Devices and systems for neural, visual, auditory, or haptic 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 stimulus to a subject, wherein the stimulus comprises a gamma frequency. The devices and systems can include visual, auditory, or haptic devices configured to emit a neural, visual, auditory, or haptic stimulus to a subject. In some embodiments, devices, systems, and methods disclosed herein may be useful for the treatment of cognitive dysfunction.

Description

DEVICES AND SYSTEMS FOR NEURAL, VISUAL, AUDITORY, OR HAPTIC STIMULATION AND METHODS OF USING THE SAME CROSS-REFERENCE

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 710,698 filed October 23, 2024, which is incorporated herein by reference for all purposes in its entirety.BACKGROUND

[0002] Neural, visual, oscillation occurs in humans or animals and includes rhythmic or repetitive neural, visual, activity in the central nervous system. Neural, visual, 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, visual, oscillations can be characterized by their frequency, amplitude, and phase. Neural, visual, oscillations can give rise to electrical impulses that form a brainwave. These signal properties can be observed from neural, visual, recordings using time-frequency analysis. System and methods can be employed to synchronize neural, visual, oscillations within a brain region, including the use of devices, systems and methods designed to direct neural, visual, oscillations via non-invasive stimulation. The devices and systems may comprise a visual stimulus emitting device, wireless headphones, wireless earphones, or wireless in-earphones. The haptic devices and systems may comprise wireless bone conduction headphones, wireless bone conduction protheses, or wireless bone conduction hearing aid devices.

[0003] In some embodiments, devices, systems, and methods can include configuring the devices to deliver visual, auditory, or haptic stimulation to treat or mitigate a disease or condition, e.g., dementia or Alzheimer’s disease. In some embodiments, a device comprises a visual module with a translucent lens.SUMMARY

[0004] The present disclosure provides systems, methods, and devices for inducing a gamma oscillation in a brain region of a subject.

[0005] In some aspects, described herein is a device for inducing a gamma oscillation in a brain region of a subject, said device comprising: one or more processors individually or collectively programmed to execute a set of instructions comprising: emitting a visual stimulus; and inducing a gamma oscillation in said brain region of said subject; and a visual module operatively coupled to said one or more processors, wherein said visual module comprises a lens that is not opaque.

[0006] In some embodiments, said visual stimulus comprises a frequency of 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.

[0007] In some embodiments, said visual stimulus comprises a frequency of about 30 pulses per second to about 60 pulses per second, about 30 pulses per second to about 60 pulses per second, about 35 pulses per second to about 45 pulses per second, or about 40 pulses per second.

[0008] In some embodiments, said lens comprises a translucent lens. In some embodiments, said lens comprises a transmittance of about 0% to about 100%.

[0009] In some embodiments, said device further comprises an auditory device or a haptic device operatively coupled to said one or more processors.

[0010] In some embodiments, said auditory device comprises headphones. In some embodiments, said headphones comprise over-ear headphones or in-ear headphones.

[0011] In some embodiments, said auditory device is configured to emit an auditory stimulus.

[0012] In some embodiments, said auditory stimulus comprises a frequency of 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.

[0013] In some embodiments, said auditory stimulus comprises a frequency of about 30 pulses per second to about 60 pulses per second, about 30 pulses per second to about 60 pulses per second, about 35 pulses per second to about 45 pulses per second, or about 40 pulses per second.

[0014] In some embodiments, said haptic device is configured to emit a haptic stimulus. In some embodiments, said haptic stimulus comprises a frequency of 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 some embodiments, said haptic stimulus comprises a vibration.

[0015] In some embodiments, said haptic stimulus comprises a frequency of about 30 pulses per second to about 60 pulses per second, about 30 pulses per second to about 60 pulses per second, about 35 pulses per second to about 45 pulses per second, or about 40 pulses per second.

[0016] In some embodiments, said device further comprises a signal emitter.

[0017] In some embodiments, said signal emitter is configured to administer said visual, auditory, or haptic stimulus to said subject based on a signal generated by said device.

[0018] In some embodiments, further comprises a feedback component.

[0019] In some embodiments, said feedback component is configured to receive an indication of a physiological, cognitive, neural, or physical assessment of said subject wearing said device and when said feedback component receives said indication said feedback component instructs said stimulus emitter to emit said visual, auditory, or haptic stimulus.

[0020] In some embodiments, said device further comprises a memory configured to store said instructions.

[0021] In some embodiments, said memory is operatively connected to said one or more processors.

[0022] In some embodiments, said device further comprises a microphone.

[0023] In some embodiments, said signal emitter comprises a speaker.

[0024] In some embodiments, said instructions further comprise receiving an indication of a physiological, cognitive, neural, or physical assessment of said subject wearing said device.

[0025] In some embodiments, subsequent to said receiving said indication, said instructions further comprise instructing said stimulus emitter to emit said visual, auditory, or haptic stimulus.

[0026] In some embodiments, said physical assessment of said subject comprises ascertaining at least one of said subject's: compliance with proper use and positioning of said device, eye status, alert or sleep status, or environment and surroundings.

[0027] In some embodiments, said cognitive assessment of said subject is obtained through questions posed to said subject, activities and tasks performed by said subject in response to a prompt, or behaviors exhibited by said subject.

[0028] In some embodiments, said instructions further comprise modulating a duration of said stimulation in response to said indication of said physiological, cognitive, neural, or physical assessment.

[0029] In some embodiments, said modulating a duration comprises lengthening a duration of said stimulation.

[0030] In some embodiments, said modulating a duration comprises shortening a duration of said stimulation.

[0031] In some embodiments, said physical assessment of said subject is performed to determine vision or hearing of said subject.

[0032] In some embodiments, said device is used to treat, prevent, or mitigate cognitive dysfunction in said subject.

[0033] In some embodiments, said indication of said physiological, cognitive, neural, or physical assessment of said subject comprises a biosignal.

[0034] In some embodiments, said biosignal comprises an electroencephalography (EEG).

[0035] In some embodiments, said device is used to treat prevent, or mitigate a disease or condition in a subject in need thereof.

[0036] In some embodiments, said disease or condition comprises dementia.

[0037] In some embodiments, said 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.

[0038] In some embodiments, said disease or condition comprises Parkinson’s disease.

[0039] In some aspects, described herein is a method comprising: stimulating a subject with a visual, auditory, or haptic stimulus generated by a device as disclosed herein, thereby inducing a gamma oscillation in a brain region of said subject.

[0040] In some embodiments, said gamma oscillation comprises synchronized gamma oscillations.

[0041] In some embodiments, said 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.

[0042] In some aspects, described herein is a method comprising: (a) using a device as disclosed herein to stimulate a subject with a visual, auditory, or haptic stimulus and (b) maintaining or reducing a level of tau phosphorylation in a brain region of said subject.

[0043] In some embodiments, said maintaining or reducing tau phosphorylation comprises maintaining or reducing punctate localization of phosphorylated tau protein in said brain region of said subject.

[0044] In some embodiments, said maintaining or reducing tau phosphorylation in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0045] In some embodiments, said maintaining or reducing tau phosphorylation in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0046] In some aspects, described herein is a method comprising: a) stimulating a subject with a visual, auditory, or haptic stimulus generated by a device as disclosed herein and (b) thereby maintaining or improving cognitive function in said subject.

[0047] In some embodiments, said maintaining or improving cognitive function comprises maintaining or improving recognition, discrimination, spatial memory, working memory, attention, or a combination thereof.

[0048] In some embodiments, said maintaining or improving cognitive function is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0049] In some embodiments, said maintaining or improving cognitive function is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0050] In some aspects, described herein is a method comprising: a) stimulating a subject with a visual, auditory, and / or haptic stimulus generated by a device as disclosed herein and (b) thereby maintaining or reducing an amount of amyloid-P (AP) peptide in said brain region of said subject.

[0051] In some embodiments, said maintaining or reducing said amount of amyloid-P (AP) peptide in said brain region comprises reducing a production of Ap peptide in said brain region of said subject.

[0052] In some embodiments, said maintaining or reducing an amount of amyloid-P (AP) peptide in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0053] In some embodiments, said maintaining or reducing an amount of amyloid-P (AP) peptide in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0054] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, or haptic stimulus generated by a device as disclosed herein, and (b) thereby maintaining or reducing an amount of C-terminal fragments (CTFs) of amyloid precursor protein (APP) in said brain region of said subject.

[0055] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, or haptic stimulus generated by a device as disclosed herein, and (b) thereby maintaining or reducing an amount of N-terminal fragments (NTFs) of amyloid precursor protein (APP) in said brain region of said subject.

[0056] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, or haptic stimulus generated by a device as disclosed herein, and (b) thereby maintaining or reducing cleavage of APP into CTFs and NTFs by P-secretase (BACE1) in said brain region of said subject.

[0057] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, or haptic stimulus generated by a device as disclosed herein, and (b) thereby maintaining or reducing cleavage of APP into CTFs and NTFs by y-secretase in said brain region of said subject.

[0058] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, and / or haptic stimulus generated by a device as disclosed herein, and (b) thereby maintaining or reducing a number of endosomes in said brain region of said subject.

[0059] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, and / or haptic stimulus generated by a device as disclosed herein, and (b) thereby promoting clearance of Ap peptide in said brain region of said subject.

[0060] In some aspects, described herein is a method comprising: (a) stimulating a subject with a visual, auditory, and / or haptic stimulus generated by a device as disclosed herein, and (b) thereby increasing uptake of Ap peptide by microglia in said brain region of said subject.

[0061] In some embodiments, said maintaining or reducing an amount of C-terminal fragments (CTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0062] In some embodiments, said maintaining or reducing an amount of C-terminal fragments (CTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0063] In some embodiments, said maintaining or reducing an amount of N-terminal fragments (NTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0064] In some embodiments, said maintaining or reducing an amount of N-terminal fragments (NTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0065] In some embodiments, said maintaining or reducing cleavage of APP into CTFs and NTFs by P-secretase (BACE1) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0066] In some embodiments, said maintaining or reducing cleavage of APP into CTFs and NTFs by P-secretase (BACE1) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0067] In some embodiments, said maintaining or reducing cleavage of APP into CTFs and NTFs by y-secretase in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0068] In some embodiments, said maintaining or reducing cleavage of APP into CTFs and NTFs by y-secretase in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0069] In some embodiments, said maintaining or reducing a number of endosomes in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0070] In some embodiments, said maintaining or reducing a number of endosomes in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0071] In some embodiments, said promoting clearance of Ap peptide in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0072] In some embodiments, said promoting clearance of Ap peptide in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0073] In some embodiments, said increasing uptake of Ap peptide by microglia in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0074] In some embodiments, said increasing uptake of Ap peptide by microglia in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0075] In some embodiments, said visual, auditory, or haptic stimulus induces a change in microglial cells in a brain region of a subject.

[0076] In some embodiments, inducing said change in microglial cells in said brain region of said subject improves cognitive function of said subject, or prevents, reduces, or treats cognitive decline in said subject.

[0077] In some embodiments, inducing said change in microglial cells in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

[0078] In some embodiments, inducing said change in microglial cells in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

[0079] In some embodiments, said visual, auditory, or haptic stimulus is administered to said subject for about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, or more than about 1 hour per day.

[0080] In some embodiments, said visual, auditory, or haptic stimulus is administered to said subject at least once, twice, three times, or more than three times per day.

[0081] In some embodiments, said subject comprises a mammal, said mammal comprises a nonhuman primate, said mammal comprises a human.

[0082] In some aspects, a method as disclosed herein further comprises a) identifying an activity being performed by a subject; and b) administering said visual, auditory, or haptic stimulus to said subject during said activity to induce a gamma oscillation in a brain region of said subject.INCORPORATION BY REFERENCE

[0083] 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 or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0084] 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:

[0085] FIG. 1 shows a computer system that is programmed or otherwise configured to implement methods provided herein.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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).

[0092] 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.

[0093] FIG. 9 provides a front view of an embodiment of an open view visual stimulation device provided herein. As shown in FIG. 9, the device comprises glasses, with foldable arms and transparent lenses. An off-ear speaker is built into the arms of the glasses, proximal to the temple tips.

[0094] FIG. 10 provides a rear-facing view of an open view visual stimulation device provided herein. As shown in FIG. 10, the device comprises glasses, with foldable arms and transparent lenses. An off-ear speaker is built into the arms of the glasses, proximal to the temple tips.

[0095] FIG. 11 depicts an embodiment of the open view visual stimulation device as a single headset device with integrated stimulation eyeglasses and stimulation headphones having user control hardware structurally and functionally integrated into the device. The external housing ofa headphone speaker includes a buton control for turning on or off the emission of a stimulus from the device. The button user control hardware can have the share of a circle, a rhombus, a triangle, a parallelogram, or any other known regular or irregular shape.

[0096] FIG. 12 depicts an embodiment of the open view visual stimulation device as a single headset device with integrated stimulation eyeglasses and stimulation headphones having user control hardware structurally and functionally integrated into the device. The frame of the eyeglasses houses a button switch control for adjusting the brightness of a visual stimulus. The button switch control integrated in the frame has functions to: (1) increase light intensity of the visual stimulus, decrease light intensity of the visual stimulus, (3) turn on or activate emission of the visual stimulus, and (4) turn off or stop emission of the visual stimulus. The external housing of a headphone speaker includes a horizontal button switch control for adjusting the volume of an auditory stimulus emitted by the device. The button switch control has a position setting to: (1) increase the volume of the auditory stimulus, (2) decrease volume of the auditory stimulus, (3) turn on or activate emission of the auditory stimulus, and (4) turn off or stop emission of the auditory stimulus. Any of the button switch user control hardware can be oriented vertically or horizontally.

[0097] FIG. 13 depicts an embodiment of the open view visual stimulation device as a single headset device with integrated stimulation eyeglasses and stimulation headphones having user control hardware structurally and functionally integrated into the device as described in FIG. 12. This embodiment of the single headset device further includes a detachable headband, which can be inserted into the housing of each headphone speaker. The detachable headband can be made of a malleable or flexible material. The headband can also comprise a synthetic material or a natural material. The detachable headband has an elongated shape and is configured to have an adjustable length to achieve a secure fit on a user’s head. A “male’ connecting member is affixed to each end of the detachable headband and is configured to fasten to a “female” connecting member that is housed within the slit on each headphone housing. As depicted on the right, the material of the headband can be affixed or joined by any structural, physical, or chemical means to a second material as a means to achieve greater user comfort or accommodate any aspect of user wearability (e.g., head size, head shape). The second material may be a soft fabric or material.

[0098] FIG. 14 depicts another embodiment of the open view visual stimulation device as a single headset device with integrated stimulation eyeglasses and stimulation headphones having user control hardware structurally and functionally integrated into the single headset device as described in FIG. 12. The detachable headband can be made of a rigid or semi-rigid material,such as a metal or plastic, to limit malleability and to substantially preserve the general shape and arch of the detachable headband of the single headset device, regardless of whether a user is wearing the single headset device. The headband can also comprise a synthetic material or a natural material. As depicted, the detachable headband is configured to have an adjustable length to achieve a secure fit on a user’s head and to position the headphones over each ear of the user. As depicted, each end of the primary rigid material of the detachable headband is molded into a connecting member, such as a “male” or “female” connecting member,” for the purpose of fastening to a complementary connecting member that is housed on each headphone housing (e.g., a “female” or “male” connecting member). In some cases, the connecting members at each end of the detachable headband can be made of a metal that magnetically connects to the housing of or a component within each headphone. As depicted on the right, the material of the headband can be affixed or joined by any structural, physical, or chemical means to a second material as a means to achieve greater user comfort or accommodate any aspect of user wearability (e.g., head size, head shape). The second material may be a soft fabric or material. Additionally, the single headset device can have vertically oriented user button, switch, or button switch controllers to enhance the user experience.

[0099] FIG. 15 depicts an embodiment of the open view visual stimulation device, including the single headset device described above, a hand-held controller, and a charging station that can recharge the rechargeable battery of the single headset device for continued use of the open view visual stimulation device. The charging station can be powered via a direct wired connection to an electrical power supply. The hand-held controller can transmit wireless commands to the single headset device to activate or de-activate emission of the visual stimulation or the auditory stimulation from the eyeglasses or headphones of the single headset device. The hand-held controller can also adjust the brightness of the light stimulus, or the volume of the sound stimulus emitted from the single headset device.

[0100] FIG. 16 depicts another embodiment of the open view visual stimulation device, including the single headset device described above, a hand-held controller, and a charging station that can recharge the rechargeable battery of the single headset device for continued use of the open view visual stimulation device. As previously described, the charging station can be powered via a direct wired connection to an electrical power supply. The hand-held controller can transmit wireless commands to the single headset device to activate or de-activate emission of the visual stimulation or the auditory stimulation from the eyeglasses or headphones of the single headset device. The hand-held controller can also adjust the brightness of the light stimulus, or the volume of the sound stimulus emitted from the single headset device viaswitches, buttons, or button switch mechanisms. The hand-held controller can also be equipped with a digital display to indicate the assigned user settings (e.g., brightness, volume, stimulus emission activation, stimulus emission de-activation, treatment duration, time remaining of a current treatment session). The digital display can be configured to display settings or information as numeric and / or alphabetic characters (as shown), as a percentage of a maximal value, or as a digital scale indicating an adjustable row of digital dots or shapes or, alternatively, an adjustable length of a digital line.DETAILED DESCRIPTION

[0101] 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.

[0102] Devices, systems, and methods of the present disclosure are directed to 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, visual, auditory, or haptic input. The neural, visual, auditory, or haptic stimulation can adjust, control, or otherwise manage the frequency of the neural, visual, 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 or Alzheimer's Disease.

[0103] External signals, e.g., stimuli, such as visual signals, audio signals or haptic signals, can be observed or perceived by the brain. The brain can observe or perceive the signals. The brain, in response to perceiving the 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 visual or auditory cortex. For example, visual signals having a predetermined modulation frequency and perceived by the visual 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 signals. Thus,devices, systems, and methods of the present disclosure can induce brainwave oscillations via non-invasive stimulation.

[0104] Devices, systems, and methods of the present disclosure can induce brainwave oscillations using a non-invasive external stimulus, such as a visual, auditory, or haptic stimulus, including stimuli such as visual, visual, audio, or haptic signals forming visual, acoustic, 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, 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, or haptic vibratory pulses can adjust to synchronize with frequency of the acoustic or haptic vibratory pulses.

[0105] The present disclosure provides devices, and systems for stimulation via visual, auditory, or haptic stimulation. The visual devices may comprise a visual module. The visual module may comprise a lens that is not opaque, e.g., a translucent lens. In some embodiments, a device as disclosed herein provides a visual stimulus to a subject using a visual module with an opaque or transparent lens (open view visual stimulation device). 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, or wireless bone conduction hearing aid devices.

[0106] The devices or systems may be configured to emit a neural, visual, auditory, or haptic stimulus. In some embodiments, the stimulus comprises a gamma frequency. In some embodiments, 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. In some embodiments, the stimulus comprises a pulse frequency. In some embodiments, the pulse frequency comprises a gamma frequency. In some embodiments, the gamma frequency is about 20 pulses per second to about 140 pulses per second, about 30 pulses per second to about 60 pulses per second, about 40 pulses per second to about 60 pulses per second, about 35 pulses per second to about 45 pulses per second, or about 40 pulses per second.Devices

[0107] In some embodiments, a device as disclosed herein includes any device that can deliver a visual, auditory, or haptic stimulus to a subject.

[0108] Systems and devices for open view visual stimulation as disclosed herein may be administered with any visual, auditory, or haptic device as disclosed herein. In someembodiments, provided herein are systems for administering a stimulus to a subject via open view visual stimulation, auditory stimulation, or haptic stimulation.

[0109] In some embodiments, a system for open view visual stimulation, auditory stimulation, or haptic stimulation can include one or more signal emitters.

[0110] In some embodiments, a system as disclosed herein comprises a device comprising an open view visual stimulation device as disclosed herein, an audio device as disclosed herein, a haptic device as disclosed herein, or a combination thereof.[OHl] In some embodiments, a system comprises a combination of an open view visual stimulation device as disclosed herein, an audio device as disclosed herein, a haptic device as disclosed herein, wherein the system comprises a single integrated headset device configured to be placed on the head of a subject. In some embodiments, an open view visual stimulation device comprises a device as shown and described in FIG. 9 - FIG. 16.

[0112] In some embodiments, a system comprises a combination of an open view visual stimulation device as disclosed herein, an audio device as disclosed herein, or a haptic device as disclosed herein, wherein the system is configured to implement a method as disclosed herein.

[0113] In some embodiments, provided herein are systems for administering a non-invasive stimulus to a subject via open view visual stimulation, auditory stimulation, or haptic stimulation.(a) Visual Devices

[0114] In some embodiments, the stimulus is delivered by a device. In some embodiments, said device comprises a pair of glasses worn by the subject with a visual module providing a visual stimulus. The visual module may comprise a lens, e.g., a translucent lens. In some embodiments, a device as disclosed herein provides a visual stimulus to a subject using a visual module with an opaque or transparent lens (open view visual stimulation device). In some embodiments, a device comprises an open view visual stimulation device.

[0115] In some embodiments, an open view visual stimulation device 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.

[0116] 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.

[0117] 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.

[0118] 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. The visual 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.

[0119] 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 30 pulses / sec to about 100 pulses / sec, from about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec.

[0120] 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 500nm to about 750 nm, from about 500 nm to about 650 nm, or from about 650 nm to about 850 nm.

[0121] In some embodiments, the visual stimulus comprises a frequency configured to modulate a neural response, such as 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.

[0122] In some embodiments, an open view visual stimulation device includes a visual module. In some embodiments, the visual module is operatively coupled to one or more processors. In some embodiments, the visual module comprises a lens. In some embodiments, the visual module comprises eyeglasses.

[0123] In some embodiments, the eyeglasses 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%.

[0124] Systems or devices as described herein may comprise an open view visual stimulation device. In some embodiments, an open view visual stimulation device comprises a frame that can be designed and constructed to be placed or positioned on a person’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, an open view visual stimulation device comprises a visual module operatively connected to one or more processors that can be configured on the frame to project light pulses towards the person’s eyes during these various positions. In some embodiments, the visual module 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 bythe 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 open view visual stimulation device can include or hold a lens. In some embodiments, the open view visual stimulation device 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.

[0125] One or more visual modules can be positioned on or adjacent to the eye wire, lens or other solid material, or bridge. For example, a visual module 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 module can be positioned at a corner of the eye wire, such as a corner of the eye wire coupled to the temple, in order to transmit light pulses towards a peripheral field.

[0126] The open view visual stimulation device can perform visual stimulation via a single eye or both eyes. For example, the open view visual stimulation device can direct light pulses to a single eye or both eyes. The visual signaling component may include a single visual module 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 module from entering a second eye. The visual signaling component can block or prevent light from entering the second eye during the brain stimulation process.

[0127] In some embodiments, the visual module can alternatively transmit or direct light pulses to the first eye and the second eye. For example, the visual module can direct light pulses to the first eye for a first time interval. The visual module 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.

[0128] 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.

[0129] In some embodiments, an open view visual stimulation device can include a tablet computing device or other computing device having a display screen.

[0130] In some embodiments, the visual module displays a pattern of light. The light can flicker, toggle or switch between two or more patterns to generate flashes of light or light pulses. Patternscan 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.

[0131] In some embodiments, the visual module 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 module 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.

[0132] 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 VI that includes neurons that respond strongly to contrast edges and helps segment the image into separate objects.

[0133] Thus, the visual module 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 module 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 module can generate images of faces flickering to target this area of the subject’s brain. In another example, the visual module can generate images that include edges orline drawings to stimulate neurons of the primary visual cortex that respond strongly to contrast edges.

[0134] The open view visual stimulation device can include, access, interface with, or otherwise communicate with at least one visual module. The visual module 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. The visual module can automatically vary a parameter of the visual signal based on profile information or feedback. The visual module can receive the feedback information from a feedback monitor. The visual module can receive instructions or information from a side effects management module. The visual module can receive profile information from a profile manager.

[0135] The open view visual stimulation device 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.

[0136] The open view visual stimulation device 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 open view visual brain stimulation. 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.

[0137] The open view visual stimulation device 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 module 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.

[0138] The side effects management module can automatically instruct a component of the open view visual stimulation device to alter or change a parameter of the visual signal. The side effectsmanagement module can be configured with predetermined thresholds to reduce side effects. For example, the side effects 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).

[0139] 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.

[0140] 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.

[0141] The open view visual stimulation device 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 corneo-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.

[0142] In some embodiments, a computing device 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 module.

[0143] The feedback sensor can interact with or communicate with open view visual stimulation device. For example, the feedback sensor can provide detected feedback information or data to the open view visual stimulation device. The feedback sensor can provide data to the open view visual stimulation device in real-time, for example as the feedback sensor detects or senses orinformation. The feedback sensor can provide the feedback information to the open view visual stimulation device 105 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 open view visual stimulation device 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 open view visual stimulation device can ping, query, or send a request to the feedback sensor 605 for information, and the feedback sensor can provide the feedback information in response to the ping, request, or query.

[0144] Feedback sensors can include, for example, EEG probes that detect brain wave activity.

[0145] 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 open view visual stimulation device 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.

[0146] 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.

[0147] 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.

[0148] 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 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 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.

[0149] 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.

[0150] 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.

[0151] In some embodiments, the open view visual stimulation device can include a filter to control the spectral range of the light emitted from the visual module. In some embodiments, the visual module 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 filteringcomponent can receive instructions from the unwanted frequency filtering module to block or attenuate one or more frequencies of light.

[0152] 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.

[0153] 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 may 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.

[0154] Systems and devices as disclosed herein may comprise one or more processors individually or collectively programmed to execute a set of instructions. Systems and devices as disclosed herein may further comprise a memory configured to store the set of instructions. In some embodiments, an open view visual stimulation device as described herein includes or is operatively coupled to at least one memory for storing processor executable instructions. In some embodiments, an open view visual stimulation device as described herein includes or is operatively coupled to one or more processors communicatively connected to the visual module of the open view visual stimulation device. In some embodiments, an open view visual stimulation device also includes at least one memory for storing processor executable instructions and at least one processor communicatively connected to the visual module of the open view visual stimulation device and the at least one memory. The one or more processors may be individually or collectively be programmed to execute a set of instructions comprising instructing the open view visual stimulation device to emit any stimulus as described herein. Upon execution of the processor executable instructions, the at least one processor may control the open view visual stimulation device such that device emits the visual stimulus at a frequency that activates neural, visual, oscillations, e.g., gamma oscillations, in a brain region of the subject corresponding to the visual frequency generated by the open view visual stimulation device. In some embodiments, the at least one processor may control the open view visual stimulationdevice such that the device actuates the visual stimulus at the frequency that activates neural, visual, oscillations, e.g., gamma oscillations, in at least one of the visual cortex at the frequency corresponding to the visual frequency generated by the open view visual stimulation device.

[0155] In some embodiments, the open view visual stimulation device includes a data interface that enables data communication between the open view visual stimulation 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 open view visual stimulation 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 visual stimulus at predetermined frequencies and receive control settings for the open view visual stimulation 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 open view visual stimulation device. In other embodiments, communication is a one-way interface with data being forwarded from the open view visual stimulation 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 audio device or be used with a control device that may be a separate device or be integrated into the open view visual stimulation device or be any other suitable device.

[0156] In some embodiments, the processor is configured to receive an indication of a physiological, cognitive, neural, visual, or physical assessment of the subject wearing the open view visual stimulation device. In some embodiments, when the processor receives the indication of the physiological, cognitive, neural, visual, or physical assessment of the subject, the processor instructs the visual module to emit the visual stimulus. 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, the indication of the physiological, cognitive, neural, visual, or physical assessment of the subject comprises a biosignal. In some embodiments, the biosignal comprises an electroencephalography (EEG).

[0157] 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.

[0158] In some embodiments, an open view visual stimulation device as disclosed herein is provided with 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 embodiments, the computer systems are programmed to implement the function of an open view visual stimulation device, such as implementing a visual stimulus delivered to a subject by the open view visual stimulation device as described herein.(b) Audio devices

[0159] Systems or devices as described herein may comprise or be coupled to an audio device. By way of example, an audio device may comprise headphones worn by a subject. In some embodiments, the headphones may be worn about the head of a subject. The headphones may comprise wireless over-ear headphones or wireless in-ear headphones suitable for delivering an auditory gamma stimulus to the subject.

[0160] 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.

[0161] 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.

[0162] 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 noiseas 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.

[0163] In some embodiments, an audio device is configured to generate an auditory stimulus such as an audio tone, a beep, a click, or a similar audio stimulus. In some embodiments, the 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.

[0164] In some embodiments, the auditory stimulus comprises one or more acoustic waves. In some embodiments, the sound comprises an ultrasound or an infrasound. In some embodiments, the sound comprises a tone or frequency perceptible to the subject. In some embodiments, the sound comprises a tone or frequency imperceptible to the subject. In some embodiments, the sound comprises an acoustic frequency from about 0 Hz to about 50 kHz. In some embodiments, the sound comprises an acoustic frequency from about 20 Hz to about 20 kHz. In some embodiments, the sound comprises an acoustic frequency from about 8 Hz to about 12 kHz. In some embodiments, the sound comprises an acoustic frequency of 10 kHz.

[0165] In some embodiments, the dynamic sound comprises a tone or acoustic frequency perceptible to the subject. In some embodiments, the dynamic sound comprises a tone or acoustic frequency imperceptible to the subject. In some embodiments, the dynamic sound comprises an acoustic frequency from about 20 Hz to about 20 kHz. In some embodiments, the auditory stimulus comprises an acoustic frequency capable of modulating a gamma waveform in the subject. In some embodiments, 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.

[0166] The 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 ofabout 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.

[0167] In some embodiments, the auditory stimulus comprises one or more sound waves. In some embodiments, the auditory stimulus is perceptible to the subject. In some embodiments, the auditory stimulus is imperceptible to the subject. 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 auditory 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 auditory stimulus comprises a frequency of about 40 pulses / sec. In some cases, the auditory stimulus comprises a gamma frequency. A gamma frequency can comprise an auditory stimulus frequency of from about 30 pulses / sec to about 100 pulses / sec, from about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec.

[0168] In some embodiments, the auditory stimulus comprises a frequency configured to modulate a neural response, such as 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.

[0169] In some embodiments, a device as described herein comprises a signal emitter. In some embodiments, an 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 an auditory stimulus such as the audio tone, beep, or click disclosed herein.

[0170] 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.

[0171] 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.

[0172] In some embodiments, 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.

[0173] In some embodiments, the 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 an 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 an auditory stimulus.

[0174] 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 embodiments, 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.

[0175] In some embodiments, an audio device comprises one or more feedback components. The feedback component can include or interface with the microphone to obtain, identify, or receivesound. The feedback component can obtain ambient noise. The feedback component can obtain sound from the speakers to facilitate the audio device adjusting a characteristic of the 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.

[0176] Systems and devices as disclosed herein, including audio devices, may comprise one or more processors individually or collectively programmed to execute a set of instructions.Systems and devices as disclosed herein may further comprise a memory configured to store the set of instructions. In some embodiments, an open view visual stimulation device as described herein includes or is operatively coupled to and at least one or more processors communicatively connected to the audio device of the open view visual stimulation device. In some embodiments, an audio device also includes or is operatively coupled to at least one memory for storing processor executable instructions and at least one processor communicatively connected to the audio device and the at least one memory. The one or more processors may be individually or collectively be programmed to execute a set of instructions comprising instructing the open view visual stimulation device to emit any stimulus as described herein. Upon execution of the processor executable instructions, the at least one processor may control the audio device such that device emits the auditory stimulus at a frequency that activates neural, visual, oscillations, e.g., gamma oscillations, in a brain region of the subject corresponding to the audio frequency generated by the audio device. In some embodiments, the at least one processor may control the audio device such that the device actuates the auditory stimulus at the frequency that activates neural, visual, 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 audio device.

[0177] In some embodiments, the audio device includes a data interface that enables data communication between the 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 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 an auditory stimulus at predetermined frequencies and receive control settings for the 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 audio device. In other embodiments, communication is a one-way interfacewith data being forwarded from the 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 audio device or be used with a control device that may be a separate device or be integrated into the audio device or be any other suitable device.

[0178] In some embodiments, the processor is configured to receive an indication of a physiological, cognitive, neural, visual, or physical assessment of the subject wearing the audio device. In some embodiments, when the processor receives the indication of the physiological, cognitive, neural, visual, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive auditory stimulus. 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, the indication of the physiological, cognitive, neural, visual, or physical assessment of the subject comprises a biosignal. In some embodiments, the biosignal comprises an electroencephalography (EEG).

[0179] 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.

[0180] In some embodiments, an audio device as disclosed herein is provided with 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 embodiments, the computer systems are programmed to implement the function of an audio device, such as implementing an auditory stimulus delivered to a subject by the audio device as described herein.(c) Haptic Devices

[0181] Systems and devices as described herein may include or be operatively coupled to one or more haptic devices. 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 theoval 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 embodiments, such as in damaged or dysfunctional hearing, this process is disrupted. A 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 embodiments, a haptic device can improve hearing perception, such as in damaged or dysfunctional hearing and can be useful in activating neural, visual, oscillations, e.g., gamma oscillations, in a brain region of a subject corresponding to the haptic frequency generated by the haptic device.

[0182] By way of example, a 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 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.

[0183] 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.

[0184] In some embodiments, the haptic device may include an implanted bone conduction prosthesis, or a bone conduction hearing aid device.

[0185] Devices or systems as described herein may be configured to emit a haptic stimulus. Devices or systems as described herein may be comprise a haptic device. In some embodiments, a haptic device is configured to generate a haptic stimulus such as a vibration, or a similar hapticstimulus. In some embodiments, the haptic stimulus can include any means that induces the perception of vibration through touch. In some embodiments, a haptic stimulus can be any stimulus that activates the somatosensory system.

[0186] In some embodiments, the frequency of the haptic stimulus comprises a haptic stimulus of 1 Hertz (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.

[0187] In some embodiments, the 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.

[0188] 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 haptic 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 haptic stimulus comprises a frequency of about 40 pulses / sec. In some cases, the haptic stimulus comprises a gamma frequency. A gamma frequency can comprise a haptic stimulus frequency of from about 30 pulses / sec to about 100 pulses / sec, from about 35 pulses / sec to about 45 pulses / sec, or about 40 pulses / sec.

[0189] In some embodiments, the haptic stimulus comprises a frequency configured to modulate a neural response, such as 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 awaveform 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.

[0190] In some embodiments, a 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.

[0191] In some embodiments, the 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 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 haptic stimulus.

[0192] 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 embodiments, 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.

[0193] In some embodiments, a 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 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.

[0194] Systems and devices as disclosed herein, including haptic devices, may comprise one or more processors individually or collectively programmed to execute a set of instructions.Systems and devices as disclosed herein may further comprise a memory configured to store the set of instructions. In some embodiments, an open view visual stimulation device as described herein includes or is operatively coupled to and at least one or more processors communicatively connected to the haptic device of the open view visual stimulation device. In some embodiments, a haptic device also includes or is operatively couple to at least one memory for storing processor executable instructions and at least one processor communicatively connected to the haptic device and the at least one memory. The one or more processors may be individually or collectively be programmed to execute a set of instructions comprising instructing the open view visual stimulation device to emit any stimulus as described herein. Upon execution of the processor executable instructions, the at least one processor may control the haptic device such that device emits the haptic stimulus at a frequency that activates neural, visual, oscillations, e.g., gamma oscillations, in a brain region of the subject corresponding to the haptic frequency generated by the haptic device. In some embodiments, the at least one processor may control the haptic device such that the device actuates the haptic stimulus at the frequency that activates neural, visual, 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 haptic device.

[0195] In some embodiments, the processor is configured to receive an indication of a physiological, cognitive, neural, visual, or physical assessment of the subject wearing the haptic device. In some embodiments, when the processor receives the indication of the physiological, cognitive, neural, visual, or physical assessment of the subject, the processor instructs the stimulus emitter to emit the non-invasive auditory, or haptic stimulus. 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, the indication of the physiological, cognitive, neural, visual, or physical assessment of the subject comprises a biosignal. In some embodiments, the biosignal comprises an electroencephalography (EEG).

[0196] 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.

[0197] In some embodiments, a haptic device as disclosed herein is provided with 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 embodiments, the computer systems are programmed to implement the function of a haptic device, such as implementing an auditory stimulus delivered to a subject by the haptic device as described herein.(d) Computing Devices and Systems

[0198] The present disclosure provides computer systems that are 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.

[0199] 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 a plurality 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 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 or extranet, or an intranet or extranet that is in communication with the Internet. The network 130 In some embodiments is a telecommunication 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 embodiments 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.

[0200] 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.

[0201] 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 embodiments, the circuit is an application specific integrated circuit (ASIC).

[0202] 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 embodiments 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.

[0203] 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.

[0204] 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 embodiments, 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.

[0205] 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.

[0206] 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 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.

[0207] 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., as 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 or data. Many of these forms ofcomputer readable media may be involved in carrying one or more sequences of one or more instructions to a processor for execution.

[0208] 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.

[0209] 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.(e) Methods of Using the Devices or Systems

[0210] In some embodiments, methods of using a device or system as disclosed herein are provided below.

[0211] In some embodiments, the method comprises administering to a subject a visual, auditory, or haptic stimulus generated by a device or system as disclosed herein. In some embodiments, the non- stimulation induces neural, visual, oscillations in a brain region of the subject, wherein the frequency of the induced neural, visual, oscillations correspond to the frequency of the haptic stimulus that is administered to the subject.

[0212] In some embodiments, the stimulus is administered at a frequency of 1 Hertz (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 embodiments, the stimulus is administered at a pulse frequency of 1 pulse per second, 2 pulses per second, 5 pulses per second, 10 pulses per second, 20 pulses per second, 25 pulses per second, 30 pulses per second, 31 pulses per second, 32 pulses per second, 33 pulses per second, 34 pulses per second, 35 pulses per second, 36 pulses per second, 37 pulses per second, 38 pulses per second, 39 pulses per second, 40 pulses per second, 41 pulses per second, 42 pulses per second, 43 pulses per second, 44 pulses per second, 45 pulses per second, 46 pulses per second, 47 pulses per second, 48 pulses per second, 49 pulses per second, 50 pulses per second, 60 pulses per second, 70 pulses per second, 80 pulses per second, 90 pulses per second, 100 pulses per second, 150 pulses per second, 200 pulses per second, 250 pulses per second, 300 pulses per second, 400 pulses per second, 500 pulses per second, 1000 pulses per second, 2000 pulses per second, 3000 pulses per second, 4,000 pulses per second, 5000 pulses per second, 6,000 pulses per second, 7,000 pulses per second, 8,000 pulses per second, 9,000 pulses per second, or 10,000 pulses per second.

[0214] In some embodiments, the 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 some embodiments, the stimulus is administered at a pulse frequency of about 20 pulses per second to about 140 pulses per second, about 30 pulses per second to about 60 pulses per second, about 40 pulses per second to about 60 pulses per second, about 35 pulses per second to about 45 pulses per second, or about 40 pulses per second. In some embodiments, the stimulus is administered at a gamma frequency. In some embodiments, administration of the gamma frequency results in the induction of synchronized gamma oscillations within a brain region of the subject.(i) Stimulus Exposure, Session duration, Session frequency, and Regimen Duration

[0215] In some embodiments, administering the stimulus comprises a stimulus exposure. In some embodiments, the stimulus exposure comprises a session duration, a session frequency, a regimen duration, or a combination thereof. In some embodiments, the stimulus exposure may comprise more than one regimen duration. In some embodiments, administering may be performed continuously for a session duration. In some embodiments, the session duration may be between 10 minutes and 2 hours. In some embodiments, 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 embodiments, 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 embodiments, the session duration may be at least 1, 2, 3, 4, 5, 6, or 7 days. In some embodiments, 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 embodiments, 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 embodiments, the session duration may be at most 1, 2, 3, 4, 5, 6, or 7 days.

[0216] In some embodiments, 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 embodiments, 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 embodiments, 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 embodiments, 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 300times, 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.

[0217] 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 embodiments, the regimen duration comprises at least one day, at least one week, at least one month, at least 3 months, at least 4 months, 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 embodiments, the regimen duration comprises the reminder of the life expectancy of the subject. In some embodiments, the regimen duration comprises the remainder of the subject’s life.

[0218] In some embodiments, the regimen duration and session frequency comprises about once a day for 6 months. In some embodiments, 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 embodiments, 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 Stimulus

[0219] In some embodiments, the administration of a stimulus to a subject is confirmed or verified within the subject by evaluating and measuring the stimulus. In some embodiments, the stimulus is measured in the brain of the subject. In some embodiments, a 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 embodiments, a 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.

[0220] In some embodiments, the measuring comprises analyzing the brain or a specific brain region of the subject. In some embodiments, the measuring comprises analyzing the stimulus in the brain or a specific brain region of the subject.

[0221] In some embodiments, 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.

[0222] In some embodiments, the measuring comprises neuroimaging. In some embodiments, the measuring comprises neuroimaging of the brain of the subject. In some embodiments, themeasuring comprises neuroimaging of the whole brain of the subject. In some embodiments, the measuring comprises neuroimaging of the specific brain regions of the subject. In some embodiments, 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, 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.

[0223] In some embodiments, the measuring comprises neuroimaging techniques. In some embodiments, the neuroimaging comprises magnetic resonance imaging (MRI), computer tomography, positron emission tomography (PET) imaging, diffusion-weighted MRI imaging, or any combination thereof in a brain region of a subject, wherein a 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 or Cognitive Assessment

[0224] In some embodiments, methods of using a device or system comprise receiving an indication of a physiological, cognitive, neural, visual, or physical assessment of a subject wearing a device or system as disclosed herein and emitting a stimulus in response to the indication.

[0225] In some embodiments, 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.

[0226] In some embodiments, 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.

[0227] In some embodiments, methods comprise instructing the device or system to lengthen or shorten a duration of stimulation in response to the indication of the physiological, cognitive, neural, visual, or physical assessment. In some embodiments, the physical assessment of the subject is performed to determine hearing of the subject.(iv) Methods of Treating Diseases or Conditions

[0228] In some embodiments, methods of using a device or system as disclosed herein includes using the device or system to treat, prevent, or mitigate cognitive dysfunction in a subject.

[0229] In some embodiments, the device or system is used to treat Alzheimer's disease or dementia in a subject in need thereof. In some embodiments, the dementia comprises, vascular dementia, Lewy body dementia, Pick's disease, fronto-temporal dementia (FTD), AIDS dementia, age-related cognitive impairments, and age-related memory impairments.

[0230] In some embodiments, the disease or condition comprises Parkinson’s disease.

[0231] In some embodiments, the method of treatment comprises stimulating a subject with a stimulus generated by a device or system disclosed herein, thereby inducing gamma oscillations in brain region of the subject.

[0232] In some embodiments, the 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.

[0233] In some embodiments, the induced gamma oscillations correspond to the frequency of the stimulus generated by a wireless audio or haptic device, or system used to administer the stimulus.(v) Tau Phosphorylation

[0234] In some embodiments, stimulating a subject with the stimulus according to the methods disclosed herein results in the maintenance or reduction of a level of tau phosphorylation in a brain region of the subject. In some embodiments, a level of tau phosphorylation in a brain region of a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0235] In some embodiments, stimulating a subject with an open view visual stimulation device results in the maintenance or reduction of punctate localization of phosphorylated tau protein in a brain region of the subject. In some embodiments, punctate localization of phosphorylated tau protein in a brain region of a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.(vi) Cognitive Function

[0236] In some embodiments, stimulating a subject with a stimulus according to the methods disclosed herein results in maintaining or improving cognitive function in the subject. In some embodiments, the maintaining or improving cognitive function comprises maintaining orimproving recognition, discrimination, spatial memory, working memory, attention, or a combination thereof.

[0237] In some embodiments, a level of cognitive function in a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% improved as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0238] In some embodiments, a level of cognitive function in a subject stimulated by an open view visual stimulation device as disclosed herein is at least 1% to at least 100% improved as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.(vii) Additional Biomarkers

[0239] In some embodiments, stimulating a subject with the stimulus according to the methods disclosed herein results in maintaining or reducing an amount of amyloid-P (AP) peptide in a brain region of a subject.

[0240] In some embodiments, a level of amyloid-P (AP) peptide in a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% improved as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0241] In some embodiments, a level of amyloid-P (AP) peptide in a subject stimulated by an open view visual stimulation device as disclosed herein is at least 1% to at least 100% improved as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0242] In some embodiments, stimulating a subject with the stimulus according to the methods disclosed herein results in maintaining or reducing an amount of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in a brain region of a subject.

[0243] In some embodiments, a level of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0244] In some embodiments, a level of C-terminal fragments (CTFs) and N-terminal fragments (NTFs) of amyloid precursor protein (APP) in a subject stimulated by an open view visual stimulation device as disclosed herein is at least 1% to at least 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0245] In some embodiments, stimulating a subject with the 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 a brain region of a subject.

[0246] In some embodiments, 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 an open view visual stimulation device as disclosed herein is about 1% to about 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0247] In some embodiments, 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 an open view visual stimulation device as disclosed herein is at least 1% to at least 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0248] In some embodiments, stimulating a subject with the stimulus according to the methods disclosed herein results in maintaining or reducing an amount of a number of endosomes in a brain region of a subject.

[0249] In some embodiments, a number of endosomes in a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0250] In some embodiments, a number of endosomes in a subject stimulated by an open view visual stimulation device as disclosed herein is at least 1% to at least 100% reduced as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0251] In some embodiments, stimulating a subject with a stimulus according to the methods disclosed herein results in clearance of Ap peptide in a brain region of the subject.

[0252] In some embodiments, clearance of Ap peptide in a brain region of a subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% increased as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0253] In some embodiments, clearance of Ap peptide in a brain region of a subject stimulated by an open view visual stimulation device as disclosed herein is at least 1% to at least 100% increased as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein. In some embodiments, stimulating a subject with a stimulus according to the methods disclosed herein results in increasing uptake of Ap peptide by microglia in a brain region of the subject.

[0254] In some embodiments, increasing uptake of Ap peptide by microglia in a brain region of the subject stimulated by an open view visual stimulation device as disclosed herein is about 1% to about 100% increased uptake as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0255] In some embodiments, increasing uptake of Ap peptide by microglia in a brain region of the subject stimulated by an open view visual stimulation device as disclosed herein is at least 1% to at least 100% increased uptake as compared to a subject stimulated by a closed view visual stimulation device as disclosed herein.

[0256] In some embodiments, stimulating a subject with an open view visual stimulus device according to the methods disclosed herein results in inducing a change in microglial cells in a brain region of a subject, thereby improving the cognitive function of the subject, or preventing, reducing, or treating cognitive decline in the subject.(f) Subjects

[0257] In some embodiments, a subject as disclosed herein comprises a mammal. In some embodiments, the mammal comprises a rodent. In some embodiments, the mammal comprises a non-human primate. In some embodiments, the mammal comprises a human.(g) Certain Definitions

[0258] 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.

[0259] 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.EXAMPLES

[0260] Example 1. Devices and Methods of Use

[0261] In some embodiments, open view visual stimulation induces a gamma oscillation in a brain region of the subject. In some embodiments, the open view visual stimulation comprises a frequency of about 30 Hz to about 60 Hz. In some embodiments, open view visual stimulation comprises a frequency of about 40 Hz.

[0262] In some embodiments, the open view visual stimulation provides advantages over an identical device comprising an opaque lens (closed view visual stimulation). For example, the induction of gamma oscillation in a brain region may be more effective when using open view visual stimulation than when using closed view visual stimulation. Additionally, from the perspective of a subject wearing the device, the open view visual stimulation may allow thesubject to readily converse and carry out other cognitive tasks and voluntary movements such as holding the hand of their caregiver while remaining seated. Additionally, the open view visual stimulation may allow the subject to receive a regimen of gamma stimulation while performing other tasks, such as and not limited to, activities of daily living.

[0263] Instructions for use are included with each device. The devices are designed for ease of use for subjects, with no requirements for high dexterity manipulation of the devices and are accompanied by simple visual instructions in large print.

[0264] The device includes a hand-held controller which allows the subject, with the assistance from a caregiver if needed, to turn the device on, independently adjust the output amplitude of the stimulation, and to pause and resume the stimulation during a session.

[0265] Example 2. Human Clinical Study of Safety, Efficacy, and Results of Treatment Open View Visual Stimulation

[0266] Recent studies highlight significant neurocognitive benefits from steady-state gamma sensory stimulation. Notably, a 6-month, daily, home-based treatment regimen demonstrated significant slowing of disease progression in mild to moderate Alzheimer’s disease. This trial used an investigational medical product for treatment administration, which provides the visual component of stimulation through an eye set with opaque (closed view visual stimulation) lenses. This current study aims to determine if allowing participants to view through a translucent (open view visual stimulation) lens during stimulation elicits comparable acute, sensory-evoked brain oscillations.

[0267] Thirty-one cognitively intact older adults (mean age 59.7 ± 8.3 years, 52% female) underwent visual tolerance and EEG-based gamma response testing. Visual (40 Hz) stimulation was delivered using both open view visual stimulation and closed view visual stimulation eye sets (3 minutes per lens configuration). Twenty-nine participants returned for a second visit one week later.

[0268] EEG data was acquired with a 32-channel cap (ANT-Neuro). Preprocessing and artifact removal were performed using EEGLAB (MATLAB). Power spectral densities of the EEG signals were computed and (globally / regionally) averaged across channels. The evoked Gamma Response was estimated as the peak power at 40Hz relative to the power at surrounding frequencies (38-39 & 41-42Hz).

[0269] One participant was excluded from analysis due to a pre-existing medical condition. Gamma Response comparisons between open view visual stimulation and closed view visual stimulation were conducted at Visit 1 (N=30) and Visit 2 (N=28) using paired t-tests and 2-waymixed effects models (GraphPad). Both global and regional brain responses were assessed. Due to the exploratory nature of this analysis, corrections for multiple comparisons were not applied.

[0270] Comparing open view visual stimulation and closed view visual stimulation within each visit separately, the mean global Gamma Response was greater for open view visual stimulation vs. closed view visual stimulation at both visits (AGRvl=0.569 dB, p=0.111; AGRv2=0.856 dB, p=0.044), but only Visit 2 reached statistical significance. The 2-way repeated measures similarly showed a significant effect of lens (p=0.027), while no visit or interaction effects were observed. Consistent results were observed for regional Gamma Responses, with a significant lens effect in the frontal (p=0.047) and temporal (p=0.009) regions and no visit or interaction effects.

[0271] This study demonstrates that open view visual stimulation produces a slightly greater evoked response compared to the closed view visual stimulation in a non-clinical population. As the open view visual stimulation may promote adoption and ease at-home use future studies in clinical populations may support interchangeability of lens configurations for administration of gamma treatment.

[0272] Example 3. Human Clinical Study of Safety, Efficacy, and Results of Treatment Using Open View Visual Stimulation

[0273] Methods and Study Design

[0274] A clinical study is performed to assess the safety, tolerability, and efficacy of long-term, daily use of open view visual stimulation on cognition, functional ability, and biomarkers in a group of experimental subjects. In some embodiments, experimental subjects include subjects with mild-to-moderate AD. The clinical study is a multi-center, randomized controlled trial evaluating daily use of the 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 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.

[0275] Study Participants and Design.

[0276] 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 visual stimulation with a non-opaque lens at a frequency of about 30 Hz to about 60 Hz, at least once per day. Of those assessed for eligibility, patients arerandomized between an active open view visual stimulation group and a closed view visual stimulation control group.

[0277] 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.

[0278] CDR global is calculated based on testing performed for six different cognitive and behavioral domains: memory, orientationjudgment, 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 udgment, 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.

[0279] 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 orientationplace. The MMSE is scaled from 0 to 30, with higher scores representing lower severity of cognitive dysfunction. The ADAS-Cog 14 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.

[0280] The study design involves primary efficacy endpoints of MADCOMS, ADAS-cog 14, 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.

[0281] The efficacy endpoints are analyzed by applying a linear model of analysis 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.

[0282] 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-terminalfragments (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 embodiments, levels of the measured biomarkers are maintained or reduced in active treatment groups as compared to groups receiving sham treatment.

[0283] Results

[0284] The subjects are randomized between open view visual stimulation and closed view visual stimulation. 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.

[0285] Demographic and Baseline Characteristics

[0286] 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 1, and CDR-sb scores at baseline being noted. Statistical models include covariates for age and MMSE at baseline.

[0287] Safety and Tolerability

[0288] The wireless gamma oscillation inducing waveform stimulus is safe and well-tolerated in the mild and moderate AD subjects. The active group is hypothesized to have a lower rate of treatment emergent adverse events (TEAE) than the sham group.

[0289] 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 groupsincluding 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.

[0290] Clinical Assessments

[0291] 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.

[0292] 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.

[0293] Selected secondary endpoints demonstrate significant effects favoring the treatment (active) group. The active group has significant benefit on functional ability as measured by the ADCS-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 (open view visual stimulation) is hypothesized to demonstrate maintained or increased recognition, discrimination, spatial memory, working memory, and attention as compared to the sham group (closed view visual stimulation). Examples of such hypothesized results are demonstrated in FIG. 3 - FIG. 7.

[0294] Biomarker Changes — MRI

[0295] 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.

[0296] Conclusions

[0297] Open view visual 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 gamma stimulation therapy leads 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 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 open view visual stimulation for AD subjects may be facilitated via differentiated pathways.

[0298] Example 4: Open View Visual Stimulation is Shown to Induce Microglial Cell-State Changes in Subjects According to some Embodiments.

[0299] A study is conducted to examine whether open view visual stimulation or administration induces microglial activation in the visual cortex of subjects in accordance with some embodiments. A 40-Hz visual stimulus is used.

[0300] To test open view visual 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 open view visual stimulation, and a second group of mice are exposed to the closed view visual stimulation (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.

[0301] 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 open view visual stimulation and mice exposed to the closed view visual stimulation is measured.

[0302] Open view visual 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 the microglial 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 closed view visual stimulation (No Stim) compared to mice exposed to the open view visual stimulation is measured (Stim). Significantly more microglial cells are hypothesized to be observed in the mice exposed to the open view visual stimulation in accordance with some embodiments. The average fold change in soma size of microglia in mice exposed to closed view visual stimulation (No Stim) compared to mice exposed to the open view visual stimulation is measured (Stim). The average fold change in soma size is hypothesized to be significantly greater in the mice exposed to the open view visual stimulation, indicating greater microglial activation in accordance with some embodiments. The average fold change in projection length of microglia in mice exposed to closed view visual stimulation compared to mice exposed to the open view visual stimulation is measured (Stim). The average fold change in projection length is hypothesized to be significantly less in the mice exposed to the open view visual stimulation in accordance with some embodiments.

[0303] 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 open view visual stimulation in accordance with some embodiments.

[0304] Example 5. Open View Visual Stimulation at Gamma Frequency Non-Invasively Reduces A in the Auditory Cortex and Hippocampus of Subjects.

[0305] Open view visual 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 5xF D Tg mice in accordance with some embodiments. On Day 8, the visual 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.

[0306] Open view visual 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 auditory cortex of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of soluble isoform AP1-42 peptide in the auditory cortex of mice exposed to closed view visual stimulus (No Stim) in accordance with some embodiments.

[0307] Smaller levels of soluble isoform AP1-40 peptide in the auditory cortex of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of soluble isoform AP1-40 peptide in the auditory cortex of mice exposed to closed view visual stimulation (No Stim) in accordance with some embodiments.

[0308] Smaller levels of soluble isoform AP1-42 peptide in the hippocampus of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of soluble isoform AP1-42 peptide in the hippocampus of mice exposed to closed view visual stimulation (No Stim) in accordance with some embodiments.

[0309] Smaller levels of soluble isoform AP1-40 peptide in the hippocampus of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of soluble isoform AP1-40 peptide in the hippocampus of mice exposed to closed view visual stimulation (No Stim) in accordance with some embodiments.

[0310] Open view visual 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 auditory cortex of mice exposed to the open view visual stimulation are hypothesized to be observed (Stim) relative to levels of insoluble isoform AP1-42 peptide in the auditory cortex of mice exposed to closed view visual stimulation (No Stim) in accordance with someembodiments. Smaller levels of insoluble isoform AP1-40 peptide in the auditory cortex of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of insoluble isoform AP1-40 peptide in the auditory cortex of mice exposed to closed view visual stimulation (No Stim) in accordance with some embodiments.

[0311] Smaller levels of insoluble isoform AP1-42 peptide in the hippocampus of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of insoluble isoform AP1-42 peptide in the hippocampus of mice exposed to closed view visual stimulation (No Stim) in accordance with some embodiments.

[0312] Smaller levels of insoluble isoform AP1-40 peptide in the hippocampus of mice exposed to the open view visual stimulation (Stim) are hypothesized to be observed relative to levels of insoluble isoform AP1-40 peptide in the hippocampus of mice exposed to closed view visual stimulation (No Stim) in accordance with some embodiments.

[0313] Thus, according to some embodiments, open view visual stimulation at a gamma frequency promotes gamma oscillations and a profound reduction in AD-associated pathology in a brain region.

[0314] Example 6. Open View Visual Stimulation at Gamma Frequency Reduces Phosphorylated Tau in Subjects

[0315] Open view visual stimulation is shown to reduce phosphorylated tau in subjects according to some embodiments. To determine if open view visual 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 open view visual stimulation or exposed to closed view visual stimulation for one hour daily for seven days, in accordance with the stim / no-stim protocol outlined above. To examine how open view visual 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.

[0316] 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 open / closed view visual 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 visual cortex are measured after seven days of open / closed view visual stimulation in accordance with some embodiments. Relative MAP2 intensity levels ofP301S in the visual cortex are measured after seven days of open view visual stimulation in accordance with some embodiments.

[0317] 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 open view visual stimulation condition as compared to closed view visual stimulation controls, while MAP2 levels will be unchanged. It is also hypothesized that less punctate and cell-body localization of pTau signal in response to open view visual stimulation compared to the closed view visual stimulation controls will be observed.

[0318] Example 7. Open View Visual Stimulation at Gamma Frequency and Positive Effects on Subject Behavior.

[0319] Open view visual stimulation is hypothesized to improve recognition in subjects according to some embodiments. A novel object recognition test is performed using 5xF D mice exposed to the open / closed view visual stimulation 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 tendency of rodents to spend more time exploring a novel object than a familiar object. A recognition index RI is used to compare the subjects.

[0320] 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 open view visual stimulation are hypothesized to have higher RI, indicating that the mice exposed to an open view visual stimulation spent much more time with the new object than the familiar object due to better recognition memory in accordance with some embodiments.

[0321] Open view visual 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 open view visual stimulation in accordance with some embodiments and 5xFAD mice exposed to silence. The test assesses spatial memory 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.

[0322] 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 open view visual stimulation are hypothesized to have higher RI, indicating that the mice exposed to the click-train or haptic vibration stimulus spent much moretime with the object that moved than the object that stayed in the same location due to better spatial memory or discrimination in accordance with some embodiments.

[0323] Open view visual stimulation is hypothesized to improve spatial memory in subjects according to some embodiments. A Morris water maze test is performed using 5xF D mice exposed to the click-train or haptic vibration stimulus in accordance with some embodiments and 5xF D mice exposed to silence. As described above, the test assesses spatial 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 or reference memory is determined by preference for the platform area when the platform is absent.

[0324] The average latency to find the platform is assessed in the mice exposed to closed view visual stimulation (No Stim) and the mice exposed to the open view visual stimulation (Stim) on each day in accordance with some embodiments. The mice exposed to the open view visual stimulation are hypothesized to spend more time searching for the missing platform in the target quadrant than did the mice exposed to closed view visual stimulation, thus indicating that the mice exposed to the open view visual stimulation have better spatial or reference memory in accordance with some embodiments.

[0325] Thus, according to some embodiments, open view visual stimulation at a gamma frequency is hypothesized to induce greater microglial activation, reduce AD-associated (e.g., AP) pathology, and significantly ameliorate cognitive deficits (in, e.g., recognition, discrimination, and spatial memory) as compared to closed view visual stimulation. With easy and accessible options for administration (including self- administration), open view visual stimulation has the potential for vast commercial applications, including but not limited to applications for home or mobile use. In addition to self-administration potential, clinicians or researchers may administer a stimulation paradigm to subjects ranging from animal models to human patients in accordance with some embodiments. Clinicians or researchers may find it useful to combine open view visual stimulation with various forms of monitoring. The subject may be monitored during the open view visual stimulation using, for example, functional magnetic resonance imaging (fMRI) for any beneficial brain-state changes.

[0326] 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 notmeant 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 device for inducing a gamma oscillation in a brain region of a subject, said device comprising:a) one or more processors individually or collectively programmed to execute a set of instructions comprising:i. emitting a visual stimulus; andii. inducing a gamma oscillation in said brain region of said subject; and b) a visual module operatively coupled to said one or more processors, wherein said visual module comprises a lens that is not opaque.

2. The device of claim 1, wherein said visual stimulus comprises a frequency of about 30 pulses per second to about 60 pulses per second.

3. The device of claim 2, wherein said visual stimulus comprises a frequency of about 40 pulses per second to about 60 pulses per second.

4. The device of claim 3, wherein said visual stimulus comprises a frequency of about 35 pulses per second to about 45 pulses per second.

5. The device of claim 4, wherein said visual stimulus comprises a frequency of about 40 pulses per second.

6. The device of claim 1, wherein said visual stimulus comprises a frequency of about 30 Hz to about 60 Hz.

7. The device of claim 6, wherein said visual stimulus comprises a frequency of about 40 Hz to about 60 Hz.

8. The device of claim 7, wherein said visual stimulus comprises a frequency of about 35 Hz to about 45 Hz.

9. The device of claim 8, wherein said visual stimulus comprises a frequency of about 40 Hz.

10. The device of claim 1, wherein said lens comprises a translucent lens.

11. The device of claim 1, wherein said lens comprises a transmittance of about 0% to about 100%.

12. The device of any one of claims 1-11, wherein said device further comprises an auditory device or a haptic device operatively coupled to said one or more processors.

13. The device of claim 12, wherein said auditory device comprises headphones.

14. The device of claim 13, wherein said headphones comprise over-ear headphones or in-ear headphones.

15. The device of claim 12, wherein said auditory device is configured to emit an auditory stimulus.

16. The device of claim 15, wherein said auditory stimulus comprises a frequency of about 30 Hz to about 60 Hz.

17. The device of claim 16, wherein said auditory stimulus comprises a frequency of about 40 Hz to about 60 Hz.

18. The device of claim 17, wherein said auditory stimulus comprises a frequency of about 35 Hz to about 45 Hz.

19. The device of claim 18, wherein said auditory stimulus comprises a frequency of about 40 Hz.

20. The device of claim 15, wherein said auditory stimulus comprises a frequency of about 30 pulses per second to about 60 pulses per second.

21. The device of claim 20, wherein said auditory stimulus comprises a frequency of about 40 pulses per second to about 60 pulses per second.

22. The device of claim 21, wherein said auditory stimulus comprises a frequency of about 35 pulses per second to about 45 pulses per second.

23. The device of claim 22, wherein said auditory stimulus comprises a frequency of about 40 pulses per second.

24. The device of claim 12, wherein said haptic device is configured to emit a haptic stimulus.

25. The device of claim 24, wherein said haptic stimulus comprises a frequency of about 30 Hz to about 60 Hz.

26. The device of claim 25, wherein said haptic stimulus comprises a frequency of about 40 Hz to about 60 Hz.

27. The device of claim 26, wherein said haptic stimulus comprises a frequency of about 35 Hz to about 45 Hz.

28. The device of claim 27, wherein said haptic stimulus comprises a frequency of about 40 Hz.

29. The device of claim 24, wherein said haptic stimulus comprises a frequency of about 30 pulses per second to about 60 pulses per second.

30. The device of claim 29, wherein said haptic stimulus comprises a frequency of about 40 pulses per second to about 60 pulses per second.

31. The device of claim 30, wherein said haptic stimulus comprises a frequency of about 35 pulses per second to about 45 pulses per second.

32. The device of claim 31, wherein said haptic stimulus comprises a frequency of about 40 pulses per second.

33. The device of any one of claims 24-32, wherein said haptic stimulus comprises a vibration.

34. The device of any one of claims 1-33 further comprising: a signal emitter.

35. The device of claim 34, wherein said signal emitter is configured to administer said visual, auditory, or haptic stimulus to said subject based on a signal generated by said device.

36. The device of any one of claims 1-35 further comprising a feedback component.

37. The device of claim 36, wherein said feedback component is configured to receive an indication of a physiological, cognitive, neural, visual, or physical assessment of said subject wearing said device and when said feedback component receives said indication said feedback component instructs said stimulus emitter to emit said visual, auditory, or haptic stimulus.

38. The device of any one of claims 1-37, further comprising a memory configured to store said instructions.

39. The device of claim 38, wherein said memory is operatively connected to said one or more processors.

40. The device of any one of claims 1-39 further comprising a microphone.

41. The device of claim 34, wherein said signal emitter comprises a speaker.

42. The device of any one of claims 1-41, wherein said instructions further comprise receiving an indication of a physiological, cognitive, neural, visual, or physical assessment of said subject wearing said device.

43. The device of claim 42, wherein subsequent to said receiving said indication, said instructions further comprise instructing said stimulus emitter to emit said visual, auditory, or haptic stimulus.

44. The device of claim 42, wherein said physical assessment of said subject comprises ascertaining at least one of said subject's: compliance with proper use and positioning of said device, eye status, alert or sleep status, or environment and surroundings.

45. The device of claim 42, wherein said cognitive assessment of said subject is obtained through questions posed to said subject, activities and tasks performed by said subject in response to a prompt, or behaviors exhibited by said subject.

46. The device of claim 43, wherein said instructions further comprise modulating a duration of said stimulation in response to said indication of said physiological, cognitive, neural, visual, or physical assessment.

47. The device of claim 46, wherein said modulating a duration comprises lengthening a duration of said stimulation.

48. The device of claim 46, wherein said modulating a duration comprises shortening a duration of said stimulation.

49. The device of claim 42, wherein said physical assessment of said subject is performed to determine vision or hearing of said subject.

50. The device of any one of claims 1-49, wherein said device is used to treat, prevent, or mitigate cognitive dysfunction in said subject.

51. The device of claim 42, wherein said indication of said physiological, cognitive, neural, visual, or physical assessment of said subject comprises a biosignal.

52. The device of claim 51, wherein said biosignal comprises an electroencephalography (EEG).

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

54. The device of claim 53, wherein said disease or condition comprises dementia.

55. The device of claim 54, wherein said 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.

56. The device of claim 53, wherein said disease or condition comprises Parkinson’s disease.

57. A method comprising: stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, thereby inducing a gamma oscillation in a brain region of said subject.

58. The method of claim 57, wherein said gamma oscillation comprises synchronized gamma oscillations.

59. The method of claim 57, wherein said 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.

60. A method comprising: (a) using said device of any one of claims 1-56 to stimulate a subject with said visual, auditory, or haptic stimulus and (b) maintaining or reducing a level of tau phosphorylation in a brain region of said subject.

61. The method of claim 60, wherein said maintaining or reducing tau phosphorylation comprises maintaining or reducing punctate localization of phosphorylated tau protein in said brain region of said subject.

62. The method of claim 60 or 61, wherein said maintaining or reducing tau phosphorylation in said brain region of said subject is increased in a subject administered said visual stimulus viaa visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

63. The method of claim 60 or 61, wherein said maintaining or reducing tau phosphorylation in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

64. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56 and (b) thereby maintaining or improving cognitive function in said subject.

65. The method of claim 64, wherein said maintaining or improving cognitive function comprises maintaining or improving recognition, discrimination, spatial memory, working memory, attention, or a combination thereof.

66. The method of claim 64 or 65, wherein said maintaining or improving cognitive function is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

67. The method of claim 64 or 65, wherein said maintaining or improving cognitive function is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

68. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby maintaining or reducing an amount of amyloid-P (AP) peptide in said brain region of said subject.

69. The method of claim 68, wherein said maintaining or reducing said amount of amyloid-P (AP) peptide in said brain region comprises reducing a production of Ap peptide in said brain region of said subject.

70. The method of claim 68 or 69, wherein said maintaining or reducing an amount of amyloid-P (AP) peptide in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

71. The method of claim 68 or 69, wherein said maintaining or reducing an amount of amyloid-P (AP) peptide in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

72. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby maintaining or reducing an amount of C-terminal fragments (CTFs) of amyloid precursor protein (APP) in said brain region of said subject.

73. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby maintaining or reducing an amount of N-terminal fragments (NTFs) of amyloid precursor protein (APP) in said brain region of said subject.

74. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby maintaining or reducing cleavage of APP into CTFs and NTFs by P-secretase (BACE1) in said brain region of said subject.

75. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby maintaining or reducing cleavage of APP into CTFs and NTFs by y-secretase in said brain region of said subject.

76. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby maintaining or reducing a number of endosomes in said brain region of said subject.

77. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby promoting clearance of Ap peptide in said brain region of said subject.

78. A method comprising: (a) stimulating a subject with said visual, auditory, or haptic stimulus generated by said device of any one of claims 1-56, and (b) thereby increasing uptake of Ap peptide by microglia in said brain region of said subject.

79. The method of claim 72, wherein said maintaining or reducing an amount of C-terminal fragments (CTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

80. The method of claim 79, wherein said maintaining or reducing an amount of C-terminal fragments (CTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

81. The method of claim 73, wherein said maintaining or reducing an amount of N-terminal fragments (NTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

82. The method of claim 73, wherein said maintaining or reducing an amount of N-terminal fragments (NTFs) of amyloid precursor protein (APP) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

83. The method of claim 74, wherein said maintaining or reducing cleavage of APP into CTFs and NTFs by P-secretase (BACE1) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

84. The method of claim 74, wherein said maintaining or reducing cleavage of APP into CTFs and NTFs by P-secretase (BACE1) in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

85. The method of claim 75, wherein said maintaining or reducing cleavage of APP into CTFs and NTFs by y-secretase in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

86. The method of claim 75, wherein said maintaining or reducing cleavage of APP into CTFs and NTFs by y-secretase in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

87. The method of claim 76, wherein said maintaining or reducing a number of endosomes in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

88. The method of claim 76, wherein said maintaining or reducing a number of endosomes in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

89. The method of claim 77, wherein said promoting clearance of Ap peptide in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

90. The method of claim 77, wherein said promoting clearance of Ap peptide in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

91. The method of claim 78, wherein said increasing uptake of Ap peptide by microglia in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

92. The method of claim 78, wherein said increasing uptake of Ap peptide by microglia in said brain region of said subject is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

93. The method of any one of claims 57-92, wherein said visual, auditory, or haptic stimulus induces a change in microglial cells in a brain region of a subject.

94. The method of claim 93, wherein inducing said change in microglial cells in said brain region of said subject improves cognitive function of said subject, or prevents, reduces, or treats cognitive decline in said subject.

95. The method of claim 93 or 94, wherein inducing said change in microglial cells in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is opaque.

96. The method of claim 93 or 94, wherein inducing said change in microglial cells in said brain region is increased in a subject administered said visual stimulus via a visual module that is not opaque as compared to a subject administered said visual stimulus via a visual module that is at least partially opaque.

97. The method of any one of claims 57-96, wherein said visual, auditory, or haptic stimulus is administered to said subject for about 10 minutes, about 30 minutes, about 45 minutes, about 1 hour, or more than about 1 hour per day.

98. The method of any one of claims 57-97, wherein said visual, auditory, or haptic stimulus is administered to said subject at least once, twice, three times, or more than three times per day.

99. The method of any one of claims 57-98, wherein said subject comprises a mammal.

100. The method of claim 99, wherein said mammal comprises a non-human primate.

101. The method of claim 99, wherein said mammal comprises a human.

102. The method of any one of claims 57-101, wherein said method further comprises a) identifying an activity being performed by a subject; and b) administering said visual, auditory, or haptic stimulus to said subject during said activity to induce a gamma oscillation in a brain region of said subject.

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