basal ganglia, a globus pallidus, a substantia nigra, or any combination thereof.

[0221] In some cases, the measuring comprises neuroimaging. In some cases, the measuring comprises neuroimaging of the brain of the subject. In some cases, the measuring comprises neuroimaging of the whole brain of the subject. In some cases, the measuring comprises neuroimaging of the specific brain regions of the subject. In some cases, the measuring comprises neuroimaging of an entorhinal cortex, a hippocampus, a cerebral cortex, a visual association cortex, an auditory association cortex, a cingulate lobe, an amygdala, a thalamic nucleus, acingulate lobe, a pons, a brainstem, a cerebellum, a lateral ventricle, an occipital lobe, a parietal lobe, a temporal lobe, a midbrain, a striatum, a basal ganglia, a globus pallidus, a substantia nigra, or any combination thereof.

[0222] In some cases, the measuring comprises neuroimaging techniques. In some cases, the neuroimaging comprises magnetic resonance imaging (MRI), computer tomography, positron emission tomography (PET) imaging, diffusion-weighted MRI imaging, or any combination thereof in at least one brain region of a subject, wherein the at least one brain region an entorhinal cortex, a hippocampus, a cerebral cortex, a visual association cortex, an auditory association cortex, a cingulate lobe, an amygdala, a thalamic nucleus, a cingulate lobe, a pons, a brainstem, a cerebellum, a lateral ventricle, an occipital lobe, a parietal lobe, a temporal lobe, a midbrain, a striatum, a basal ganglia, a globus pallidus, a substantia nigra, or any combination thereof.(iii) Physical and / or Cognitive Assessment

[0223] In some cases, methods of using a wireless non-invasive auditory and / or haptic device and / or system comprise receiving an indication of a physiological, cognitive, neural, or physical assessment of a subject wearing a wireless non-invasive auditory and / or haptic device or system and emitting a wireless non-invasive auditory, and / or haptic stimulus in response to the indication.

[0224] In some cases, the indication of the physical assessment of the subject comprises ascertaining at least one of the subject's: compliance with proper use and positioning of the system, eye status, alert or sleep status, or environment and surroundings.

[0225] In some cases, the indication of the cognitive assessment of the subject is obtained through questions posed to the subject, activities and tasks performed by the subject in response to a prompt, or behaviors exhibited by the subject.

[0226] In some cases, methods comprise instructing the wireless non-invasive auditory and / or haptic device or system to lengthen or shorten a duration of stimulation in response to the indication of the physiological, cognitive, neural, or physical assessment. In some cases, the physical assessment of the subject is performed to determine hearing of the subject.Methods of Treating Diseases or Conditions

[0227] In some cases, methods of using a wireless non-invasive visual, auditory and / or haptic device or systems include using the device or system to treat, prevent, or mitigate cognitive dysfunction in a subject.

[0228] In some cases, the wireless non-invasive visual, auditory and / or haptic device or system is used to treat Alzheimer's disease or dementia in a subject in need thereof. In some cases, thedementia comprises, vascular dementia, Lewy body dementia, Pick's disease, fronto-temporal dementia (FTD), AIDS dementia, age-related cognitive impairments, and age-related memory impairments.

[0229] In some cases, the disease or condition comprises Parkinson’s disease.

[0230] In some cases, the method of treatment comprises stimulating a subject with a wireless non-invasive auditory and / or haptic stimulus generated by a wireless audio and / or haptic device or system disclosed herein, thereby inducing gamma oscillations in at least one brain region of the subject.

[0231] In some cases, the at least one brain region comprises an entorhinal cortex, a hippocampus, a cerebral cortex, a visual association cortex, an auditory association cortex, a cingulate lobe, an amygdala, a thalamic nucleus, a cingulate lobe, a pons, a brainstem, a cerebellum, a lateral ventricle, an occipital lobe, a parietal lobe, a temporal lobe, a midbrain, a striatum, a basal ganglia, a globus pallidus, a substantia nigra, or any combination thereof.

[0232] In some cases, the induced gamma oscillations correspond to the frequency of the wireless non-invasive auditory and / or haptic stimulus generated by a wireless audio and / or haptic device or system used to administer the wireless non-invasive auditory and / or haptic stimulus.(i) Tau Phosphorylation

[0233] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in the maintenance or reduction of a level of tau phosphorylation in at least one brain region of the subject. In some cases, a level of tau phosphorylation in at least one brain region of a subject stimulated by a wireless non- invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% reduced as compared to a subject not stimulated by a wireless non-invasive auditory and / or haptic stimulus as disclosed herein.

[0234] In some cases, a level of tau phosphorylation in at least one brain region of a subject stimulated by a wireless non-invasive auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% reduced as compared to a subject not stimulated by a wireless non- invasive auditory and / or haptic stimulus as disclosed herein.

[0235] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus results in the maintenance or reduction of punctate localization of phosphorylated tau protein in at least one brain region of the subject. In some cases, punctate localization of phosphorylated tau protein in at least one brain region of a subject stimulated by a wireless non- invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100%reduced as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0236] In some cases, punctate localization of phosphorylated tau protein in at least one brain region of a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% reduced as compared to a subject not stimulated by a wireless non-invasive auditory and / or haptic stimulus as disclosed herein.(ii) Cognitive Function

[0237] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in maintaining or improving cognitive function in the subject. In some cases, the maintaining or improving cognitive function comprises maintaining or improving recognition, discrimination, spatial memory, working memory, attention, or a combination thereof.

[0238] In some cases, a level of cognitive function in a subject stimulated by a wireless non- invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% improved as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0239] In some cases, a level of cognitive function in a subject stimulated by a wireless non- invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% improved as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.(iii) Additional Biomarkers

[0240] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in maintaining or reducing an amount of amyloid-P (Ap) peptide in at least one brain region of a subject.

[0241] In some cases, a level of amyloid-P (A p) peptide in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% improved as compared to a subject not stimulated by a wireless non-invasive auditory and / or haptic stimulus as disclosed herein.

[0242] In some cases, a level of amyloid-P(Ap) peptide in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% improved as compared to a subject not stimulated by a wireless non-invasive auditory and / or haptic stimulus as disclosed herein.

[0243] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in maintaining or reducing anamount of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in at least one brain region of a subject.

[0244] In some cases, a level of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% improved as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0245] In some cases, a level of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% improved as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0246] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in maintaining or reducing an amount of cleavage of APP into CTFs and NTFs by at least one of P-secretase (BACE1) and y- secretase in at least one brain region of a subject.

[0247] In some cases, a level of cleavage of APP into CTFs and NTFs by at least one of P- secretase (BACE1) and y-secretase in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% improved as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0248] In some cases, a level of cleavage of APP into CTFs and NTFs by at least one of P- secretase (BACE1) and y-secretase in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% improved as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0249] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in maintaining or reducing an amount of a number of endosomes in at least one brain region of a subject.

[0250] In some cases, a number of endosomes in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% reduced as compared to a subject not stimulated by a wireless non-invasive auditory and / or haptic stimulus as disclosed herein.

[0251] In some cases, a number of endosomes in a subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% reduced as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0252] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in clearance of Ap peptide in at least one brain region of the subject.

[0253] In some cases, clearance of Ap peptide in at least one brain region of the subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% increased as compared to a subject not stimulated by a wireless non- invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0254] In some cases, clearance of Ap peptide in at least one brain region of the subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% increased as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0255] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in increasing uptake of Ap peptide by microglia in at least one brain region of the subject.

[0256] In some cases, increasing uptake of Ap peptide by microglia in at least one brain region of the subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is about 1% to about 100% increased uptake as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0257] In some cases, increasing uptake of Ap peptide by microglia in at least one brain region of the subject stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein is at least 1% to at least 100% increased uptake as compared to a subject not stimulated by a wireless non-invasive visual, auditory and / or haptic stimulus as disclosed herein.

[0258] In some cases, stimulating a subject with the wireless non-invasive visual, auditory and / or haptic stimulus according to the methods disclosed herein results in inducing a change in microglial cells in at least one brain region of a subject, thereby improving the cognitive function of the subject, or preventing, reducing, or treating cognitive decline in the subject.Subjects

[0259] In some embodiments, a subject as disclosed herein comprises a mammal. In some cases, the mammal comprises a rodent. In some cases, the mammal comprises a non-human primate. In some cases, the mammal comprises a human.Certain Definitions

[0260] Whenever the term “at least,” “greater than,” or “greater than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “at least,” “greater than” or “greater than or equal to” applies to each of the numerical values in that series of numerical values. For example, greater than or equal to 1, 2, or 3 is equivalent to greater than or equal to 1, greater than or equal to 2, or greater than or equal to 3.

[0261] Whenever the term “no more than,” “less than,” or “less than or equal to” precedes the first numerical value in a series of two or more numerical values, the term “no more than,” “less than,” or “less than or equal to” applies to each of the numerical values in that series of numerical values. For example, less than or equal to 3, 2, or 1 is equivalent to less than or equal to 3, less than or equal to 2, or less than or equal to 1.EXAMPLESExample 1. Human Clinical Study of Safety Efficacy and Results of Treatment

[0262] Methods And Study Design

[0263] A clinical study was performed to assess the safety, tolerability, and efficacy of longterm, daily use of gamma sensory stimulation therapy on cognition, functional ability, and biomarkers in a mild-to-moderate AD population via a prospective clinical study. The clinical study was a multi-center, randomized controlled trial evaluating daily gamma sensory stimulation received at home for a 6-month treatment period. Subjects included in the study were adults 50 years and older with a clinical diagnosis of mild to moderate AD (MMSE: 14- 26, inclusive), a reliable care partner, and successful tolerance and entrainment screening via EEG. Key exclusion criteria included profound hearing or visual impairment, use of memantine, major psychiatric illness, clinically relevant history of seizure, or contraindication to imaging studies. Study Participants and Design. A total of 135 patients were assessed for eligibility to participate in the study. Patients were first given a screening EEG, and then split into groups. One group was a sham control group that was not given treatment; the other was a group that was subjected to 1 hour of therapy, which involved subjecting the subject to audio and visual stimulation at a frequency of 40 Hz per day. Of those assessed for eligibility, 76 were randomized between the active treatment and sham control. Forty-seven of the randomized patients were allocated to the active group and 29 were allocated to the sham group. Of the active group, two patients withdrew prior to therapy and three had no post baseline efficacy and were not included in the modified intent to treat (mITT) population. In sham group, one patient received active treatment and was not in the sham population. Completers included 33 patients in the active group and 28 in thesham group, with 10 early discontinuations in the active group. Seven of those discontinuations were due to consent withdraw and 23 were attributed to adverse events, whereas in the sham group, only six withdrew consent and one discontinued as a result of adverse events.

[0264] The study employed various clinical outcome assessment scales to assess cognitive decline or dysfunction. These included the Neuropsychiatric Inventory (NPI), Clinical Dementia Rating-Sum of Boxes (CDR-sb), the Clinical Dementia Rating-Global Score (CDR global), the Mini-Mental State Exam (MMSE), the Alzheimer’s Disease Assessment Scale - Cognitive Subscale- 14 (ADAS-Cogl4), and a variation of the Alzheimer’s Disease Composite Score (ADCOMS) as optimized for patients with mild or moderate Alzheimer’s Disease. NPI examines 12 sub-domains of behavioral functioning: delusions, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / lability, and aberrant motor activity, night-time behavioral disturbances, and appetite and eating abnormalities. The NPI can be used to screen for multiple types of dementia, and it involves giving the caregiver of a subject the questions and then, based on the answers, rating the frequency of the symptoms, their severity, and the distress the symptoms cause on a three, four, and five-point scale, respectively.

[0265] CDR global is calculated based on testing performed for six different cognitive and behavioral domains: memory, orientation, judgment and problem solving, community affairs, home and hobbies performance, and personal care. To test these areas, an informant is given a set of questions about a subject’s memory problem, judgment and problem-solving ability of the subject, community affairs of the subject, home life and hobbies of the subject, and personal questions related to the subject. The subject is given another set of questions that includes memory -related questions, orientation-related questions, and questions about judgment and problem-solving ability. The CDR global score is calculated based on the results of those questions, and it is measured using a scale of 0 to 3, with 0 representing no dementia, 0.5 indicating very mild dementia, 1 indicating mild dementia, 2 indicating moderate dementia / cognitive impairment, and 3 indicating severe dementia / cognitive impairment. CDR-sb is a clinical outcome assessment that looks at functional impact of cognitive impairment: memory, executive function, instrumental and basic activities of daily living and assesses them based on interviews with an informant and the patient. The CDR-sb score is based on assessment of items including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The CDR-sb is scored from 0 to 18, with higher scores representing greater severity of cognitive and functional impairment. The MMSE looks at 11 items to assess memory, language, praxis and executive function based on a cognitive assessment of the patient. Items assessed include registration, recall, constructional praxis, attention andconcentration, language, orientation time, and orientation place. The MMSE is scaled from 0 to 30, with higher scores representing lower severity of cognitive dysfunction. The ADAS-Cogl4 assesses memory, language, praxis and executive function. The score is based on a cognitive assessment of the patient and assesses fourteen items: spoken language, maze, comprehension spoken language, remembering word recognition test instructions, ideational praxis, commands, naming, word finding difficulty, constructional praxis, orientation, digit cancellation, word recognition, word recall, and delayed recall. A score is based on points allocated to each item, and the maximum total score is 90, with higher numbers indicating greater severity of cognitive dysfunction. The Alzheimer’s Disease Composite Score (ADCOMS) considers items from all of the above- discussed scores: items from Alzheimer’s Disease Assessment Scale-cognitive subscale items, MMSE items, and all of the CDR-sb items. ADCOMS combines portions of the ADAS-cog, Clinical Dementia Rating (CDR) scale, and MMSE that have been shown to change the most over time in people who do not have functional impairment yet. MADCOMS, which was used in the present example, optimizes the scale instead by combining items more significant for mild and moderate dementia.

[0266] The study design involved primary efficacy endpoints of MADCOMS, ADAS- cogl4, and CDR-sb. Unlike ADCOMS, MADCOMS is optimized for patients with moderate or mild Alzheimer’s Disease. These were optimized for AD-specific decline. A separate optimization was done for moderate and mild AD. Secondary efficacy endpoints consisted of ADCS-ADL, ADCOMs (adjusted), MMSE, CDR-global score and the Neuropsychiatric Inventory (NPI). Of the secondary endpoints, ADCS-ADL was measured monthly and MMSE was measured at the last time point.

[0267] The efficacy endpoints were analyzed by applying a linear model of analysis and / or a separate means model of analysis. The linear model of analysis involved employing a linear fit model to determine a value at TO based on the difference from baseline in conditions at the end of the study. The separate means analysis employed estimates of mean values at each assess timepoint, which was either a monthly timepoint or at three and six months after treatment began, depending on the score that was being analyzed. In evaluating MADCOMS composite score, for example, the separate means analysis was applied using mean values that were estimated at three and six months. The linear model was applied by using the estimates of treatment difference at the end of the study and connecting a straight line to 0. Similar models were used for the other efficacy endpoints. FIGs. 3, 4, 5, 6, and 7 show the various linear and separate means models generated for these endpoints.

[0268] To assess biomarkers, researchers used MRI, volumetric analyses, EEG, Amyloid positron emission tomography (PET), actigraphy, and plasma biomarkers. The study employed structural MRIs, taken before any treatment began and at the end of the sixth months and assessed these for volume-base morphology. Volumetric changes for the hippocampus, lateral ventricles, whole cortex (cerebral cortical gray matter) and whole brain (cerebrum and cerebellum) were determined, and the rate of atrophy was compared for active and sham groups using a linear model, as demonstrated in FIG. 8 To analyze for safety and tolerability, researchers looked for adverse events and presence of amyloid related imaging abnormalities (ARIA) on MRI. Therapy adherence was also analyzed. Blinding effectiveness for subjects, care partners, and assessors were prospectively analyzed by assessing baseline and follow up ascertainment of whether the care partner, assessor, or patient thought the patient was on active or sham treatment.

[0269] ANALYSIS

[0270] For the MADCOMS composite scores, both means of analysis demonstrated 35% slowing in decline rate, indicating that the active group progressed less than the placebo arm over the six-month study. When a linear and means analysis were both employed, the sham group was slightly favored, but non-significantly. When these two separate means analyses were applied to the ADAS-cogl4 data, both slightly favored the sham group, although not in a statistically significant manner. When CDR-sb results were analyzed, the mean-estimate model found a 28% slowing rate, whereas the linear extraction showed a 26% slowing rate, but the comparisons were not statistically significant.

[0271] Of the secondary endpoints, ADCS-ADL was measured monthly and MMSE was measured at the last time point. When analyzing ADCS-ADL values, the first analysis model employed used estimates for each month and showed 84% slowing over the 6-month time period. The linear fit model was again employed, and the same 84% slowing was found. When analyzing MMSE values, an 83% slowing was identified.

[0272] RESULTS

[0273] FIG. 1 and FIG. 9 summarize the efficacy findings of the study. Following informed consent and screening, a total of 76 subjects were randomized between the active treatment and sham control. The safety population for the study included 74 subjects who received at least one treatment, and the modified intent to treat (mITT) population included a total of 70 subjects, 53 of whom completed the 6-month study, which form the basis for analysis of outcome measures.

[0274] Demographic and baseline characteristics

[0275] In terms of demographic and baseline characteristics of the mITT population, following randomization, the populations were balanced across gender, baseline MMSE, ApoE4 status,activities of daily living (ADL), and PET amyloid standardized uptake value ratio (SUVR) status; imbalances between the two groups were observed in age, ADAS-Cogl 1, and CDR-sb scores at baseline. Statistical models included covariates for age and MMSE at baseline.

[0276] Safety and tolerability

[0277] Non-invasive gamma sensory stimulation was safe and well-tolerated in the mild and moderate AD subjects. The active group had a lower rate of treatment emergent adverse events (TEAE) than the sham group (67% vs 79%).

[0278] Treatment related AEs (TRAEs) deemed definitely, probably, and possibly related to the therapy were elevated in the active group versus the sham group (41% vs 32%). One treatment related SAE was noted in the active group for a patient hospitalized for wandering while their care partner was located; this subject discontinued the study subsequently. Of the randomized subjects, withdraw rates were similar between both groups (active 28%, sham 29%) including withdraw rates due to an adverse event (active 7%, sham 7%). TEAEs that occurred more often in the active group are tinnitus, delusions, broken bone. TEAEs that occurred more often in the sham group are upper respiratory infection, confusion, anxiety and dizziness.

[0279] Clinical assessments

[0280] Over the treatment period of 6-months, subjects were evaluated in-clinic and via phone visits for cognitive, functional, and biomarker changes on multiple measures. The primary efficacy endpoints demonstrated effects favoring the active group on the MADCOMS (35% slowing; n.s.) and CDR-sb (27%; n.s.) and favoring the Sham group on the ADAS-cogl4 (-15% slowing; n.s.). MADCOMS initially leaned in favor of active group, but the results were not statistically different. ADAS-cogl4 was slightly in favor of the sham group but not statistically different. CDR-sb was also in favor of the active group, but the difference was not significant, as shown by the p-values that ranged between 0.39 and 0.7920.

[0281] Selected secondary endpoints demonstrated significant effects favoring the treatment (active) group. The active group had significant benefit on functional ability as measured by the ADCS-ADL (p=0.0009), which represented an 84% slowing of decline and a treatment difference of 7.59 points over the six-month duration of the trial (FIG. 9). The active group demonstrated significant benefit on the MMSE (ANCOVA p=0.013), which represented an 83% slowing in the rate of decline versus the Sham group and a treatment difference of 2.42 points.

[0282] Biomarker changes - MRI

[0283] Structural MR imaging was analyzed for volume-base morphometry using an automated image processing pipeline (Biospective, Montreal, Canada). Volumetric changes of the hippocampus, lateral ventricles, whole cortex (cerebral cortical gray matter) and whole brain(cerebrum and cerebellum, no cerebrospinal fluid (CSF)) for each subject were determined; no manual corrections were performed. No significant benefit on hippocampal volume was determined. Statistically- significant benefit favoring the active group (p=0.0154) on whole brain volume (WBV) was established, representing a 61% slowing compared to the Sham group progression. The treatment value for the active group was 9.34 cm3.

[0284] CONCLUSIONS

[0285] Gamma sensory stimulation was safe and well tolerated. Two of three primary efficacy outcomes (MADCOMS, CDR-sb) favored the active group but did not reach significance. Selected secondary endpoints demonstrated that active treatment with gamma sensory stimulation therapy led to significant benefits in the ability to perform activities of daily living via the ADCS-ADL and cognition via the MMSE, representing important treatment and management objectives for AD patients. Quantitative MR analysis demonstrated slowing of brain atrophy as measured by whole brain volume in the active group. The combined clinical and biomarker findings suggest beneficial effects of gamma sensory stimulation for AD subjects may be facilitated via differentiated pathways. These surprising results indicates that the gamma sensory stimulation may be used to treat a range of diseases and disorders that cause or are caused by brain atrophy.Example 2. Wireless Non-Invasive Visual, Audio, and Haptic Devices and Methods of Use

[0286] Wireless Non-Invasive Visual, Audio, and Haptic Devices and Systems

[0287] In some embodiments, the wireless non-invasive visual device is a non-invasive means of providing a stimulus to a subject, and in some cases, non-invasively inducing gamma brainwave activity in a brain region of the subject. In some embodiments, the wireless non-invasive visual device is comprised of a reusable visual signal generator and signal emitter in the form of subject worn wireless eyeglasses and / or frames. In some embodiments, the wireless non-invasive visual device generates short-duration visual stimuli, such as pulses of light, that typically occur at a repetition rate of about 30 Hz to about 60 Hz, and in some cases about 40 Hz, and at a pulse rate about from about 30 pulses per second to about 60 pulses per second.

[0288] In some embodiments, the wireless non-invasive audio device is a non-invasive means of providing a stimulus to a subject, and in some cases, non-invasively inducing gamma brainwave activity in a brain region of the subject. In some embodiments, the wireless non-invasive audio device is comprised of a reusable audio signal generator and signal emitter in the form of subject worn wireless headphones. In some embodiments, the wireless non-invasive audio device generates short-duration audio stimuli, such as clicks of sound, that typically occur at a repetitionrate of about 30 Hz to about 60 Hz, and in some cases about 40 Hz, and at a pulse rate about from about 30 pulses per second to about 60 pulses per second.

[0289] Similarly, in some embodiments, the wireless non-invasive haptic device is a non- invasive means of providing a stimulus to a subject, and in some cases, non-invasively inducing gamma brainwave activity in a brain region of the subject. In some embodiments, the wireless non-invasive haptic device is comprised of a reusable haptic signal generator and signal emitter in the form of subject worn bone conduction headphones. In some embodiments, the wireless non-invasive haptic device generates short-duration haptic stimuli, such as pulses of vibration, that typically occur at a repetition rate of about 30 Hz to about 60 Hz, and in some cases about 40 Hz at a pulse rate about from about 30 pulses per second to about 60 pulses per second.

[0290] From a subject's perspective, the wireless non-invasive visual, auditory and / or haptic stimulation results in a desired outcome, such as the desired induced gamma brainwave activity, but an individual wearing the device is readily able to converse and carry out other cognitive tasks and voluntary movements such as holding the hand of their caregiver while remaining seated. The visual stimulus, audio click and / or haptic vibration is quite quick, so it is less apparent to the subject that there is an off period for the audio and / or haptic gamma stimulation. For comparison, most modern flat screen displays (computer monitors and televisions) refresh the content on the screen at 60 Hz; at this rate, the flickering is not apparent to the viewer.

[0291] In one embodiment, the wireless non-invasive visual device is worn on the head, and it is positioned over the eyes if using a glasses embodiment. In one embodiment, the wireless non- invasive audio device is worn on the head, and it is positioned over the ears if using an over-ear headphone embodiment or within the ears if using an in-ear headphone embodiment. In another embodiment, the wireless non-invasive haptic device is worn on the head and is positioned over the subject’s ear and aligned with the subject’s temples if using a bone conduction headphone embodiment. The devices can be placed on the head by the subject or with assistance from a caregiver.

[0292] Instructions for use are included with each wireless non-invasive visual, audio and / or haptic device. The devices are designed for ease of use for older adults, with no requirements for high dexterity manipulation of the devices and are accompanied by simple visual instructions in large print.

[0293] The wireless non-invasive visual, audio and / or haptic device includes a hand-held controller which allows the subject, with the assistance from a caregiver if needed, to turn thedevice on, independently adjust the output amplitude for both the wireless non-invasive auditory and / or haptic stimulation, and to pause and resume the stimulation during a session.Example 3. Animal Models and Experimental Design

[0294] This example demonstrates methods and devices of the present technology in the prevention or treatment of Alzheimer's Disease (AD) animal in models and human subjects.

[0295] Animal Models: Murine models of AD suitable for use in this example include, but are not limited to, animals having loss-or gain-of-function mutations, and transgenic animals, for example, the 3xTg-AD and / or 5xFAD transgenic mouse. Protocols for use of the 3xTg-AD mouse are provided below as illustrative.

[0296] Animal Groups: 3xTg-AD mice are obtained by crossing heterozygous APPswe / PSldE9 double transgenic mice (Jackson Laboratory, Bar Harbor, Me., USA) with heterozygous P301L tau transgenic mice (Taconic Labs, Germantown, N.Y.). Male C57BL / 6J mice (Shanghai SLAC Laboratory Animal CO., Ltd, Shanghai, China) and 3xTg-AD mice are maintained in a controlled environment at 25+1° C. with a 12 / 12 h light-dark cycle. Experimental protocols are performed according to accepted guidelines for animal experimentation.

[0297] Fifty male 3xTg-AD mice are randomly divided into five groups (each n !4 = 10): the 3xTg-AD group, three groups of 3xTg-AD mice treated with methods and devices of the present technology. Wildtype C57BL / 6J mice are used for the control group.

[0298] Subjects are behaviorally tested after 2 months of treatment using methods known and accepted in the art, including, but not limited to, open field testing (OFT), elevated plus-maze (EPM), and / or Morris water maze (MWM). The animals are sacrificed, and the brains preserved for analysis. Half of the brain is used for immunofluorescence, and half for western blotting and enzyme-linked immunosorbent assay (ELISA).

[0299] Immunohistochemistry: The 3xTg-AD mice are anesthetized with pentobarbital, perfused with saline, and then perfused with 4% paraformaldehyde in 0.1 M phosphate-buffered saline (PBS), pH 7.4. Brains are fixed in 4% paraformaldehyde for 24 h and transferred into PBS containing 30% sucrose. Each brain is sectioned in the coronal plane at an instrument setting of 10 mm. Free floating sections are washed with PBS three times before being permeabilized with 0.3% Triton X-100 for 10 min, blocked with 3% bovine serum albumin (BSA) for 1 h, and incubated overnight at 4° C. with the following primary antibodies: rabbit anti-Ap42 (1:200, Abeam, Cambridge, Cambs, UK) and mouse anti-202 / 205 phosphorylated tau (ATB, 1:100, Life Technologies, Carlsbad, Calif., USA). After several washes in PBS, the slides are incubated for 1 h at room temperature with the secondary antibody: DyLight 594 goat anti-rabbit IgG (1:500,Thermo Scientific, Rockford, Ill., USA). Nuclei are detected using 40, 6-diamidino-2- phenylindole (DAPI, 1:500, Thermo Scientific). After washing three times in PBS, the sections are mounted on charged slides for immunofluorescence detection using an Olympus microscope with DP-70 software. The imaging data are analyzed and quantified using Image pro-plus version 6.0.

[0300] Western Blotting Analysis: Frozen brains are lysed with an ice-cold RIPA lysis buffer (Beyotime Institute of Biotechnology, Jiangsu, China) with complete protease inhibitor cocktail and phosphatase inhibitor cocktail (Roche, Indianapolis, Ind., USA). Lysates are centrifuged at 12,000 g for 20 min at 4° C. The supernatants are collected, and total protein concentrations are estimated using the Bradford method by means of the protein assay kit (Beyotime Institute of Biotechnology). Total proteins are denatured at 100° C for 8 min and 60 mg proteins per lane are separated on 10% SDS-poly acrylamide gel and electro-transferred onto a poly vinylidene difluoride membrane (Millipore, Bedford, Mass., USA). Membranes are blocked with 5% BSA in Tris-buffered saline with 1% Tween-20 (TBST) for 2 h at room temperature and then incubated overnight at 4° C. with the following primary antibodies: rabbit anti-interleukin- ip (IL-ip), rabbit anti-APP Thr668, rabbit anti-tumor-necrosis-factor-a(TNFa), rabbit anti-bcl-2 and anti-bax (1:1000, Life Technologies); rabbit anti-PSl (1:2000, Life Technologies); rabbit anti-interleukin-6 (IL-6) and mouse anti-caspase-3 (1:1000, Abeam), mouse anti-202 / 205 phosphorylated tau (ATB, 1:100). GAPDH (1:8000, Life Technologies) is used as a loading control. Membranes are washed with TBST three times for 10 min and then incubated in the secondary antibody, anti-rabbit or anti-mouse IgG HRP-linked antibody (1:4000, Life Technologies) for 2 h. Blots are visualized by chemiluminescence (Amersham, Arlington Heights, Ill., USA). Optical densities are measured, and protein levels normalized to GAPDH.

[0301] ELISA: Brain hemispheres are homogenized in ice-cold PBS containing 5 M guanidine hydrochloric acid and Ixprotease inhibitor mixture (pH 8.0). The levels of Ap42 are quantified by ELISA according to manufacturer instructions (Invitrogen, Camarillo, Calif., USA) and expressed as ng / g protein. The oxidant- antioxidant status of tissues is assessed by determining the activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and the concentration of malondialdehyde (MDA).

[0302] Statistical Analyses: SPSS statistical software 16.0 for windows is used. All results are evaluated using one-way ANOVA and Dunnett's multiple range tests. All values are expressed as mean+standard error of the mean (S.E.M). Statistical significance is assumed if P<0.05.

[0303] Results: It is predicted that methods of the present technology will induce reversal of symptoms and / or pathologies of AD in animal models. These results will show that methods of the present technology are useful and effective for the prevention or treatment of AD.

[0304] Human Clinical Trials: Human subjects diagnosed as having or suspected to have AD presently displaying one or more symptoms and / or pathologies of AD, including, but not limited to memory loss, cognitive disorder, and AD biomarkers, such as, but not limited to beta-amyloid in cerebrospinal fluid, amyloid-positive PET imaging, and genotypic markers (e.g., ApoE), are recruited using selection criteria known and accepted in the art.

[0305] In some studies, subjects are diagnosed as having or suspected to have a sporadic AD. In some studies, subjects are diagnosed as having or suspected to have a familial AD. In some studies, subjects are diagnosed as having or suspected to have early-onset AD. In some studies, subjects are diagnosed as having or suspected to have late-onset AD.

[0306] Clinical studies are conducted in accordance with accepted practices, such as, for example, the protocol of An, et al., J. Alzheimer's Dis. Oct. 4 (2016).

[0307] Methods of Prevention and Treatment: Subjects are administered methods of the present technology at a dosage and frequency commensurate with the stage and severity of disease. In some embodiments the method is administered once daily, once weekly, or once monthly. In some embodiments, the method is administered multiple times daily, weekly, or monthly.

[0308] To demonstrate methods of prevention and treatment in human subjects and animal models, subjects are administered methods of the present technology prior to or subsequent to the development of symptoms and / or pathologies or AD and assessed for reversal of symptoms / pathologies or attenuation of expected symptoms / pathologies using methods known in the art.

[0309] Efficacy of prevention and treatment methods of the present technology may be assessed using methods known in the art, including, but not limited to the Alzheimer's Disease Assessment Scale Cognitive Portion (ADAS-Cog), the MMSE, and the Neuropsychological Test Battery (NTB). In addition, global assessments and assessments of activities of daily living may be obtained through the subject's caregiver, including, but not limited to the Basic Activities of Daily Living (BADL), the Clinical Dementia Rating (CDR), the Dependence Scale, the Instrumental Activities of Daily Living (IADLS), and the Neuropsychiatric Inventory (NPI).

[0310] Results: It is predicted that methods of the present technology will induce reversal of symptoms and / or pathologies of AD in human subjects. These results will show that methods of the present technology are useful and effective for the prevention or treatment of AD.Example 4. Human Clinical Study of Safety, Efficacy, and Results of Treatment Using Wireless Visual, Audio and / or Haptic Stimulation

[0311] Methods and Study Design

[0312] A clinical study is performed to assess the safety, tolerability, and efficacy of long-term, daily use of a wireless non-invasive sensory visual, auditory and / or haptic stimulation device as described herein on cognition, functional ability, and biomarkers in a group of experimental subjects. In some cases, experimental subjects include subjects with mild-to-moderate AD. The clinical study is a multi-center, randomized controlled trial evaluating daily use of the wireless non-invasive sensory visual, auditory or haptic stimulation device, with therapy to be received at home for a 6-month treatment period. Subjects included in the study are adults and adults 50 years and older with a clinical diagnosis of mild to moderate AD (MMSE: 14-26, inclusive), a reliable care partner, and successful tolerance and entrainment screening via EEG. Key exclusion criteria include profound hearing or visual impairment, use of memantine, major psychiatric illness, clinically relevant history of seizure, or contraindication to imaging studies.

[0313] Study Participants and Design.

[0314] A total number of patients are assessed for eligibility to participate in the study. Patients are first given a screening EEG, and then split into groups. One group is a sham control group that is not given treatment; the other is a group that is subjected to 1 hour of therapy, which involves subjecting the subject to wireless non-invasive visual, auditory and / or haptic stimulation at a frequency of 40 Hz, at least once per day. Of those assessed for eligibility, patients are randomized between the active treatment and sham control groups.

[0315] The study employs various clinical outcome assessment scales to assess cognitive decline or dysfunction. These include the Neuropsychiatric Inventory (NPI), Clinical Dementia Rating- Sum of Boxes (CDR-sb), the Clinical Dementia Rating-Global Score (CDR global), the MiniMental State Exam (MMSE), the Alzheimer's Disease Assessment Scale-Cognitive Subscale- 14 (ADAS-Cogl4), and a variation of the Alzheimer's Disease Composite Score (ADCOMS) as optimized for patients with mild or moderate Alzheimer's Disease. NPI examines 12 sub-domains of behavioral functioning: delusions, hallucinations, agitation / aggression, dysphoria, anxiety, euphoria, apathy, disinhibition, irritability / lability, and aberrant motor activity, night-time behavioral disturbances, and appetite and eating abnormalities. The NPI can be used to screen for multiple types of dementia, and it involves giving the caregiver of a subject the questions and then, based on the answers, rating the frequency of the symptoms, their severity, and the distress the symptoms cause on a three, four, and five-point scale, respectively.

[0316] CDR global is calculated based on testing performed for six different cognitive and behavioral domains: memory, orientation, judgment, and problem solving, community affairs, home and hobbies performance, and personal care. To test these areas, an informant is given a set of questions about a subject's memory problem, judgment and problem- solving ability of the subject, community affairs of the subject, home life and hobbies of the subject, and personal questions related to the subject. The subject is given another set of questions that includes memory -related questions, orientation-related questions, and questions about judgment and problem-solving ability. The CDR global score is calculated based on the results of those questions, and it is measured using a scale of 0 to 3, with 0 representing no dementia, 0.5 indicating very mild dementia, 1 indicating mild dementia, 2 indicating moderate dementia / cognitive impairment, and 3 indicating severe dementia / cognitive impairment. CDR-sb is a clinical outcome assessment that looks at functional impact of cognitive impairment: memory, executive function, instrumental and basic activities of daily living and assesses them based on interviews with an informant and the patient. The CDR-sb score is based on assessment of items including memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. The CDR-sb is scored from 0 to 18, with higher scores representing greater severity of cognitive and functional impairment.

[0317] The MMSE looks at 11 items to assess memory, language, praxis, and executive function based on a cognitive assessment of the patient. Items assessed include registration, recall, constructional praxis, attention and concentration, language, orientation time, and orientation place. The MMSE is scaled from 0 to 30, with higher scores representing lower severity of cognitive dysfunction. The ADAS-Cogl4 assesses memory, language, praxis, and executive function. The score is based on a cognitive assessment of the patient and assesses fourteen items: spoken language, maze, comprehension spoken language, remembering word recognition test instructions, ideational praxis, commands, naming, word finding difficulty, constructional praxis, orientation, digit cancellation, word recognition, word recall, and delayed recall. A score is based on points allocated to each item, and the maximum total score is 90, with higher numbers indicating greater severity of cognitive dysfunction. The Alzheimer's Disease Composite Score (ADCOMS) considers items from all of the above-discussed scores: items from Alzheimer's Disease Assessment Scale-cognitive subscale items, MMSE items, and all of the CDR-sb items. ADCOMS combines portions of the ADAS-cog, Clinical Dementia Rating (CDR) scale, and MMSE that have been shown to change the most over time in people who do not have functional impairment yet. MADCOMS, which is used in the present example, optimizes the scale instead by combining items more significant for mild and moderate dementia.

[0318] The study design involves primary efficacy endpoints of MADCOMS, ADAS-cogl4, and CDR-sb. Unlike ADCOMS, MADCOMS is optimized for patients with moderate or mild Alzheimer's Disease. These are optimized for AD-specific decline. A separate optimization is done for moderate and mild AD. Secondary efficacy endpoints consist of ADCS-ADL, ADCOMs (adjusted), MMSE, CDR-global score and the Neuropsychiatric Inventory (NPI). Of the secondary endpoints, ADCS-ADL is measured monthly and MMSE is measured at the last time point.

[0319] The efficacy endpoints are analyzed by applying a linear model of analysis and / or a separate means model of analysis. The linear model of analysis involves employing a linear fit model to determine a value at TO based on the difference from baseline in conditions at the end of the study. The separate means analysis employs estimates of mean values at each timepoint, which is either a monthly timepoint or at three and six months after treatment begins, depending on the score that is being analyzed. In evaluating MADCOMS composite score, for example, the separate means analysis is applied using mean values that are estimated at three and six months. The linear model is applied by using the estimates of treatment difference at the end of the study and connecting a straight line to 0.

[0320] To assess biomarkers, researchers use MRI, volumetric analyses, EEG, Amyloid positron emission tomography (PET), actigraphy, and plasma biomarkers. In some embodiments the study measures gamma oscillations within brain regions, levels of tau phosphorylation, levels of amyloid-P(AP) peptide, levels of at least one of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP), numbers of endosomes, or a combination thereof. The study employs structural MRIs, taken before any treatment begins and at the end of six months and assesses these for volume -base morphology. Volumetric changes for the hippocampus, lateral ventricles, whole cortex (cerebral cortical gray matter) and whole brain (cerebrum and cerebellum) are determined, and the rate of atrophy is compared for active and sham groups using a linear model. To analyze for safety and tolerability, researchers look for adverse events and presence of amyloid related imaging abnormalities (ARIA) on MRI. Therapy adherence is also analyzed. Blinding effectiveness for subjects, care partners, and assessors are prospectively analyzed by assessing baseline and follow up ascertainment of whether the care partner, assessor, or patient thought the patient is on active or sham treatment. In some cases, levels of the measured biomarkers are maintained or reduced in active treatment groups as compared to groups receiving sham treatment.

[0321] Results

[0322] The subjects are randomized between the active treatment and sham control. The safety population for the study includes subjects who received at least one treatment, and the modified intent to treat (mITT) population includes subjects who complete the 6-month study, which form the basis for analysis of outcome measures. FIG. 2 demonstrates an example efficacy summary chart for a modified intent to treat (mITT) population, including hypothesized p- values, difference, confidence intervals (CI), and a hypothesized standardized estimate of efficacy based on the values.

[0323] Demographic and Baseline Characteristics

[0324] In terms of demographic and baseline characteristics of the mITT population, following randomization, the populations are balanced across gender, baseline MMSE, ApoE4 status, activities of daily living (ADL), and PET amyloid standardized uptake value ratio (SUVR) status; imbalances between the two groups are categorized with differences in age, ADAS-Cogl l, and CDR-sb scores at baseline being noted. Statistical models include covariates for age and MMSE at baseline.

[0325] Safety and Tolerability

[0326] The wireless gamma oscillation inducing waveform stimulus is safe and well-tolerated in the mild and moderate AD subjects, consistent with previous studies, e.g., studies described in US 15 / 816,222, US 16 / 415,825, US 15 / 816,238, US 18 / 160,674, US 17 / 300,314, and US 17 / 953,253, the disclosures of which each are incorporated by reference herein. The active group is hypothesized to have a lower rate of treatment emergent adverse events (TEAE) than the sham group.

[0327] Treatment related AEs (TRAEs) deemed definitely, probably, and possibly related to the therapy is hypothesized to be elevated in the active group versus the sham group. Of the randomized subjects, withdraw rates are hypothesized to be similar between both groups including withdraw rates due to adverse events. TEAEs that occur most often in the active group are hypothesized to be tinnitus, delusions, and broken bones. TEAEs that occur most often in the sham group are hypothesized to be upper respiratory infection, confusion, anxiety, and dizziness.

[0328] Clinical Assessments

[0329] Over the treatment period of 6-months, subjects are evaluated in-clinic and via phone visits for cognitive, functional, and biomarker changes on multiple measures.

[0330] The primary efficacy endpoints are hypothesized to demonstrate effects favoring the active group on the MADCOMS and CDR-sb and favoring the Sham group on the ADAS-cogl4.

[0331] Selected secondary endpoints demonstrate significant effects favoring the treatment (active) group. The active group has significant benefit on functional ability as measured by theADCS-ADL. The active group demonstrates significant benefit on the MMSE, which represents slowing in the rate of decline versus the Sham group. The active group is hypothesized to demonstrate maintained or increased recognition, discrimination, spatial memory, working memory, and attention as compared to the sham group. Examples of such hypothesized results are demonstrated in FIG. 3 - FIG. 7.

[0332] Biomarker Changes — MRI

[0333] Structural MR imaging is analyzed for volume-base morphometry using an automated image processing pipeline (Biospective, Montreal, Canada). Volumetric changes of the hippocampus, lateral ventricles, whole cortex (cerebral cortical gray matter) and whole brain (cerebrum and cerebellum, no cerebrospinal fluid (CSF)) for each subject are determined; no manual corrections are performed. The active group is hypothesized to demonstrate maintained or increased volumetric changes as compared to the sham group. An example of hypothesized magnetic resonance imaging (MRI) results is demonstrated in FIG. 8.

[0334] Conclusions

[0335] Wireless non-invasive visual, auditory and / or haptic stimulation is hypothesized to be safe and well tolerated in accordance with previous studies. Primary efficacy outcomes (MADCOMS, CDR-sb) are hypothesized to favor the active group over the sham group. Selected secondary endpoints will demonstrate that active treatment with wireless non-invasive visual, auditory and / or haptic stimulation therapy leads to significant benefits in the ability to perform activities of daily living via the ADCS-ADE and cognition via the MMSE, representing important treatment and management objectives for AD patients. Quantitative MR analysis is hypothesized to demonstrate slowing of brain atrophy as measured by whole brain volume in the active group. The combined clinical and biomarker findings are hypothesized to suggest the beneficial effects of wireless gamma sensory visual, auditory and / or haptic stimulation for AD subjects may be facilitated via differentiated pathways.Example 5: Experimental Stimulation Protocol and Biomarker Changes Following Wireless Non-invasive Visual, Auditory and / or Haptic Stimulation at Gamma Frequency

[0336] In some embodiments, wireless non-invasive exposure and / or administration includes wireless non-invasive visual, auditory and / or haptic stimulation. The visual stimulation may include light pulses, including a pulse frequency of about 30 pulses per second to about 60 pulses per second. The auditory stimulation may include sound pulses or clicks. A sound stimulus may include a click train of about 30 sound pulses or clicks per second (clicks / s) to about 60 clicks / s. In some embodiments, a sound stimulus includes a click train of about 40 sound pulses or clicksper second. In an embodiment, an auditory stimulus having a click frequency of 40 clicks / s, with 25 ms between each click, and each click having a duration of 1 ms is used.

[0337] The haptic stimulation may include vibration and may be referred to in some embodiments as a haptic stimulus or a vibration stimulus. A haptic stimulus may include a vibration of about 30 vibrations per second to about 60 vibrations per second. In some embodiments, a haptic stimulus includes a vibration of about 40 vibrations per second. In an embodiment, a haptic stimulus having a vibration frequency of 40 Hz, with 25 ms between each vibration, and each vibration having a duration of 1 ms is used.

[0338] Wireless Visual, Auditory and / or Haptic Gamma Stimulation is Shown to Induce Microglial Cell-State Changes in Subjects According to some Embodiments.

[0339] A study is conducted to examine whether wireless non-invasive visual, auditory and / or haptic exposure and / or administration induces microglial activation in the visual or auditory cortex of subjects in accordance with some embodiments. A 40-Hz visual, auditory, and / or haptic stimulus is used, the visual stimulus having a pulse frequency of about 40 Hz and about 40 pulses per second, the auditory stimulus having a click frequency of about 40 clicks / s with each click having a duration of about 1 ms at a tone of about 10 kHz and about 60-65 dB and the haptic stimulus having a vibration frequency of 40 Hz. The click- train and / or vibration stimulus is hypothesized to entrain PV+ interneurons in the auditory cortex, thereby exogenously regulating gamma oscillations in the auditory cortex.

[0340] To test wireless non-invasive visual, auditory and / or haptic gamma stimulation, in one embodiment, WT mice are housed in a home cage. For one hour per day, for seven consecutive days (Days 1-7), the mice are moved to a behavior box (i.e., a soundproof chamber). While in the behavior box , a first group of mice are exposed to silence, and a second group of mice are exposed to the click-train or haptic vibration stimulus in accordance with some embodiments (Termed Stim / No Stim Study). After each hour in the behavior box , the mice are returned to their home cage. On Day 8, the mice are sacrificed for tissue collection and staining.

[0341] The tissue is examined for levels of microglia, morphologic changes in the microglial cells, and microglial activation, as indicated by soma size. The average number, projection length, and soma size of microglia cells in mice exposed to silence and mice exposed to the wireless auditory and / or haptic vibration stimulus is measured.

[0342] Wireless visual, auditory and / or haptic gamma stimulation is shown to induce a microglial activation-like phenotype in subjects according to some embodiments. The above Stim / No-Stim study is repeated with 5xFAD transgenic (Tg) mice in accordance with some embodiments. The tissue is examined for a level of microglia cells, morphologic changes in themicroglial cells (e.g., projection length), and microglial activation (e.g., as indicated by soma size). The average number of microglia per field of image in mice exposed to silence (No Stim) compared to mice exposed to the click-train stimulus and / or haptic vibration stimulus is measured (Stim). Significantly more microglial cells are hypothesized to be observed in the mice exposed to the click-train and / or haptic vibration stimulus in accordance with some embodiments. The average fold change in soma size of microglia in mice exposed to silence (No Stim) compared to mice exposed to the click-train and / or haptic vibration stimulus is measured (Stim). The average fold change in soma size is hypothesized to be significantly greater in the mice exposed to the click-train and / or haptic vibration stimulus, indicating greater microglial activation in accordance with some embodiments. The average fold change in projection length of microglia in mice exposed to silence (No Stim) compared to mice exposed to the click-train and / or haptic vibration stimulus is measured (Stim). The average fold change in projection length is hypothesized to be significantly less in the mice exposed to the click-train and / or haptic vibration stimulus in accordance with some embodiments.

[0343] The projections and soma of the microglia are visibly different between No Stim and Stim groups, with comparatively shorter projection length and larger soma size hypothesized in the microglia from a mouse exposed to the click-train and / or haptic vibration stimulus in accordance with some embodiments.

[0344] Visual, Auditory and / or Haptic Stimulation at Gamma Frequency Non-Invasively Reduces Ap in the Visual Cortex, Auditory Cortex and Hippocampus of Subjects.

[0345] Wireless non-invasive visual, auditory and / or haptic stimulation is shown to decrease levels of Ap in subjects according to some embodiments. The Stim / No Stim study is repeated with six-month old 5xFAD Tg mice in accordance with some embodiments. On Day 8, the visual and auditory cortex and hippocampus are dissected. ELISA is used to measure levels of soluble and insoluble Ap isoforms, including isoform AP1-40 peptide and isoform AP1-42 peptide. Insoluble Ap is treated with 5M guanidine-HCl for three hours to solubilize plaques.

[0346] Wireless visual, auditory and / or haptic gamma stimulation is shown to decrease levels of soluble Ap in subjects according to some embodiments. Smaller levels of soluble isoform AP1-42 peptide in the visual cortex and auditory cortex of mice exposed to the visual stimulus, click-train stimulus and / or haptic vibration stimulus (Stim) are hypothesized to be observed relative to levels of soluble isoform AP1-42 peptide in the visual cortex, auditory cortex of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0347] Smaller levels of soluble isoform AP1-40 peptide in the visual cortex and the auditory cortex of mice exposed to the visual stimulus, click-train and / or haptic vibration stimulus (Stim)are hypothesized to be observed relative to levels of soluble isoform AP1-40 peptide in the auditory cortex of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0348] Smaller levels of soluble isoform AP1-42 peptide in the hippocampus of mice exposed to the visual, click-train and / or haptic vibration stimulus (Stim) are hypothesized to be observed relative to levels of soluble isoform Ap 1-42 peptide in the hippocampus of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0349] Smaller levels of soluble isoform AP1-40 peptide in the hippocampus of mice exposed to the visual, click-train and / or haptic vibration stimulus (Stim) are hypothesized to be observed relative to levels of soluble isoform Ap 1-40 peptide in the hippocampus of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0350] Wireless non-invasive visual, auditory and / or haptic stimulation is shown to decrease levels of insoluble Ap in subjects according to some embodiments. Smaller levels of insoluble isoform AP1-42 peptide in the visual and / or auditory cortex of mice exposed to the visual, clicktrain and / or haptic vibration stimulus are hypothesized to be observed (Stim) relative to levels of insoluble isoform AP1-42 peptide in the auditory cortex of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments. Smaller levels of insoluble isoform AP1-40 peptide in the auditory cortex of mice exposed to the visual, click-train and / or haptic vibration stimulus (Stim) are hypothesized to be observed relative to levels of insoluble isoform AP1-40 peptide in the auditory cortex of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0351] Smaller levels of insoluble isoform Api-42 peptide in the hippocampus of mice exposed to the visual, click-train and / or haptic vibration stimulus (Stim) are hypothesized to be observed relative to levels of insoluble isoform Ap 1-42 peptide in the hippocampus of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0352] Smaller levels of insoluble isoform Api-40 peptide in the hippocampus of mice exposed to the visual, click-train and / or haptic vibration stimulus (Stim) are hypothesized to be observed relative to levels of insoluble isoform Ap 1-40 peptide in the hippocampus of mice exposed to silence or no visual stim (No Stim) in accordance with some embodiments.

[0353] Thus, according to some embodiments, non-invasive wireless auditory and / or haptic stimulation at a gamma frequency promotes gamma oscillations and a profound reduction in AD- associated pathology in the auditory cortex and the hippocampus.

[0354] Wireless Visual, Auditory and / or Haptic Stimulation at Gamma Frequency Reduces Phosphorylated Tau in Subjects

[0355] Wireless non-invasive visual, auditory, and / or haptic stimulation is shown to reduce phosphorylated tau in subjects according to some embodiments. To determine if wireless non- invasive visual, auditory, and / or haptic stimulation improves another key AD-related pathology, tau phosphorylation is investigated using a TauP301S tauopathy mouse model. Four TauP301S Tg mice, which show phosphorylated tau localized to the cell body at this age, are treated with either auditory and / or haptic gamma stimulation or exposed to silence for one hour daily for seven days, in accordance with the stim / no-stim protocol outlined above. To examine how visual, auditory and / or haptic gamma stimulation alters tau phosphorylation, immunohistochemical characterization of the visual cortex is performed using pTau antibodies against three different epitopes of pTau (S202, S396, and S400 / T403 / S404; 11834S, 9632S, 11837S) and dendritic marker MAP2 as a control.

[0356] A series of immunofluorescence images are obtained illustrating immunohistochemistry with the anti-pTau (S202, S396, and S400 / T403 / S404; 11834S, 9632S, 11837S) and anti-MAP2 antibodies in the four- month-old P301S mice after seven days of one hour / day under visual, auditory and / or haptic vibration gamma stimulation conditions in accordance with some embodiments. Images are taken with a 40x objective. Relative pTau (S202, S396, and S400 / T403 / S404; 11834S, 9632S, 11837S) intensity levels within the P301S auditory cortex are measured after seven days of auditory and / or haptic vibration gamma stimulation in accordance with some embodiments. Relative MAP2 intensity levels of P301S auditory cortex are measure after seven days of auditory and / or haptic vibration gamma stimulation in accordance with some embodiments.

[0357] It is hypothesized that the signal intensity of the pTau(S202, S396, and S400 / T403 / S404; 11834S, 9632S, 11837S) will be significantly reduced in the auditory and / or haptic vibration gamma stimulation condition as compared to silent controls, while MAP2 levels will be unchanged. It is also hypothesized that less punctate and cell-body localization of pTau signal in response to visual, auditory and / or haptic vibration gamma stimulation compared to the silent controls will be observed.

[0358] Auditory and / or Haptic Stimulation at Gamma Frequency and Positive Effects on Subject Behavior.

[0359] Wireless visual, non-invasive auditory and / or haptic gamma stimulation is hypothesized to improve recognition in subjects according to some embodiments. A novel object recognition test is performed using 5xFAD mice exposed to the visual, click-train and / or haptic vibration stimulus in accordance with the Stim / No-Stim study above. The test assesses an ability of a subject to recognize novel from familiar objects (i.e., recognition memory) based on the tendencyof rodents to spend more time exploring a novel object than a familiar object. A recognition index RI is used to compare the subjects.

[0360] 5xFAD mice are habituated to an environment. At time Tl, two novel objects are introduced into the environment. Then at time T2, following one hour of rest, the mice are exposed to one familiar object and one novel object for one hour. The mice exposed to the visual, click-train and / or haptic vibration stimulus are hypothesized to have higher RI, indicating that the mice exposed to a visual, click-train and / or haptic vibration stimulus spent much more time with the new object than the familiar object due to better recognition memory in accordance with some embodiments.

[0361] Wireless visual, auditory and / or haptic gamma stimulation is hypothesized to improve discrimination in subjects according to some embodiments. A novel object location test is performed using 5xFAD mice exposed to the visual, click-train and / or haptic vibration stimulus in accordance with some embodiments and 5xFAD mice exposed to silence or no visual stim. The test assesses spatial memory and / or discrimination based on the tendency of rodents to spend more time exploring a newly located object. A recognition index RI is used to compare the subjects.

[0362] 5xFAD mice are habituated to an environment. At time Tl, two objects are introduced at first locations. Then at time T2, following one hour of rest, the mice are exposed to one of the objects at its first location and the other object located at a new second location, for one hour. The mice exposed to the visual, click-train and / or haptic vibration stimulus are hypothesized to have higher RI, indicating that the mice exposed to the visual, click-train and / or haptic vibration stimulus spent much more time with the object that moved than the object that stayed in the same location due to better spatial memory and / or discrimination in accordance with some embodiments.

[0363] Wireless visual, auditory and / or haptic gamma stimulation is hypothesized to improve spatial memory in subjects according to some embodiments. A Morris water maze test is performed using 5xFAD mice exposed to the visual, click-train and / or haptic vibration stimulus in accordance with some embodiments and 5xFAD mice exposed to silence or no visual stim. As described above, the test assesses spatial and / or reference memory based on distal cues used by subjects to navigate from start locations around the perimeter of an open swimming arena to locate a submerged escape platform. The test is assessed across repeated trials, and spatial and / or reference memory is determined by preference for the platform area when the platform is absent.

[0364] The average latency to find the platform is assessed in the mice exposed to silence (No Stim) and the mice exposed to the visual, click-train and / or haptic vibration stimulus (Stim) oneach day in accordance with some embodiments. The mice exposed to the visual, click-train and / or haptic vibration stimulus are hypothesized to spend more time searching for the missing platform in the target quadrant than did the mice exposed to silence, thus indicating that the mice exposed to the click-train and / or haptic vibration stimulus have better spatial and / or reference memory in accordance with some embodiments.

[0365] Thus, according to some embodiments, wireless non-invasive visual, auditory and / or haptic stimulation at a gamma frequency is hypothesized to induce microglial activation, reduce AD-associated (e.g., AP) pathology, and significantly ameliorate cognitive deficits (in, e.g., recognition, discrimination, and spatial memory). With easy and accessible options for administration (including self- administration), wireless visual, auditory and / or haptic gamma stimulation has the potential for vast commercial applications, including but not limited to applications for home or mobile use (e.g., using noise-canceling wireless headphones). In addition to self-administration potential, clinicians and / or researchers may administer a stimulation paradigm to subjects ranging from animal models to human patients in accordance with some embodiments. Clinicians and / or researchers may find it useful to combine auditory gamma stimulation with various forms of monitoring. For example, a therapeutic session may include locating a subject in a soundproof room or supplying the subject with noise-canceling headphones or another device to limit interference. The subject may be monitored during the stimulation using, for example, functional magnetic resonance imaging (fMRI) for any beneficial brain-state changes.

[0366] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. It is not intended that the invention be limited by the specific examples provided within the specification. While the invention has been described with reference to the aforementioned specification, the descriptions and illustrations of the embodiments herein are not meant to be construed in a limiting sense. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. Furthermore, it shall be understood that all aspects of the invention are not limited to the specific depictions, configurations or relative proportions set forth herein which depend upon a variety of conditions and variables. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is therefore contemplated that the invention shall also cover any such alternatives, modifications, variations or equivalents. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A wireless device configured to administer a non-invasive stimulus to a subject, wherein the non-invasive stimulus comprises a gamma frequency and wherein the administration of the non-invasive stimulus induces gamma oscillations within at least one brain region of the subject.

2. The wireless device of claim 1, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

3. The wireless device of claim 1, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

4. The wireless device of claim 1, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

5. The wireless device of claim 1, wherein the gamma frequency comprises about 40 Hz.

6. The wireless device of claim 1, wherein the non-invasive stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

7. The wireless device of claim 1, wherein the non-invasive stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

8. The wireless device of claim 1, wherein the non-invasive stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

9. The wireless device of claim 1, wherein the non-invasive stimulus comprises a pulse frequency of about 35 pulses per second.

10. The wireless device of claim 1, wherein the non-invasive stimulus comprises a visual stimulus, auditory stimulus, a haptic stimulus, or a combination thereof.

11. The wireless device of claim 10, wherein the haptic stimulus comprises a vibration.

12. The wireless device of claim 10, wherein the wireless device comprises a wireless non- invasive visual device configured to administer the visual stimulus.

13. The wireless device of claim 12, wherein the wireless non-invasive visual device comprises wireless glasses.

14. The wireless device of claim 12, wherein the visual stimulus comprises a gamma frequency.

15. The wireless device of claim 14, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

16. The wireless non-invasive visual device of claim 15, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

17. The wireless non-invasive visual device of claim 15, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

18. The wireless non-invasive visual device of claim 15, wherein the gamma frequency comprises about 40 Hz.

19. The wireless non-invasive visual device of claim 12, wherein the visual stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

20. The wireless non-invasive visual device of claim 19, wherein the visual stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

21. The wireless non-invasive visual device of claim 19, wherein the visual stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

22. The wireless non-invasive visual device of claim 19, wherein the visual stimulus comprises a pulse frequency of about 40 pulses per second.

23. The wireless device of claim 10, wherein the wireless device comprises a wireless non- invasive audio device configured to administer the auditory stimulus.

24. The wireless non-invasive audio device of claim 23, wherein the wireless non-invasive audio device comprises wireless headphones.

25. The wireless headphones of claim 24, wherein the wireless headphones comprise wireless over-ear headphones or wireless in-ear headphones.

26. The wireless non-invasive audio device of any one of claims 23-25, wherein the auditory stimulus comprises a gamma frequency.

27. The wireless non-invasive audio device of claim 26, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

28. The wireless non-invasive audio device of claim 26, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

29. The wireless non-invasive audio device of claim 26, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

30. The wireless non-invasive audio device of claim 26, wherein the gamma frequency comprises about 40 Hz.

31. The wireless non-invasive audio device of claim 26, wherein the auditory stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

32. The wireless non-invasive audio device of claim 26, wherein the auditory stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

33. The wireless non-invasive audio device of claim 26, wherein the auditory stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

34. The wireless non-invasive audio device of claim 26, wherein the auditory stimulus comprises a pulse frequency of about 40 pulses per second.

35. The wireless device of claim 10, wherein the wireless device comprises a wireless non- invasive haptic device configured to deliver the haptic stimulus.

36. The wireless non-invasive haptic device of claim 35, wherein the haptic stimulus comprises a vibration.

37. The wireless non-invasive haptic device of claim 36, wherein the vibration comprises a gamma frequency.

38. The wireless non-invasive haptic device of claim 37, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

39. The wireless non-invasive haptic device of claim 37, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

40. The wireless non-invasive haptic device of claim 37, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

41. The wireless non-invasive haptic device of claim 37, wherein the gamma frequency comprises about 40 Hz.

42. The wireless non-invasive haptic device of claim 35, wherein the haptic stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

43. The wireless non-invasive haptic device of claim 42, wherein the haptic stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

44. The wireless non-invasive haptic device of claim 42, wherein the haptic stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

45. The wireless non-invasive haptic device of claim 42, wherein the haptic stimulus comprises a pulse frequency of about 40 pulses per second.

46. A wireless device configured to administer a non-invasive stimulus to a subject, the wireless device comprising: a) a signal emitter, wherein the signal emitter is configured to administer the non- invasive stimulus to the subject based on a signal generated by the wireless device; b) a feedback component; and c) a memory for storing processor executable instructions and at least one processor communicatively connected to the wireless non-invasive audio device and the at least one memory; wherein the non-invasive stimulus comprises a gamma frequency.

47. The wireless device of claim 46, further comprising a microphone.

48. The wireless device of claim 46, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

49. The wireless device of claim 46, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

50. The wireless device of claim 46, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

51. The wireless device of claim 46, wherein the non-invasive stimulus comprises a visual stimulus, auditory stimulus and / or a haptic stimulus.

52. The wireless device of claim 46, wherein the non-invasive stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

53. The wireless device of claim 46, wherein the non-invasive stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

54. The wireless device of claim 46, wherein the non-invasive stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

55. The wireless device of claim 46, wherein the non-invasive stimulus comprises a pulse frequency of about 40 pulses per second.

56. The wireless device of claim 51, wherein the haptic stimulus comprises vibration.

57. The wireless device of claim 51, wherein the wireless device comprises a wireless non- invasive audio device configured to administer the auditory stimulus.

58. The wireless non-invasive audio device of claim 57, wherein the wireless non-invasive audio device comprises wireless headphones.

59. The wireless headphones of claim 58, wherein the wireless headphones comprise wireless over-ear headphones or wireless in-ear headphones.

60. The wireless non-invasive audio device of any one of claims 57-59, wherein the auditory stimulus comprises a gamma frequency.

61. The wireless non-invasive audio device of claim 60, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

62. The wireless non-invasive audio device of claim 60, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

63. The wireless non-invasive audio device of claim 60, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

64. The wireless device of claim 60, wherein the auditory stimulus comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

65. The wireless device of claim 60, wherein the auditory stimulus comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

66. The wireless device of claim 60, wherein the auditory stimulus comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

67. The wireless device of claim 60, wherein the auditory stimulus comprises a pulse frequency of about 40 pulses per second.

68. The wireless non-invasive audio device of any one of claims 57-63, wherein the signal emitter comprises a speaker.

69. The wireless device of claim 56, wherein the wireless device comprises a wireless non- invasive haptic device configured to deliver the vibration.

70. The wireless non-invasive haptic device of claim 69, wherein the vibration comprises a gamma frequency.

71. The wireless non-invasive haptic device of claim 70, wherein the gamma frequency comprises about 30 Hz to about 60 Hz.

72. The wireless non-invasive haptic device of claim 70, wherein the gamma frequency comprises about 40 Hz to about 60 Hz.

73. The wireless non-invasive haptic device of claim 70, wherein the gamma frequency comprises about 35 Hz to about 45 Hz.

74. The wireless non-invasive haptic device of claim 70, wherein the vibration comprises a pulse frequency of about 30 pulses per second to about 60 pulses per second.

75. The wireless non-invasive haptic device of claim 70, wherein the vibration comprises a pulse frequency of about 40 pulses per second to about 60 pulses per second.

76. The wireless non-invasive haptic device of claim 70, wherein the vibration comprises a pulse frequency of about 35 pulses per second to about 45 pulses per second.

77. The wireless non-invasive haptic device of claim 70, wherein the vibration comprises a pulse frequency of about 40 pulses per second.

78. The wireless non-invasive haptic device of any one of claims 69-73, wherein the signal emitter comprises a vibrator.

79. The wireless device of any one of claims 46-78 further comprising: c) a processor configured to receive an indication of a physiological, cognitive, neural, or physical assessment of the subject wearing the wireless device.

80. The wireless device of claim 79, wherein when the processor receives the indication of the physiological, cognitive, neural, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive auditory, or haptic stimulus.

81. The wireless device of claim 79, wherein the physical assessment of the subject comprises ascertaining at least one of the subject's: compliance with proper use and positioning of the system, eye status, alert or sleep status, or environment and surroundings.

82. The wireless device of claim 79, wherein the cognitive assessment of the subject is obtained through questions posed to the subject, activities and tasks performed by the subject in response to a prompt, or behaviors exhibited by the subject.

83. The wireless device of claim 79, wherein the processor further instructs the device to lengthen or shorten the duration of stimulation in response to the indication of the physiological, cognitive, neural, or physical assessment.

84. The wireless device of claim 79, wherein the physical assessment of the subject is performed to determine hearing of the subject.

85. The wireless device of any one of claims 1-84, wherein the device is used to treat, prevent, or mitigate cognitive dysfunction in the subject.

86. The wireless device of claim 79, wherein the indication of the physiological, cognitive, neural, or physical assessment of the subject comprises a biosignal.

87. The wireless device of claim 86, wherein the biosignal comprises an electroencephalography (EEG).

88. The wireless device of any one of the preceding claims, wherein the wireless device is used to treat prevent, or mitigate a disease or condition in a subject in need thereof.

89. The wireless device of claim 88, wherein the disease or condition comprises dementia.

90. The wireless device of claim 89, wherein the dementia comprises Alzheimer’s disease, vascular dementia, Lewy body dementia, Pick's disease, fronto-temporal dementia (FTD), AIDS dementia, age-related cognitive impairments, and age-related memory impairments.

91. The wireless device of claim 88, wherein the disease or condition comprises Parkinson’s disease.

92. A method comprising: a) stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby inducing gamma oscillations in at least one brain region of the subject.

93. The method of claim 92 wherein the gamma oscillations comprise synchronized gamma oscillations.

94. The method of claim 92, wherein the at least one brain region comprises an entorhinal cortex, a hippocampus, a cerebral cortex, a visual association cortex, an auditory association cortex, a cingulate lobe, an amygdala, a thalamic nucleus, a cingulate lobe, a pons, a brainstem, acerebellum, a lateral ventricle, an occipital lobe, a parietal lobe, a temporal lobe, a midbrain, a striatum, a basal ganglia, a globus pallidus, a substantia nigra, or any combination thereof.

95. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby maintaining or reducing a level of tau phosphorylation in at least one brain region of the subject.

96. The method of claim 95, the maintaining or reducing tau phosphorylation including maintaining or reducing punctate localization of phosphorylated tau protein in the at least one brain region of the subject.

97. The method of claim 95, the maintaining or reducing tau phosphorylation including maintaining or reducing cell body localization of phosphorylated tau protein in the auditory cortex of the subject.

98. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby maintaining or improving cognitive function in the subject.

99. The method of claim 98, wherein the maintaining or improving cognitive function comprises maintaining or improving recognition, discrimination, spatial memory, working memory, attention, or a combination thereof.

100. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby maintaining or reducing an amount of amyloid-P(Ap) peptide in at least one brain region of the subject.

101. The method of claim 100, wherein maintaining or reducing an amount of amyloid- P (AP) peptide in at least one brain region comprises reducing production of Ap peptide in the at least one brain region of the subject.

102. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby maintaining or reducing an amount of at least one of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in at least one brain region of the subject.

103. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby maintaining or reducing cleavage of APP into CTFs and NTFs by at least one of P-secretase (BACE1) and y-secretase in at least one brain region of the subject.

104. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby maintaining or reducing a number of endosomes in at least one brain region of the subject.

105. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby promoting clearance of Ap peptide in at least one brain region of the subject.

106. A method comprising: stimulating a subject with the non-invasive stimulus generated by the wireless device of any one of claims 1-91, thereby increasing uptake of Ap peptide by microglia in the at least one brain region of the subject.

107. The method of any one of claims 92-106, wherein the non-invasive stimulus induces a change in microglial cells in at least one brain region of a subject.

108. The method of claim 107, wherein inducing the change in microglial cells in at least one brain region of a subject improves the cognitive function of the subject, or prevents, reduces, or treats cognitive decline in the subject.

109. The method of any one of claims 92-108, wherein the non-invasive stimulus is administered to the subject for about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, or more than about 1 hour per day.

110. The method of any one of claims 92-109, wherein the non-invasive stimulus is administered to the subject at least once, twice, three times, or more than three times per day.

111. The method of any one of claims 92- 110, wherein the subject comprises a mammal.

112. The method of claim 111, wherein the mammal comprises a non-human primate.

113. The method of claim 112, wherein the mammal comprises a human.

114. A system comprising the wireless device of any one of claims 1-91 and further comprising: a) a signal emitter; b) a feedback component; c) at least one memory for storing processor executable instructions; and d) at least one processor communicatively connected to the wireless device and the at least one memory; wherein the system is configured to implement the method of any one of claims 92- 113.

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