Systems and methods for treating mental disorders

Abstract

The present invention provides devices, systems, and methods for treating a mental disease or disorder. In particular, the invention recognizes that certain light therapy can induce an electrical effect in the brain that replicates the effect of some pharmaceutical compounds without the associated side effects. The invention provides for treating mental diseases and / or disorders using light of a defined waveform and pulse frequency to effectuate electrical activity in the brain. This electrical activity activates microglia cells in the brain to target perineuronal net (PNN) structures in the brain.

Description

[0001] SYSTEMS AND METHODS FOR TREATING MENTAL DISORDERS

[0002] Cross-Reference to Related Applications

[0003] This application claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 786,605, filed April 10, 2025, U.S. Provisional Application No. 63 / 747,558, filed January 21, 2025, and U.S. Provisional Application No. 63 / 663,903, filed June 25, 2024, the contents of each of which are incorporated by reference herein in their entirety.

[0004] Field of the Invention

[0005] The invention relates generally to systems and methods for treating mental disorders, such as but not limited to systems, devices, and methods for increasing neuroplasticity via microglia-mediated remodeling of the perineuronal net (PNN) in the brain.

[0006] Background

[0007] Mental disorders are a leading cause of disability worldwide. The global burden of disease associated with mental disorders is compounded by a widening mental health treatment gap where more than 70% of persons who need mental health services lack access to high- quality mental health care. Interrelated challenges that contribute to these deficiencies and exacerbate the treatment gap include shortages of mental health workers, lack of research capacity, stigmatization of mental illness, and the siloing of mental health services apart from other health services for physical health conditions. Further, this gap exists at a time when evidence-based mental health interventions such as psycho-pharmacological treatment and evidence-based psychotherapies for treating mental disorders are found to be effective in low- resource areas.

[0008] While most global mental health research has focused on common mental disorders due to the associated public health burden, research is also needed to address treatment for serious mental illnesses, such as psychotic disorders. More than 26 million people worldwide are diagnosed with severe mental illness, with psychotic disorders ranking fifth among men and sixth among women as a leading cause of years lived with disability. Without treatment, the consequences of mental illness for the individual and society are staggering. Untreated mental health conditions can result in unnecessary disability, unemployment, substance abuse, homelessness, inappropriate incarceration, reduced quality of life, and suicide. Psychopharmacological treatment approaches, i.e. antipsychotics, antidepressants, and mood stabilizers, play an important role in treating mental diseases and conditions. However, current pharmacological treatment options include side effects that include, Disorientation, confusion, or loss of motor coordination., dizziness, nausea, vomiting, increased blood pressure, heart rate, breathing, or body temperature, and changes in sensory perceptions, including visual or auditory hallucinations.

[0009] Summary

[0010] The invention recognizes that there exists a need for improved treatment options for treating mental diseases, disorders, and related symptoms, particularly options that address the current treatment gap in access to mental health services. In this manner, the present invention addresses the drawbacks of current psychopharmacological treatments for mental disorders, and provides novel systems, devices, and methods for treating these disorders and related symptoms. Specifically, the invention recognizes that certain light therapy, or other modes of stimulation, can induce an electrical effect in the brain that replicates the effect of some pharmaceutical compounds and does so without the associated side effects.

[0011] To that end, the invention provides systems and methods for treating mental diseases, disorders, and / or related symptoms using modes of stimulation, such as light of a defined waveform and pulse frequency, to effectuate electrical activity in the brain. Without being limited by any particular theory or mechanism of action, it is believed that this electrical activity activates microglia cells in the brain to target perineuronal net (PNN) structures in the brain. Perineuronal nets (PNNs) are specialized extracellular matrix structures responsible for multiple functions, including regulating synaptic plasticity, and protecting neurons from oxidative stress and neurotoxins. PNNs surround neurons in the brain which can make it difficult for the neurons to form new connections or to change the structure of old connections. This reduction in neuroplasticity is implicated in various mental disorders. By inducing entrainment to activate microglia cells to target the PNN, the invention provides novel systems and methods for treating mental disorders by increasing neuroplasticity via microglia-mediated remodeling of the PNN structures.

[0012] The invention provides devices and methods for inducing the mechanism of action, i.e. electrical activity, through various stimulation modalities, for example, via visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound.

[0013] Aspects of the invention include devices for treating a mental disease or disorder in a subject. The devices comprise at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, such that the visual stimulus induces entrainment thereby activating microglia cells to target the perineuronal net (PNN) in the brain of the subject to thereby cause remodeling of the PNN. By doing so, neuroplasticity in the brain of the subject is improved.

[0014] In some embodiments, the mental disease, disorder, or related symptoms is one or more of general depression, resistant depression, postpartum depression, perinatal depression, post- traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

[0015] In some embodiments, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive. In some embodiments, the light source includes one or more of a single point of light and an array of light sources. For example, the light source is one or more of a lightemitting diode (LED) and an array of LEDs, in some embodiments.

[0016] In particular embodiments, a waveform of light emitted from the light source comprises repeating pattern of stimulation. For example, the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave, in some embodiments. In some embodiments, the light source comprises a pre-defined wavelength range.

[0017] Further, in some embodiments, the device includes one or more sensors. In some embodiments, the device further includes a computing system operably associated with the device comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program. The computer program is executable by the processor to cause the computing system to receive data from the device and / or the one or more sensors; analyze, via one or more algorithms, the received data; and control one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus. For example, the one or more sensors includes one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eyetracking sensor, in some embodiments.

[0018] In some embodiments, the device includes a head-worn frame, such that at least a portion of the frame defines eyewear such that the light source is housed within a frame of the eyewear. In some embodiments, the eyewear includes one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject.

[0019] In some embodiments of the device, the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0020] In some embodiments of the device, the computing system further comprises a user interface operably associated with the computing system, wherein the user interface is provided via a software application accessible using one or more of a computer, a smartphone, and a tablet, wherein the received and analyzed data is displayed on an associated display device via the software application.

[0021] In some embodiments, the device further includes a sound source comprising an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus.

[0022] In some embodiments, the device includes a display sized and configured for placement on a tabletop, such that the light source comprises an LED array positioned on a front side of the display such that the visual stimulus is delivered to the subject when a subject is positioned facing the front side of the display.

[0023] In some embodiments, the device is configured as a lighting fixture, wherein the device is operable to actuate the light source for delivery of the visual stimulus and actuate normal room lighting once delivery of the visual stimulus is complete. In some embodiments of the device, the device is configured for attachment to one or more of a cell phone, a tablet, a display device, a television, and a headset. In other aspects, the invention provides systems for treating a mental disease or disorder in a subject. The systems include a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN.

[0024] The system further includes one or more sensors operably associated with the device; and a computing system operably coupled to the device. The computing system includes a non- transitory, computer-readable storage medium coupled to a processor and encoded with a computer program. The computer program is executable by the processor to cause the computing system to receive data from the device and / or the one or more sensors; analyze, via one or more algorithms, the received data; and control one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

[0025] The mental disease, disorder, or related symptoms may be one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age- related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

[0026] In some embodiments of the systems, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz including. In some embodiments, the light source includes one or more of a single point of light and an array of light sources. In some embodiments of the systems, a wave form of light emitted from the light source comprises a repeating pattern of stimulation. For example, the repeating pattern of stimulation may include one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave. In particular embodiments, the light source comprises a pre-defined wavelength range.

[0027] In some embodiments of the systems, the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals. In some embodiments of the systems, the device comprises a head-worn frame, wherein at least a portion of the frame defines eyewear such that the light source is housed within a frame of the eyewear. For example, in some embodiments, the one or more sensors includes one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, an eye-tracking sensor. In some embodiments, the sensor is an EEG array and the system automatically controls the delivery of the visual stimulus based on feedback from the EEG array.

[0028] In particular embodiments of the systems, the eyewear includes one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject. Further, in some embodiments, the virtual reality content comprises one or more of a virtual therapy session, a wellness application, a brain-training application, a mindfulness application, a video, a meditation application, rehabilitation therapy, functional training, and fitness training.

[0029] In some embodiments of the system, the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0030] In some embodiments of the systems, the system further includes a sound source. In particular embodiments, the sound source includes an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus. In other embodiments, the sound source comprises bone conduction in a same or different frequency as the light source.

[0031] In some embodiments of the system, the computing system further comprises a user interface operably associated with the computing system, wherein the user interface is provided via a software application accessible using one or more of a computer, a smartphone, and a tablet, wherein the received and analyzed data is displayed on an associated display device via the software application.

[0032] Aspects of the invention include methods for treating a mental disease or disorder in a subject. The method includes the steps of providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined pulse frequency, and a computing system operably associated with the device, the computing system comprising a non- transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

[0033] In some embodiments of the methods, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive. In particular embodiments of the methods, a wave form of light emitted from the light source comprises a repeating pattern of stimulation. For example, in some embodiments, the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave. In some embodiments, the light source comprises a pre-defined wavelength range.

[0034] In further embodiments of the methods, the device includes one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor. In particular, the method further includes receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

[0035] In some embodiments of the method, the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals. For example, the one or more sensors includes an electroencephalography (EEG) array, such that the device controls the delivery of the visual stimulus based on feedback from the EEG array, in some embodiments. In some embodiments, the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0036] In some embodiments of the method, the mental disease, disorder, or related symptoms is one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

[0037] In particular embodiments, the mental disease or disorder is depression. Further, in some embodiments of the methods, the visual stimulus is delivered for two hours per day for five days. In some embodiments, the visual stimulus is delivered for thirty minutes per day for thirty days. In some embodiments of the method, delivery of the visual stimulus is combined with a pharmacological treatment.

[0038] In some embodiments, the method further comprises obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level. The saliva sample is obtained at a defined time after delivery of the visual stimulus, in some embodiments. In some embodiments, the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

[0039] Aspects of the invention provide methods of promoting or improving cognitive function in a subject. The subject may be a healthy or “normal” subject. “Normal subject” in this context may mean a subject or patient who is not suffering from a clinical disorder, e.g. a neuropsychiatric disorder. Thus a “normal subject” may refer to a healthy subject. The present invention (e.g. the methods, devices, and systems described herein) may be used in non- therapeutic treatment of such subjects.

[0040] The method for promoting and / or improving cognitive function in a subject comprises providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

[0041] In some embodiments of the method, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive. In some embodiments, a wave form of light emitted from the light source comprises a repeating pattern of stimulation. Further, the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave, in some embodiments.

[0042] In some embodiments, light source comprises a pre-defined wavelength range.

[0043] In some embodiments of the method, the device further comprises one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor. For example, in some embodiments, the method further comprises receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject. Further, in some embodiments, the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals. In particular embodiments, the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0044] In some embodiments, cognitive function is promoted and / or improved in a subject experiencing one or more of stress, burn-out, chronic stress, accelerated aging, and / or brain injury. For example, in some embodiments of the method, one or more of learning, attention, memory, language, executive functions, social cognition and / or visual-spatial abilities is promoted and / or improved.

[0045] In some embodiments, the visual stimulus is delivered for two hours per day for five days. In some embodiments, the visual stimulus is delivered for thirty minutes per day for thirty days.

[0046] In some embodiments, the method further comprises obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level. The saliva sample is obtained at a defined time after delivery of the visual stimulus, in some embodiments. In some embodiments, the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

[0047] Aspects of the invention provide methods for monitoring cognitive function or treating a mental disease, disorder, or related symptoms. The methods include obtaining a first saliva sample from a subject; measuring a first salivary cortisol level from the first saliva sample; conducting a treatment on the subject that is designed to impact cognitive function or treat a mental disease, disorder, or related symptoms; obtaining a second saliva sample from the subject; measuring a second salivary cortisol level from the second saliva sample; and comparing the second salivary cortisol level to the first salivary cortisol level, wherein a difference between the second salivary cortisol level and the first salivary cortisol level indicates an effect of the treatment.

[0048] Aspects of the invention provide methods for treating stress in a subject. The methods include the steps of providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer- readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject. In some embodiments of the method the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

[0049] In some embodiments of the method the wave form of light emitted from the light source comprises a repeating pattern of stimulation. The repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave, in some embodiments.

[0050] In some embodiments, the light source comprises a pre-defined wavelength range.

[0051] In some embodiments of the method, the device further comprises one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor. Further, the method further comprises, receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject, in some embodiments. Is some embodiments, the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals. In some embodiments, the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0052] In some embodiments of the method, the stress comprises one or more of burn-out, acute stress, chronic stress, episodic acute stress, and toxic stress.

[0053] In some embodiments of the method, the visual stimulus is delivered for two hours per day for five days. In some embodiments, the visual stimulus is delivered for thirty minutes per day for thirty days.

[0054] In some embodiments of the method, the method further comprises obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level. The saliva sample is obtained at a defined time after delivery of the visual stimulus, in some embodiment. In some embodiments, the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

[0055] Brief Description of the Drawings

[0056] FIG. 1 illustrates waveforms of light that may be used with devices of the invention.

[0057] FIG. 2 illustrates a device 100 according to one embodiment of the invention.

[0058] FIG. 3 illustrates a device for treating a mental disease or disorder in a subject according to one embodiment of the invention.

[0059] FIG. 4 illustrates a system 400 according to one embodiment of the invention.

[0060] FIG. 5 illustrates a representation of a method 500 for treating a mental disease or disorder in a subject according to one embodiment of the invention.

[0061] FIG. 6D is a graph illustrating increasing cortical plasticity through the activation of microglia using ketamine.

[0062] FIG. 6G illustrates that cortical entrainment with a 60Hz flashing light, of 2 hours duration (matching the clearance time of ketamine), had the same effects on the microglia and PNN as ketamine.

[0063] FIG. 7A illustrates a device according to one embodiment of the invention. FIG. 7B diagrams the experimental protocol from Example 2.

[0064] FIG. 7C illustrates a diagram of the experimental timeline from Example 2.

[0065] FIG. 7D illustrates a distinct peak at 60Hz during the stimulus-modulated light exposure on day 1, Day 5, and Day 19 of Example 2. FIG. 7E illustrates topographic maps showing normalized changes in 60Hz PSD (relative to baseline) averaged across participants of each group.

[0066] FIG. 7F shows the normalized power in the active group on Day 1 across channels was significantly higher than in sham groups.

[0067] FIG. 7G illustrates Short-Time Fourier Transform (STFT) of a representative active group participant, demonstrating visible 60Hz entrainment during light stimulation.

[0068] FIG. 8 A and FIG. 8B illustrate synchronization of brain activity during 60Hz entrainment.

[0069] FIG. 9A illustrates a notable trend toward reduced cortisol levels over the course of the stimulation.

[0070] FIG. 9B illustrates observed levels of levels of CRP on Day 1, 5 and 19 in active and sham groups.

[0071] FIG. 9C shows day by day record of side effects during stimulation from Example 2.

[0072] FIG. 10A illustrates a graph showing the light spectrum of the LEDs ranging from 440 nm to 770 nm, similar to daylight wavelengths.

[0073] FIG. 10B illustrates an experimental setup on EEG Days: subjects were seated on a chair during the stimulation.

[0074] FIG. 10C illustrates the location of the 8 EEG channels utilized in the study, mapped according to the 10-20 electrode placement system.

[0075] FIG. 10D shows scalp EEG power spectral density (PSD) averaged across all channels for participants in each group under (I.) No light and (II.) Constant light conditions. The gray bar indicates the 50 Hz line noise, which was notch-filtered.

[0076] FIG. 10E shows topographic maps showing normalized changes in 60Hz PSD (relative to baseline) averaged across participants of each group under no light and constant light conditions.

[0077] FIG. 10F and FIG. 10G illustrate that statistical significance for inter-group comparisons of FIG. 10E.

[0078] FIG. 10H displays the average PSD of all channels for each subject in both groups over days 1, 5, and 19.

[0079] FIG. 101 illustrates Short-Time Fourier Transform (STFT) of a representative sham group participant. FIG. 11 A illustrates normalized PLV across all channel pairs between the active and sham groups under no light and constant light conditions on Days 1, 5, and 19.

[0080] FIG. 1 IB shows PLV matrices for the active and sham groups across experimental days under no light and constant light conditions.

[0081] FIG. 12, panels A-E illustrate that 60Hz intermittent white light induces robust and widespread increased neuronal activity in mice, associated with microglia-mediated remodeling of perineuronal nets (PNN) in brain regions relevant to depression.

[0082] FIG. 13, panels A and B illustrate that 60Hz intermittent white light treatment is well tolerated by wild type mice, with no indication of weight loss or reduced water / food intake.

[0083] FIG. 14, panels A-C illustrate experimental design and schedule of procedures as preliminary results related to Example 3.

[0084] FIG. 15, panels A and B illustrate one embodiment of the device used in the study of Example 3.

[0085] FIG. 16 illustrates one embodiment of a system of the invention.

[0086] FIG. 17 illustrates a system according to one embodiment of the invention.

[0087] FIG. 18 illustrates device set-up via a user interface according to one embodiment of the invention.

[0088] FIG. 19A illustrates the demographics for study participants for Example 2.

[0089] FIG. 19B illustrates safety and tolerability data for Example 2.

[0090] FIG. 20 illustrates the schedule of procedures for Example 3.

[0091] Detailed Description

[0092] The invention provides devices, systems, and methods for treating mental diseases and / or disorders using a mode of stimulation, such as light of a defined waveform and pulse frequency, to stimulate electrical activity in the brain. Without being limited by any particular theory or mechanism of action, it is believed that this electrical activity induces entrainment that activates microglia cells in the brain to target perineuronal net (PNN) structures in the brain. Thus, the invention induces an electrical effect in the brain to activate microglia cells to target the perineuronal nets (PNNs) such that neuroplasticity is improved. The invention provides devices and methods for inducing this mechanism of action, i.e. electrical activity, through various stimulation modalities, for example, via visual stimulus, magnetic field exposure, high- and mid- range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound.

[0093] Perineuronal nets (PNNs) are specialized extracellular matrix structures responsible for multiple functions, including regulating synaptic plasticity, protecting neurons from oxidative stress and neurotoxins, and synaptic stabilization in the adult brain.

[0094] The PNN may be thought of as a cage that surrounds the neurons in the brain and which can make it more difficult for neurons to form new connections between each other. Some drugs, such as ketamine, are known to impact PNN density. Repeated exposure to ketamine leads to PNN loss and re-opening of PNN-dependent plasticity. However, there is a strong desire to find alternatives to ketamine because its therapeutic use is not without dangers, not least because of its side effects and ease of misuse.

[0095] It is an insight of the invention that ketamine induces an electrical effect in the brain and that this effect may be replicated by activating microglia cells to target the PNN. It was only by the present invention that it was surprisingly discovered stimulating microglia cells causes the cells to target PNNs, where the microglia cells essentially create holes in this structure. By inducing microglia cells to target the PNNs, neuroplasticity is increased making it easier for neurons to form new connections or to change the structure of old connections.

[0096] The invention provides for devices, systems, and methods of using that include use of a stimulus to replicate the effect of ketamine on PNN loss and plasticity. The invention includes devices, systems, and methods for inducing this mechanism of action, i.e. electrical activity, through various stimulation modalities, for example, via visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound.

[0097] The particular embodiments, the invention provides for the use of a visual stimulus in a pulse frequency range of about 50 to 70 Hz to replicate the effect of ketamine on PNN loss and plasticity. Thus, the invention provides novel devices, systems, and methods for treating mental disorders by increasing neuroplasticity via microglia-mediated remodeling of the PNN structures.

[0098] Overview The invention addresses the drawbacks of current psychopharmacological treatments for mental disorders. Specifically, the invention discloses devices, systems, and methods for providing a stimulus modality to induce an electrical effect in the brain that replicates the effect of some pharmaceutical compounds, without the associated side effects. In non-limiting examples, the stimulus modality may be one or more of a visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound. In some embodiments, the invention provides for the use of light therapy to induce an electrical effect in the brain that replicates the effect of some pharmaceutical compounds, without the associated side effects.

[0099] In particular, the invention recognizes that some drugs, such as ketamine, stimulate gamma cortical activity, and that this effect can be replicated via a mode of stimulation such as a visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound. For example, the stimulation of gamma cortical activity may be replicated via pulsed light stimulation at frequencies of 50 Hz to 70 Hz, or frequencies comparable to cortical oscillations stimulated by the drug. In this regard, the invention provides for cortical entrainment with, for example, a 60Hz flashing light, such that the resulting effects on the microglia and the PNN are the same or similar as those of a drug such as ketamine.

[0100] Accordingly, the invention provides devices, systems, and methods for treating mental disorders and related symptoms associated with neurological conditions by stimulating microglia cells to target PNNs, thus promoting improved neuronal plasticity.

[0101] Reductions in neuronal plasticity have been implicated in various neurological disorders. For example, stress-induced changes in neural plasticity have been linked to depression. A decrease in brain plasticity is thought to underlie age-related changes including cognitive decline. In schizophrenia, there is evidence for disrupted neuroplasticity resulting in cortical inhibition and dysfunctional intracortical connectivity. The invention provides devices, systems, and method for treating mental disorders and related symptoms by improving neuronal plasticity through microglia-mediated remodeling of the PNN. Specifically, neuronal plasticity is improved by inducing entrainment which activates microglia cells to target the PNN by creating holes in the PNN. Thus, as described herein, neuronal plasticity is promoted by inducing microglia cells to target the PNN such that removal of the PNN occurs. By “removal” of the PNN, it is typically meant that the PNN is at least partially lost or decreased in one or more brain regions. For instance the absolute number and / or density of PNN-covered cells may be reduced in at least one brain region, for example, by at least 5%, 10%, 30% or 50% compared to a control (untreated subjects). Without being limited by any particular theory or mechanism of action, it is believed that removal of the PNN may provide an opportunity to induce changes and allow the brain to learn by permitting the formation of new functional circuits or connections.

[0102] PNNs are found around certain neuron cell bodies and proximal neurites in the central nervous system. Through their physiological roles, PNNs are also involved in cognition, including encoding, maintaining, and updating memories. Current strategies have applied complete removal of the extracellular matrix in animal models using chondronitase ABC, which also digests the PNN, and has shown to increase plasticity, leading to enhanced memory interference from competing information during the encoding process. Environmental factors, such as physical activity, drugs, and nutrition, can influence brain plasticity, and some of these effects may be mediated by changes in PNN structure. Due to the biochemical composition, the PNN is largely negatively charged and composed of chondroitin sulphate proteoglycans, molecules that play a key role in development and plasticity during postnatal development and in the adult.

[0103] PNNs are mainly present in the cortex, hippocampus, thalamus, brainstem, and the spinal cord. In the cortex, PNNs are associated mostly with inhibitory interneurons and are thought to be responsible for maintaining the excitatory / inhibitory balance in the adult brain. The PNN shows widespread distribution in the brain and preferentially surrounds cortical parvalbumin- positive interneurons. Thus in some embodiments, the invention provides for inducing removal of the perineuronal net surrounding parvalbumin-positive interneurons, preferably cortical parvalbumin-positive interneurons.

[0104] Microglial cells are the most prominent immune cells of the central nervous system (CNS) and account for approximately 10% of the cells in the brain. The microglial population is not uniformly distributed throughout the adult brain and can vary in density up to 5-fold in different brain regions. Microglia are known as major actors in brain defense. The immune function of microglia means that microglia are involved in virtually all pathological processes in the brain, including inflammation, stroke, neurodegenerative diseases, and viral and bacterial infection. Microglia respond to tissue injury or disease through receptors for neurotransmitters and receptors that recognize danger-associated molecular patterns (DAMPs), such as adenosine triphosphate (ATP), and pathogen-associated molecular patterns (PAMPs), such as lipopolysaccharide (LPS) and viral DNA and RNA.

[0105] Microglial cells encompass regional and temporal heterogeneity, and observed patterns of response, which may be regulated by different neural circuits. For example, microglia respond differently to diverse pathological stimuli and change their behavior over the evolution of any given pathology in relation to different phagocytic activities and transcriptional profiles in different brain regions and at different ages. As a result, while microglia have been shown to contribute to brain pathology in both deleterious and beneficial ways, the contribution of microglia to cognition and behavior is not well -understood. It was only by the present invention that it was surprisingly discovered that microglia cells can be activated, according to systems, devices, and methods of the invention, to target PNN structures in the brain.

[0106] Devices for treatins a mental disease or disorder

[0107] Aspects of the invention provide devices for treating a mental disease, disorder, or related symptoms in a subject. The devices include at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, such that the visual stimulus induces entrainment thereby activating microglia cells to target the perineuronal net (PNN) in the brain of the subject. The activation of the microglia cells to target the PNN causes remodeling of the PNN such that neuroplasticity is improved.

[0108] Devices of the invention are designed for use in treating any brain-related disease, disorder, and / or related symptoms. In non-limiting examples, the mental disease, disorder, or related symptoms is one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, postmenopausal depression, fear based disorders, and sleep disorders. “Neuronal plasticity” is generally meant to refer to the ability of the CNS (e.g. brain) to change structure and / or function, for example in response to a stimulus. Neuronal plasticity may involve e.g. the formation of new functional circuits and / or connections, and thus the term includes synaptic plasticity — the ability to form new or stronger synapses interconnecting neurons. The terms “brain plasticity”, “neuroplasticity” or “neural plasticity” may be used interchangeably with “neuronal plasticity”. As used herein, the terms “subject”, “user”, and “patient” are used interchangeably. “Entrainment” may be used to refer to induced entrainment resulting in activation of microglia cells, and / or neural entrainment, cortical entrainment, brainwave entrainment. For example, entrainment may be used to refer to a state in which microglia cells are induced to target the PNN in the brain of a subject.

[0109] As disclosed in more detail herein, devices of the invention may be configured as a head- worn device. The head-worn device may be configured to accommodate a certain stimulus modality. For example, the head-worn device may include a light source housed within the head-worn device and the visual stimulus is delivered to the user’s eyes while the user wears the device. For example, the head-worn device may be a headset or eyewear that fits a user similarly to a pair of glasses. The device may be configured as reading glasses such that the light source may be housed in a frame of the glasses. The head-worn device, i.e. headset and / or eyewear, may partially cover the user’s face and eyes, for example, similar to a VR headset. In some embodiments, the head-worn device may entirely cover the user’s face and eyes, in the manner of a mask. The head-worn device partially or fully covers the user’s head in the manner of a helmet. In some embodiments, the eyewear comprises a one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject.

[0110] Additionally and / or alternatively, devices of the invention may be configured as a tabletop device designed for a user to sit or stand in front of to receive the visual stimulus delivered by the device. In this way, it is not necessary for the user to wear the device to receive the visual stimulus. For example, the device may be built into a display device, for example, a television, cell phone, tablet, and the like. In some embodiments, devices of the invention may be configured for incorporation into room lighting fixtures. The devices of the invention may be configured to alternate between delivering a defined visual stimulus and providing normal room lighting. Devices of the invention may also be configured to attach to one or more external devices such as a laptop or phone. For example, in some embodiments, the device is configured to attach to one or more of an external cell phone, a tablet a display device, a television, and a headset.

[0111] In some embodiments, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz, inclusive. As used herein, “frequency” of light means the frequency of the pulses of light, and not the electromagnetic frequency of light itself. In general, any suitable light intensity may be used. For example, the light may have an intensity of about 1 x 1018to x 1019photons / cm2 / s, e.g. 2 - 6 x 1018photons / cm2 / s, for example about 4 x 1018photons / cm2 / s. The power and electromagnetic frequency of the light may be selected to achieve the desired light intensity.

[0112] The visual stimulus may be a burst of light, and / or pulsing, flashing or flickering light. As used herein, the terms “burst”, “bursts”, “pulsing”, “flashing” and “flickering” are used interchangeably, in general to refer to an intermittent or pulsing light source. The device may deliver a plurality of light pulses. The light pulses may have a frequency of at least 51 Hz, at least 52 Hz, at least 55 Hz, at least 57 Hz, or at least 58 Hz. In other embodiments the light pulses have a frequency of up to 70 Hz, up to 68 Hz, up to 65 Hz or up to 63 Hz. Suitable preferred frequency ranges for the light pulses include e.g. about 50 to about 70 Hz, 51 to 70 Hz, 53 to 70 Hz, 55 to 70 Hz, 55 to 65 Hz and 57 to 63 Hz. Most preferably the light pulses have a frequency of about 60 Hz.

[0113] Delivery of the visual stimulus may be at a pre-defined pulse frequency. Delivery of the visual stimulus may be at a varying frequency. Each light pulse may, for example, have a duration of less than 20, less than 15 or less than 10 milliseconds, e.g. about 1 ms, about 5 ms or about 8 ms. For instance the light pulses may have a duration of about 5 to 12 ms or about 6 to 10 ms. For example, in some embodiments, the light pulses have a frequency of about 60 Hz, each light pulse has a duration of about 8.3 ms and the light pulses are separated by an interval of about 8.3 ms (i.e. a dark interval of 8.3 ms with no light).

[0114] The light source may be any source capable of delivering a visual stimulus at defined wavelengths and / or pulse frequencies. In some embodiments, the light source may be one or more of a single point of light and an array of light sources. The light source may be one or more of a light-emitting diode (LED) and an array of LEDs. The device may include a single light source configured to deliver the visual stimulus to both eyes of the patient. The device may include a two light sources configured to deliver the visual stimulus to a respective eye of the patient.

[0115] In some embodiments, the wave form of light emitted from the light source may be a repeating pattern of stimulation. The wave form may be any possible wave form. In nonlimiting examples, the repeating pattern of stimulation may be one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

[0116] FIG. 1 illustrates waveforms of light that may be used with devices of the invention. The light waves may have a form that is sinusoidal. The waveform may be non-sinusoidal. As illustrated in Panels A-F of FIG. 1, in non-limiting examples, the light may have a sine waveform (Panel A), a square waveform (Panel B or alternatively Panel C), a rectangular waveform (Panel D), a sawtooth waveform (Panel E), and / or a triangle waveform (Panel F). In particular embodiments, the light may be square wave light as shown in Panel B of FIG. 1. The square wave light may be 60 Hz square wave light. The shape of the waveform may be configured to provide a desired effect and / or strength of effect of the visual stimulus.

[0117] The light source may be white light containing all the colors in the color spectrum. In some embodiments, light of a specific color may be used. The light may be any wavelength or range of wavelengths. In some embodiments, light of a specific wavelength or range of wavelengths is used. In some embodiments, the color, the wavelength, and / or the range of wavelengths of the light of the light source used provides a desired strength of or effect on the activation of microglia cells.

[0118] The visual stimulus may be a single point of light or an array of light sources. It will be appreciated that the devices of the invention may employ any light source for generating a visual stimulus at desired wavelengths and / or pulse frequencies. In some embodiments, the light source comprises a pre-defined wavelength range. For example, the light pulses may be in the visible wavelength range, typically the range of what the human eye can detect: 380 to 740 nm. Thus, the light may be of any color. Devices of the invention may include one or more light sources of varying wavelengths such that the visual stimulus may be delivered at different frequencies and wavelengths. In non-limiting embodiments, the light spectrum utilized may range from 440 nm to 770 nm corresponding to daylight wavelengths. In some embodiments, the light intensity may be adjustable to ensure comfort during delivery of the therapy. For example, the light intensity may be adjustable to between 14 and 113 pW.

[0119] In some embodiments of the devices of the invention, the devices include one or more sensors. For example, the device may include a sensor / feedback component. The sensor may be any sensor. In non-limiting examples, the sensor may be one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eyetracking sensor. The EEG may be an EEG array. The device, via the one or more sensors, may allow for real-time feedback on how the device is operating. For example, the one or more sensors may deliver feedback as to whether the visual stimulation is delivered at a desired frequency and / or strength of stimulation. The one or more sensors may be configured to provide feedback to a clinician as to the patient’s improvement or progression before, during, or after treatment. For example, the device may provide feedback to a user and / or a clinician as to whether the patient is correctly using the technology. The device may provide feedback to the user and / or the clinician as to whether the patient is adhering to a treatment regimen using the device. In some embodiments, the device is configured to provide brain imaging and / or brain activity data as feedback.

[0120] Further, the device may include a computing system operably associated with the device. The computing system may comprise a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program. The computer program may be executable by the processor to cause the computing system to receive data from the device and / or the one or more sensors, analyze, via one or more algorithms, the received data, and control one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus.

[0121] As disclosed in more detail herein, the device, via the computing system, may interface with a control system architecture comprising, in non-limiting examples, one or more of a computer, a processor, a network, and / or a graphical user interface (GUI) for controlling one or more user inputs, defining a treatment protocol, controlling and / or monitoring the delivery of the visual stimulus, and displaying one or more outputs from the device. The control system architecture, via the computing system, may generate a stimulus, control emission of the stimulus, monitor emission of the stimulus / results, and / or process feedback regarding the stimulus / results. The control system architecture may provide for detecting and providing feedback regarding delivery of the visual stimulus including, for example, whether microglia cells are activated, changes in the PNN are induced, neuroplasticity is improved, subject sensitivity, cognitive function, physical or chemical changes, stress, safety, and the like.

[0122] The user interface may allow the user to interact with and control the operation of the device. For example, the device, via the user interface, may include one or more input / output mechanisms, such as a keyboard, knobs, buttons, scroll wheels, or the like, with which a user can interact so as to operate the device. The user interface may be physically connected to the device, may be integrally formed with the device, or may be located remotely. The user interface may be a handheld device, e.g., a smart tablet, a smart phone, or a specialty device produced for the device. User interaction may be implemented on a computer having an VO device, e.g., a CRT, LCD, LED, or projection device for displaying information to the user and an input or output device such as a keyboard and a pointing device, (e.g., a mouse or a trackball), by which the user may provide input to the computer. In some embodiments, the device may include a display integrated into the device, for example, a display screen as part of a head-worn device or a table-top device. In some embodiments, the device includes a display that is operably associated with the device via, for example, a wired or wireless connection.

[0123] In some embodiments of the device, user interaction with the device may be via a form of sensory feedback, for example, visual feedback, auditory feedback, or tactile feedback, and input from the user may be received in any form, including acoustic, speech, or tactile input. In some embodiments, the computing system further comprises a user interface operably associated with the computing system, wherein the user interface is provided via a software application accessible using one or more of a computer, a smartphone, and a tablet, wherein the received and analyzed data is displayed on an associated display device via the software application.

[0124] As disclosed herein, the device, via the computing system, may provide for monitoring and controlling various aspects or parameters associated with delivery of the stimulus, e.g., the visual stimulus. For example, the device may include a communication interface as part of the user interface to provide for communication with the subject, a healthcare provider, a caretaker, a clinical research investigator, a database, a monitoring application, and the like.

[0125] Monitoring and controlling various parameters related to the operation of the device may be performed using any type of computing system or device. The computing system may be integrated into the device such as into a head-worn device or in a standalone device. Alternatively and additionally, the computing system may be operably connected to the device via a wired or wireless connection. The device may be operably connected with, for example, a personal and / or portable computing device, such as a smartphone, tablet, laptop computer, or the like.

[0126] In some embodiments, the computing system includes a user interface operably associated with the computing system. The user interface may be provided via a software application accessible using an associated device, such as one or more of a computer, a smartphone, and a tablet. In some embodiments, the received and analyzed data may be displayed on an associated display device via the software application.

[0127] In some embodiments, the computing system may be configured to communicate with and exchange data over a network. The network may represent, for example, a private or nonprivate local area network (LAN), personal area network (PAN), storage area network (SAN), backbone network, global area network (GAN), wide area network (WAN), or collection of any such computer networks such as an intranet, extranet or the Internet (i.e., a global system of interconnected network upon which various applications or service run including, for example, the World Wide Web). In alternative embodiments, the communication path between the user interface and the systems of the invention may be, in whole or in part, a wired connection.

[0128] The network may be any network that carries data. Non-limiting examples of suitable networks that may be used as network include Wi-Fi wireless data communication technology, the internet, private networks, virtual private networks (VPN), public switch telephone networks (PSTN), integrated services digital networks (ISDN), digital subscriber link networks (DSL), various second generation (2G), third generation (3G), fourth generation (4G), fifth generation (5G), and future generations of cellular-based data communication technologies, Bluetooth radio, Near Field Communication (NFC), the most recently published versions of IEEE 802.11 transmission protocol standards, other networks capable of carrying data, and combinations thereof. In some embodiments, the device may utilize any suitable radio communication method (e.g. Bluetooth) to communicate with the user interface, e.g. a mobile device operating a suitable app-

[0129] In some embodiments, the network may be chosen from the internet, at least one wireless network, at least one cellular telephone network, and combinations thereof. As such, the network may include any number of additional devices, such as additional computers, routers, and switches, to facilitate communications. In some embodiments, the network may be or include a single network, and in other embodiments the network may be or include a collection of networks.

[0130] In some embodiments, the device includes a head-worn frame. At least a portion of the head-worn frame may define eyewear such that the light source is housed within a frame of the eyewear. The eyewear may include a virtual reality display configured to display virtual reality content to the subject in conjunction with delivery of the visual stimulus to the subject. The device may be configured as a headset that fits similar to a pair of glasses. The device may be configured to cover the eyes and at least partially cover the face of a user, similar to a virtual reality headset. The device may be configured to fully cover the eyes and face of a user, similar to a mask. The device may be configured to at least partially or fully cover the eyes, face, and head of a user, similar to a helmet.

[0131] In some embodiments of the device configured to fit as a pair of glasses, the light source may be housed in a frame of the glasses. The glasses may be any type of glasses, for example sunglasses, and / or prescription or non-prescription reading glasses such that the delivery of the visual stimulus to the user is incorporated into a user’s daily activities. In this way, treatment may be integrated into a patient’s daily activities. The glasses may be virtual reality glasses or other glasses designed for spatial computing.

[0132] The device may be configured similar to a virtual reality (VR) headset or other spatial computing device. In such embodiments, the light source may be housed at the edges of a display screen, such as a virtual reality (VR) screen. In this way, the glasses, and / or VR headset may be transparent so that the user may see through the device while the head-worn device is worn. Where the device is configured as glasses or a VR headset, a transparent display may allow for a user to use the center of the screen for reading, watching a video, engaging in a virtual therapy session, etc. Accordingly, the head-worn device may comprise one or more lenses and / or display that may be transparent, semi-transparent, opaque, or may partially or completely block external light.

[0133] In some embodiments, the eyewear includes a virtual reality (VR) display configured to display virtual reality content to the subject in conjunction with delivery of the visual stimulus to the subject. The eyewear may include an augmented reality (AR) display and / or a cross reality (XR) display. In some embodiments, the eyewear comprises a one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject. As discussed in more detail herein, in some embodiments, delivery of the visual stimulus may be incorporated into a form of video such that delivery of the visual stimulus may be unnoticeable by the user. In some embodiments, the VR, MR, and / or XR content may include one or more of virtual reality content comprises one or more of a virtual therapy session, a wellness application, a brain-training application, a mindfulness application, a video, a meditation application, rehabilitation therapy, functional training, and fitness training.

[0134] The frame of the head-worn device may be any material suitable for housing the one or more light sources. For example, the frame may be one or more of a metal, alloy, polymer, or other material that is suitably light-weight with the structural strength and flexibility for housing the components of the device.

[0135] FIG. 2 illustrates a device 100 according to one embodiment of the invention. The device 100 may be a head- worn device designed to cover the user’s eyes and to partially cover the user’s face, similar to a VR headset. The head-worn device may be transparent, semitransparent, opaque, or may partially or completely block external light from the user’s eyes. The device may include at least one light source configured to deliver to the subject a visual stimulus at a defined pulse frequency, such that the visual stimulus activates microglia cells to target the perineuronal net (PNN) in the brain of the subject such that neuroplasticity is improved.

[0136] The device may be worn around the face and head, resembling a pair of safety goggles. The device may be designed to be compatible with an EEG cap. For example, the EEG cap may be an 8-channel system configured to cover a range of frequency spectrum due to a higher sampling rate.

[0137] The light source (not shown) may be integrated into the frame of the headwear. The light source may be configured to direct flashing light at 50-70 Hz (e.g. 60 Hz) towards the eyes of a subject. The light source may be e.g. a series of LEDs, which may be mounted in the suitable headset for directing light towards the eyes. The light source may be, for example, a strip of LEDs integrated around the ocular component to direct light tangentially to, for example, the periphery of the wearer’s eyes. The LED strip may have any number of LEDs per meter. For example, the LED strip may have 120 LEDs per meter. The LED strip may be integrated at any position in or on the device that is suitable to deliver to the subject a visual stimulus. In one embodiment, the device may include an LED strip integrated into a headset such that the LEDs emit a square-wave function of white light at a 60Hz band with a duty cycle of 50%.

[0138] As disclosed herein, the device may include one or more sensors (i.e. pressure, temperature, eye-tracking, heart rate — not shown), such as an EEG array 103. The device may include any sensor. In non-limiting examples, the sensor(s) may be one or more pressure sensors, temperature sensors, eye-tracking sensors, heart rate sensors, brain activity sensors, and biometric sensors. Further, the device may include a computing system 105 operably associated with the device 100. The computing system may be integrally formed with the head-worn device or may be operably connected to the head-worn device. The computing system may comprise a non-transitory, computer-readable storage medium 107 coupled to a processor 109 and encoded with the computer program. The computing system may interface with control system architecture on a user interface 111, such as a smart phone. The user interface may be integrally formed with the device, may be connected to the device via a wired or wireless connection, or may be located remotely.

[0139] The head-worn frame may include one or more sensors, for example, pressure, temperature, eye-tracking, and heart rate sensors. The one or more sensors may be integrally formed with the head-worn frame. The one or more sensors may be operably connected to the device via a wired or wireless connection. For example, the device may include an EEG apparatus, such as an EEG array integrated into the head-worn frame. The EEG array may be removable from the head-worn frame. The EEG may be a removable component of the device that may be added and / or removed as needed. The EEG array may be a full array. The EEG array may be a few electrodes to give certain desired data. In non-limiting examples, the device may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more EEG electrodes integrated as part of the device and / or removably associated with the device. The EEG apparatus, i.e. EEG array may detect brain activity in the subject via a series of electrodes. The detected brain activity may be transmitted to the user interface 111.

[0140] The device may be configured to eliminate electromagnetic emissions from the components of the device that would result in electrical noise interference with the EEG setup, for example by enclosing the light source within a copper mesh and / or using shielded cables grounded to the EEG acquisition board. As is known to persons skilled in the art, the device may comprise one or more electrical circuit components / boards, potentiometers, photoresistors, and the like to effectuate the functions of the device to deliver the visual stimulus as disclosed.

[0141] Transmission of data from the one or more sensors to the user interface may be via any suitable communications protocol or network, for example via Bluetooth. Transmitted data may be one or more of brain imaging data and / or brain activity recordings. In some embodiments, the device is configured to control parameters of the delivery of the visual stimulus based on the data received and analyzed.

[0142] The user interface 111 may also communicate with the light source to allow a user to set parameters such as the duration, intensity and frequency of the emitted light based on feedback from the one or more sensors. The device may thus modulate the intensity and / or duration of the visual stimulus and automatically turn on or off as needed. A user may interact with the device and monitor the brain activity directly from the user interface. For example, the EEG recording may be transmitted to the user interface such that the EEG recording may be saved and transmitted to a clinician.

[0143] Parameters of the delivery of the visual stimulus may be modulated based on data received and analyzed. For example, the frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus may be modulated based on whether, for example, 60 Hz activity in the brain is detected. If this activity is not detected or only weak signals are detected, the device may increase the intensity of the light emitted by the light source. Alternatively the device may modulate the frequency of emitted light, e.g. by 1 or 2 Hz within the 50-70 Hz frequency band, in order to identify a suitable frequency for generating 60 Hz activity. If the processor determines that 50-70 Hz activity is detected for a sufficient period of time, the processor may switch off the light source.

[0144] The period of time may be any time period determined to provide increased neuroplasticity via microglia-mediated remodeling of the PNN. For example, the visual stimulus may be emitted for at least e.g. 1 min, 5 mins, 10 mins, 20 mins, 30 minutes, 1 hour, 1.5 hours or 2 hours, preferably for at least 1 hour, at least 1.5 hours or at least 2 hours, more preferably 1 to 3 hours. The duration of the exposure of the subject to the visual stimulus and / or the administration of the visual stimulus to the subject may be e.g. 1 to 3 hours, for instance about one hour. The exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated over a time period. For example, the exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated at least once per day over the time period. The time period may include, but is not limited to, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, and / or one month (or longer, such as once daily for the rest of the subject's life). In a particular example, the period of time is 2 hours for 5 consecutive days. In some embodiments, the device is used in combination with pharmacologic treatments.

[0145] Thus, the device may constantly, regularly, or intermittently track and analyze the brain activity of the subject. The device may provide a real-time neurofeedback to the user. Therefore in some embodiments, the duration or intensity of the visual stimulus, i .e. flickering light, is adjusted for each subject on a personalized basis. As disclosed herein, the components of the device may be embodied in the same device or in separate linked devices.

[0146] The device may include a means for measuring stimulation frequency. The means for measuring stimulation frequency may include, for example, an oscilloscope.

[0147] As disclosed herein, the computing system may be operable to receive data from the device and / or one or more sensors and analyze the data via one or more algorithms. Thus, the device may provide a feedback loop for automatically adjusting the visual stimulus parameters. For example, based on data received by the EEG and analyzed by the computing system, the device may automatically adjust parameters associated with delivering the visual stimulus such that treatment is personalized for the user. The parameters may be, for example, one or more of duration, intensity and / or frequency of the emitted light, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus. In some embodiments, data received and analyzed includes bran imaging data and / or brain activity recording.

[0148] The algorithms may be one or more supervised or unsupervised machine learning (ML) algorithms such as artificial neural networks, linear discriminant analysis, decision tree / random forest, K-nearest neighbor, naive Bayes, and support vector machine for analyzing EEG data. In some embodiments, the one or more algorithms may include a cross coupling analysis method, wherein low frequency signal data may be received and correlated to high frequency signals, for example signals from the EEG.

[0149] The device may include one or more pressure sensors on the headset (not shown) to record if the device is being worn correctly and to provide feedback as to whether the patient is adhering to a treatment protocol. In some embodiments, eye tracking sensors may be incorporated to provide feedback as to the patient’s use of the device and the effectiveness of the therapy. In some embodiments, the device may include other sensors, such as heart rate and / or skin temperature sensors. The sensors may be used to provide feedback during a treatment protocol. In some embodiments, the device is operable to communicate with external sensors not part of the device itself.

[0150] In some embodiments, the device includes a display sized and configured for placement on a tabletop. The light source may include an LED array positioned on a front side of the display such that the visual stimulus is delivered to the subject when a subject is positioned facing the front side of the display.

[0151] FIG. 3 illustrates a device for treating a mental disease or disorder in a subject according to one embodiment of the invention. The device 300 may be configured as a desktop or tabletop device. The device may include a display screen. In non-limiting examples, the device may be integrated into any display type, such as a television, tablet, or phone. The device may include at least one light source 301. The at least one light source may be integrated into a frame of the device, for example, positioned around the display screen. In some embodiments, the light source 301 may be an integrated part of the display screen of the device. The device may be placed in front of the patient rather than being a wearable device. The device may include an eye-tracking component. The eye-tracking component may provide feedback as to whether a patient is using the device according to a defined treatment protocol.

[0152] The at least one light source 301 may be configured to deliver to the subject a visual stimulus at a defined pulse frequency. The visual stimulus activates microglia cells to target the perineuronal net (PNN) in the brain of the subject such that neuroplasticity is improved. The device may include one or more sensors (i.e. pressure, temperature, eye-tracking, heart rate — not shown), such as an EEG array 303. Further, the device may include a computing system 305 operably associated with the device 300. The computing system may be the device controller. The device controller, e.g. the computing system may serve as the central unit for managing the light stimulation parameters and session control. The device controller may communicate with the device wirelessly or via a wired connection, such as a USB-C connection.

[0153] The computing system may comprise a non-transitory, computer-readable storage medium 307 coupled to a processor 309 and encoded with the computer program. The computing system may interface with control system architecture on a user interface 311. The user interface may be a smart phone, tablet, or the like. As discussed herein, the user interface may be integrally formed with the device, may be wirelessly connected to the device, may be hardwired to the device, or may be located remotely.

[0154] The EEG array may be a full array. The EEG array may be a few electrodes to give certain desired data. In non-limiting examples, the device may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more EEG electrodes operably connected to the device.

[0155] As disclosed herein, in some embodiments, the computing system may be operable to receive data from the device and / or one or more sensors and analyze the data via one or more algorithms. Thus, the device may provide a feedback loop for automatically adjusting the visual stimulus parameters. For example, based on data received by the EEG and analyzed by the computing system, the device may automatically adjust parameters associated with delivering the visual stimulus such that treatment is personalized for the user. The parameters may be, for example, one or more of a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus.

[0156] In some embodiments, the one or more algorithms may include a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals, for example signals from the EEG.

[0157] The device may be configured as a lighting fixture. The lighting fixture may be a floor lamp, a table lamp, a ceiling fixture, a sconce, or the like. The device may be operable to actuate the light source for delivery of the visual stimulus and actuate normal room lighting once delivery of the visual stimulus is complete. For example, the device may actuate the light source for delivery of the visual stimulus for a set period of time. The set period of time may be programmed such that the visual stimulus is actuated at certain hours of the day. In some embodiments, the device comprises one or more sensors for sensing if a patient is in the room before actuating the light source to deliver the visual stimulus. For example, the one or more sensors may be a motion sensor, a biometric sensor, or the like.

[0158] In some embodiments, the device may include other forms of sensory stimulation. For example, the device may include a sound source comprising an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus. In some embodiments, the device may include a means for tactile stimulation delivered at certain frequencies to correspond with delivery of the visual stimulus.

[0159] In some embodiments, the devices include a sound source configured to generate auditory pulses in a similar frequency to delivered by the light source. For instance, the device may comprise an electroacoustic transducer to convert an electrical audio signal into a corresponding sound stimulus. The sound source may generate, for example, a click train with a click frequency of e.g. 50 to 70 Hz, 51 to 70 Hz, 53 to 70 Hz, 55 to 70 Hz, 55 to 65 Hz and 57 to 63 Hz. The clicks may have a preferred frequency of about 60 Hz. The sound may be generated at a same or different frequency as delivery of the visual stimulus.

[0160] The sound source may include bone conduction, i.e. direct vibration of the bones in the head, in the same or different frequency as the visual stimulation. The bone conduction may be an integrated headset or headphones. The bone conduction may be a headset / headphones operably connected to the device.

[0161] Each click in the click train may preferably have a duration of less than 10 ms, e.g. about 1 ms. Each click in the click train may have a sound pressure level of e.g. about 1 dB to about 85 dB, about 30 dB to about 70 dB, or about 60 dB to about 65 dB. Alternatively or in addition, the sound may be emitted at a volume that varies over a selected period of time. The at least one electroacoustic transducer may include at least one headphone or speaker. The device may include noise-cancelling features for reducing ambient noise. The device may reduce ambient noise using passive noise isolation and / or active noise cancellation.

[0162] The sound source may be integrally formed with the device. The sound source may be operably connected to the device via a wired or wireless connection.

[0163] In some embodiments, the device may comprise a timer connected to the one or more light sources. The timer may enable the light source to emit light for a selected period of time. For example, the visual stimulus may be emitted for at least e.g. 1 min, 5 mins, 10 mins, 20 mins, 30 minutes, 1 hour, 1.5 hours or 2 hours, preferably for at least 1 hour, at least 1 .5 hours or at least 2 hours, more preferably 1 to 3 hours. The duration of the exposure of the subject to the visual stimulus and / or the administration of the visual stimulus to the subject may be e.g. 1 to 3 hours, for instance about one hour. The exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated over a time period. For example, the exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated at least once per day over the time period. The time period may include, but is not limited to, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, and / or one month (or longer, such as once daily for the rest of the subject's life). In a particular example, the period of time is 2 hours for 5 consecutive days.

[0164] Systems for treatins a mental disease or disorder

[0165] Aspects of the invention provide systems for treating a mental disease or disorder in a subject. The systems include a device comprising a stimulus modality. For example, the device may include at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN. The systems include one or more sensors operably associated with the device; and a computing system operably coupled to the device, the computing system comprising a non-transitoiy, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor. The computer program causes the computing system to receive data from the device and / or the one or more sensors, analyze, via one or more algorithms, the received data, and control the stimulus modality. For example, the computer program may cause the computing system to control one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

[0166] As disclosed in more detail herein, devices of the invention may be configured as a head- worn device with the stimulation modality housed within the head-worn device. For example, the head-worn device may include a light source housed within the head-worn device such that the visual stimulus is delivered to the user’s eyes while the user wears the device. For example, the head-worn device may be a headset or eyewear that fits a user similarly to a pair of glasses. The device may be configured as reading glasses such that the light source may be housed in a frame of the glasses. The head-worn device, i.e. headset and / or eyewear, may partially cover the user’s face and eyes, for example, similar to a VR headset. In some embodiments, the head- worn device may entirely cover the user’s face and eyes, in the manner of a mask. The head- worn device partially or fully covers the user’s head in the manner of a helmet.

[0167] Additionally and / or alternatively, devices of the invention may be configured as a tabletop device designed for a user to sit or stand in front of to receive the visual stimulus delivered by the device. In this way, it is not necessary for the user to wear the device to receive the visual stimulus. For example, the device may be built into a display device, for example, a television, cell phone, tablet, and the like. In some embodiments, devices of the invention may be configured for incorporation into room lighting fixtures. The systems of the invention may be configured such that the device may alternate between delivering a defined visual stimulus and providing normal room lighting. In some embodiments, devices of the system may be configured to attach to an external device such as a cell phone, laptop, tablet or headset.

[0168] In general, any suitable light intensity may be used. For example, the light may have an intensity of about 1 x 1018to x 1019photons / cm2 / s, e.g. 2 - 6 x 1018photons / cm2 / s, for example about 4 x 1018photons / cm2 / s. The power and electromagnetic frequency of the light may be selected to achieve the desired light intensity.

[0169] The visual stimulus may be delivered at any desired pulse frequency. In some embodiments, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz, inclusive. The visual stimulus may be a burst of light, and / or pulsing, flashing or flickering light. The light pulses may have a frequency of at least 51 Hz, at least 52 Hz, at least 55 Hz, at least 57 Hz, or at least 58 Hz. In other embodiments the light pulses have a frequency of up to 70 Hz, up to 68 Hz, up to 65 Hz or up to 63 Hz. Suitable preferred frequency ranges for the light pulses include e.g. about 50 to about 70 Hz, 51 to 70 Hz, 53 to 70 Hz, 55 to 70 Hz, 55 to 65 Hz and 57 to 63 Hz. Most preferably the light pulses have a frequency of about 60 Hz.

[0170] Delivery of the visual stimulus may be at a pre-defined pulse frequency. Delivery of the visual stimulus may be at a varying frequency. Each light pulse may, for example, have a duration of less than 20, less than 15 or less than 10 milliseconds, e.g. about 1 ms, about 5 ms or about 8 ms. For instance the light pulses may have a duration of about 5 to 12 ms or about 6 to 10 ms. For example, in some embodiments, the light pulses have a frequency of about 60 Hz, each light pulse has a duration of about 8.3 ms and the light pulses are separated by an interval of about 8.3 ms (i.e. a dark interval of 8.3 ms with no light).

[0171] The light source may be any source capable of delivering a visual stimulus at defined wavelengths and / or pulse frequencies. In some embodiments, the light source may be one or more of a single point of light and an array of light sources. The light source may be one or more of a light-emitting diode (LED) and an array of LEDs. The device may include a single light source configured to deliver the visual stimulus to both eyes of the patient. The device may include two light sources configured to deliver the visual stimulus to a respective eye of the patient. As disclosed herein, the wave form of light emitted from the light source may be a repeating pattern of stimulation. The wave form may be any form. In some embodiments, the repeating pattern of stimulation may be one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

[0172] The light source may be white light containing all the colors in the color spectrum. In some embodiments, light of a specific color may be used. The light may be any wavelength or range of wavelengths. In some embodiments, light of a specific wavelength or range of wavelengths is used. In some embodiments, the color, the wavelength, and / or the range of wavelengths of the light of the light source used provides a desired strength of or effect on the activation of microglia cells. In some embodiments, the light source may be a pre-defined wavelength or wavelength range.

[0173] The visual stimulus may be a single point of light or an array of light sources. It will be appreciated that the devices of the invention may employ any light source for generating a visual stimulus at desired wavelengths and / or pulse frequencies. In some embodiments, the light source comprises a pre-defined wavelength range. For example, the light pulses may be in the visible wavelength range, typically the range of what the human eye can detect: 380 to 740 nm. Thus, the light may be of any color. Devices of the invention may include one or more light sources of varying wavelengths such that the visual stimulus may be delivered at different frequencies and wavelengths. In non-limiting embodiments, the light spectrum utilized may range from 440 nm to 770 nm corresponding to daylight wavelengths. In some embodiments, the light intensity may be adjustable to ensure comfort during delivery of the therapy. For example, the light intensity may be adjustable to between 14 and 113 pW. Systems of the invention include one or more sensors. For example, the systems may include a sensor / feedback component such as one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, an eye-tracking sensor, brain imaging data, brain activity data, and / or biometric sensors. The EEG may be an EEG array. The sensors may allow for real-time feedback on how the system is operating. For example, the one or more sensors may deliver feedback as to whether the visual stimulation is delivered at a desired frequency and / or strength of stimulation. The systems, via the one or more sensors, may be configured to provide feedback to a clinician as to the patient’s improvement or progression before, during, or after treatment. For example, the systems may provide feedback to a user and / or a clinician as to whether the patient is correctly using the device. The systems may provide feedback to the user and / or the clinician as to whether the patient is adhering to a treatment regimen using the device.

[0174] Further, the systems include a computing system operably associated with the device. The computing system may comprise a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program. The computer program may be executable by the processor to cause the computing system to receive data from the device and / or the one or more sensors, analyze, via one or more algorithms, the received data, and control one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

[0175] As disclosed in more detail herein, the systems, via the computing system, may interface with a control system architecture comprising, in non-limiting examples, one or more of a computer, a processor, a network, and / or a graphical user interface (GUI) for controlling one or more user inputs, defining a treatment protocol, controlling and / or monitoring the delivery of the visual stimulus, and displaying one or more outputs from the system. The control system architecture, via the computing system, may generate a stimulus, control emission of the stimulus, monitor emission of the stimulus / results, and / or process feedback regarding the stimulus / results. The control system architecture may provide for detecting and providing feedback regarding delivery of the visual stimulus including, for example, whether microglia cells are activated, changes in the PNN are induced, neuroplasticity is improved, subject sensitivity, cognitive function, physical or chemical changes, stress, safety, and the like. In some embodiments, the computing system further comprises a user interface operably associated with the computing system. The user interface may be provided via a software application accessible using one or more of a computer, a smartphone, and a tablet. The received and analyzed data may be displayed on an associated display device via the software application.

[0176] The user interface of the systems may allow the user to interact with and control the operation of the device. For example, the user interface, may include one or more input / output mechanisms, such as a keyboard, knobs, buttons, scroll wheels, or the like, with which a user can interact so as to operate the device. The user interface may be physically connected to the device, may be integrally formed with the device, or may be located remotely. The user interface may be a handheld device, e.g., a smart tablet, a smart phone, or a specialty device produced for the device. User interaction may be implemented on a computer having an VO device, e.g., a CRT, LCD, LED, or projection device for displaying information to the user and an input or output device such as a keyboard and a pointing device, (e.g., a mouse or a trackball), by which the user may provide input to the computer. In some embodiments, the systems may include a display integrated into the device, for example, a display screen as part of a head-worn device or a table-top device. In some embodiments, the systems includes a display that is operably associated with the device via, for example, a wired or wireless connection.

[0177] In some embodiments of the systems, user interaction with the system may be via a form of sensory feedback, for example, visual feedback, auditory feedback, or tactile feedback, and input from the user may be received in any form, including acoustic, speech, or tactile input.

[0178] As disclosed herein, the systems may provide for monitoring and controlling various aspects or parameters associated with delivery of the visual stimulus. For example, the systems may include a communication interface as part of the user interface to provide for communication with the subject, a healthcare provider, a caretaker, a clinical research investigator, a database, a monitoring application, and the like.

[0179] Monitoring and controlling various parameters related to the operation of the systems may be performed using any type of computing system or device. The computing system may be integrated into the device such as into a head-worn device or in a standalone device. Alternatively and additionally, the computing system may be operably connected to the device via a wired or wireless connection. The systems may be operably connected with, for example, a personal and / or portable computing device, such as a smartphone, tablet, laptop computer, or the like.

[0180] In some embodiments, the computing system may be configured to communicate with and exchange data over a network. The network may represent, for example, a private or nonprivate local area network (LAN), personal area network (PAN), storage area network (SAN), backbone network, global area network (GAN), wide area network (WAN), or collection of any such computer networks such as an intranet, extranet or the Internet (i.e., a global system of interconnected network upon which various applications or service run including, for example, the World Wide Web). In alternative embodiments, the communication path between the user interface and the systems of the invention may be, in whole or in part, a wired connection.

[0181] The network may be any network that carries data. Non-limiting examples of suitable networks that may be used as network include Wi-Fi wireless data communication technology, the internet, private networks, virtual private networks (VPN), public switch telephone networks (PSTN), integrated services digital networks (ISDN), digital subscriber link networks (DSL), various second generation (2G), third generation (3G), fourth generation (4G), fifth generation (5G), and future generations of cellular-based data communication technologies, Bluetooth radio, Near Field Communication (NFC), the most recently published versions of IEEE 802.11 transmission protocol standards, other networks capable of carrying data, and combinations thereof.

[0182] In some embodiments, the network may be chosen from the internet, at least one wireless network, at least one cellular telephone network, and combinations thereof. As such, the network may include any number of additional devices, such as additional computers, routers, and switches, to facilitate communications. In some embodiments, the network may be or include a single network, and in other embodiments the network may be or include a collection of networks.

[0183] In some embodiments of the systems, the device includes a head-worn frame. At least a portion of the head-worn frame may define eyewear such that the light source is housed within a frame of the eyewear. The eyewear may include a virtual reality display configured to display virtual reality content to the subject in conjunction with delivery of the visual stimulus to the subject. The device may be configured as a headset that fits similar to a pair of glasses. The device may be configured to cover the eyes and at least partially cover the face of a user, similar to a virtual reality headset. The device may be configured to fully cover the eyes and face of a user, similar to a mask. The device may be configured to at least partially or fully cover the eyes, face, and head of a user, similar to a helmet.

[0184] Where the device is configured to fit as a pair of glasses, the light source may be housed in a frame of the glasses. The glasses may be any type of glasses, for example sunglasses, and / or prescription or non-prescription reading glasses such that the delivery of the visual stimulus to the user is incorporated into a user’s daily activities. In this way, treatment may be integrated into a patient’s daily activities. The glasses may be virtual reality glasses or other glasses designed for spatial computing.

[0185] Devices of the systems may be configured similar to a virtual reality (VR) headset or other spatial computing device. In such embodiments, the light source may be housed at the edges of a display screen, such as a virtual reality (VR) screen. In this way, the glasses, and / or VR headset may be transparent so that the user may see through the device while the head-worn device is worn. Where the device is configured as glasses or a VR headset, a transparent display may allow for a user to use the center of the screen for reading, watching a video, engaging in a virtual therapy session, etc. Accordingly, the head-worn device may comprise one or more lenses and / or display that may be transparent, semi-transparent, opaque, or may partially or completely block external light.

[0186] In some embodiments of systems of the invention, the eyewear includes one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject.

[0187] As discussed in more detail herein, in some embodiments, delivery of the visual stimulus is incorporated into a form of video such that delivery of the visual stimulus may be unnoticeable by the user. In some embodiments, the virtual reality content includes one or more of a virtual therapy session, a wellness application, a brain-training application, a mindfulness application, a video, a meditation application, rehabilitation therapy, functional training, and fitness training.

[0188] The frame of the head-worn device may be any material suitable for housing the one or more light sources. For example, the frame may be one or more of a metal, alloy, polymer, or other material that is suitably light-weight with the structural strength and flexibility for housing the components of the device.

[0189] FIG. 4 illustrates a system 400 according to one embodiment of the invention. The systems may include a device 401 that may be a head-worn device designed to cover the user’s eyes and to partially cover the user’s face, similar to a VR headset. The head-worn device 401 may be transparent, semi-transparent, opaque, or may partially or completely block external light from the user’s eyes. The device may include at least one light source configured to deliver to the subject a visual stimulus at a defined pulse frequency, such that the visual stimulus activates microglia cells to target the perineuronal net (PNN) in the brain of the subject such that neuroplasticity is improved.

[0190] The device may be worn around the face and head, resembling a pair of safety goggles. The device may be designed to be compatible with an EEG cap. For example, the EEG cap may be an 8-channel system configured to cover a range of frequency spectrum due to a higher sampling rate.

[0191] The light source (not shown) may be integrated into the frame of the headwear. The light source may be configured to direct flashing light at 50-70 Hz (e.g. 60 Hz) towards the eyes of a subject. The light source may be e.g. a series of LEDs, which may be mounted in the suitable headset for directing light towards the eyes. The light source may be, for example, a strip of LEDs integrated around the ocular component to direct light tangentially to, for example, the periphery of the wearer’s eyes. The LED strip may have any number of LEDs per meter. For example, the LED strip may have 120 LEDs per meter. The LED strip may be integrated at any position in or on the device that is suitable to deliver to the subject a visual stimulus. In one embodiment, the device may include an LED strip integrated into a headset such that the LEDs emit a square-wave function of white light at a 60Hz band with a duty cycle of 50%.

[0192] As disclosed herein, the systems may include one or more sensors 413, for example pressure, temperature, and hear rate sensors, eye-tracking sensors and / or an EEG array.

[0193] Further, the systems may include a computing system 405 operably associated with the device 401 and the one or more sensors 413. The computing system may be integrally formed with the head-worn device or may be operably connected to the head-worn device 401. The computing system may comprise a non-transitory, computer-readable storage medium 407 coupled to a processor 409 and encoded with the computer program. The computing system may interface with control system architecture on a user interface 411, such as a computer, table, display, and / or smart phone. The user interface may be integrally formed with the system and / or the device, may be connected to the system and / or the device via a wired or wireless connection, or may be located remotely.

[0194] The head-worn frame may include one or more sensors, such as pressure, temperature, eye-tracking, heart rate sensors, or biometric sensors. The one or more sensors may be integrally formed with the head-worn frame. The one or more sensors may be operably connected to the device and / or the system via a wired or wireless connection. For example, the device may include an EEG apparatus, such as an EEG array integrated into the head-worn frame. The EEG array may be removable from the head-worn frame. The EEG may be a removable component of the system and / or the device that may be added and / or removed as needed. The EEG array may be a full array. The EEG array may be a few electrodes to give certain desired data. In nonlimiting examples, the device may include 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more EEG electrodes integrated as part of the device and / or removably associated with the device. The EEG apparatus, i.e. EEG array may detect brain activity in the subject via a series of electrodes. The detected brain activity may be transmitted to the user interface 411. Transmission of data from the one or more sensors to the user interface may be via any suitable communications protocol or network, for example via Bluetooth.

[0195] The user interface 411 may also communicate with the light source to allow a user to set parameters such as the duration, intensity and frequency of the emitted light based on feedback from the one or more sensors. The systems may thus modulate the intensity and / or duration of the visual stimulus and automatically turn the device on or off as needed. A user may interact with the system and monitor the brain activity directly from the user interface. The EEG recording may be transmitted to the user interface such that the EEG recording may be saved and transmitted to a clinician.

[0196] The intensity, frequency and / or duration of the light emitted by the light source may be modulated based on whether, for example, 60 Hz activity in the brain is detected. If this activity is not detected or only weak signals are detected, the device may increase the intensity of the light emitted by the light source. Alternatively the device may modulate the frequency of emitted light, e.g. by 1 or 2 Hz within the 50-70 Hz frequency band, in order to identify a suitable frequency for generating 60 Hz activity. If the processor determines that 50-70 Hz activity is detected for a sufficient period of time, the processor may switch off the light source.

[0197] The period of time may be any time period determined to provide increased neuroplasticity via microglia-mediated remodeling of the PNN. For example, the visual stimulus may be emitted for at least e.g. 1 min, 5 mins, 10 mins, 20 mins, 30 minutes, 1 hour, 1.5 hours or 2 hours, preferably for at least 1 hour, at least 1.5 hours or at least 2 hours, more preferably 1 to 3 hours. The duration of the exposure of the subject to the visual stimulus and / or the administration of the visual stimulus to the subject may be e.g. 1 to 3 hours, for instance about one hour. The exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated over a time period. For example, the exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated at least once per day over the time period. The time period may include, but is not limited to, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, and / or one month (or longer, such as once daily for the rest of the subject's life). In a particular example, the period of time is 2 hours for 5 consecutive days. In some embodiments, the system is used in combination with pharmacological treatments.

[0198] Thus, the systems may constantly, regularly, or intermittently track and analyze the brain activity of the subject. The systems may provide a real-time neurofeedback to the user. Therefore in some embodiments, the duration or intensity of the visual stimulus, i.e. flickering light, is adjusted for each subject on a personalized basis. As disclosed herein, the components of the systems may be embodied in the device or in separate linked devices.

[0199] As disclosed herein, the computing system may be operable to receive data from the system and / or device and / or one or more sensors and analyze the data via one or more algorithms. Thus, the system may provide a feedback loop for automatically adjusting the visual stimulus parameters. For example, based on data received by the EEG and analyzed by the computing system, the system may automatically adjust parameters associated with delivering the visual stimulus such that treatment is personalized for the user. In non-limiting examples, the parameters may be, for example, one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject. The algorithms may be one or more supervised or unsupervised machine learning (ML) algorithms such as artificial neural networks, linear discriminant analysis, decision tree / random forest, K-nearest neighbor, naive Bayes, and support vector machine for analyzing EEG data. In some embodiments, the one or more algorithms may include a cross coupling analysis method, wherein low frequency signal data may be received and correlated to high frequency signals, for example signals from the EEG. In some embodiments, the one or more algorithms may include a cross coupling analysis method, wherein low frequency signal data may be received and correlated to high frequency signals, for example signals from the EEG.

[0200] The systems may include one or more pressure sensors on the headset to record if the device is being worn correctly and to provide feedback as to whether the patient is adhering to a treatment protocol. In some embodiments, eye tracking sensors may be incorporated to provide feedback as to the patient’s use of the system and the effectiveness of the therapy. In some embodiments, the systems may include other sensors, such as heart rate, skin temperature sensors, and / or other biometric sensors. The sensors may be used to provide feedback during a treatment protocol. In some embodiments, the system is operable to communicate with external sensors not part of the system itself. In some embodiments, the data received and analyzed may include brain imaging and brain activity recording. Thus, the device may be configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0201] In some embodiments, the system includes a display sized and configured for placement on a tabletop. The light source may include an LED array positioned on a front side of the display such that the visual stimulus is delivered to the subject when a subject is positioned facing the front side of the display. In non-limiting examples, the devices of the system may be integrated into any display type, such as a television, tablet, or phone. Devices of the system may include at least one light source. The at least one light source may be integrated into a frame of the device, for example, positioned around the display screen. In some embodiments, the light source may be an integrated part of the display screen of the device. The device may be placed in front of the patient rather than being a wearable device. The device may include an eye-tracking component. The eye-tracking component may provide feedback as to whether a patient is using the device according to a defined treatment protocol.

[0202] The systems may be configured such that the device is a lighting fixture. The lighting fixture may be a floor lamp, a table lamp, a ceiling fixture, a sconce, or the like. The systems may be operable to actuate the light source for delivery of the visual stimulus and actuate normal room lighting once delivery of the visual stimulus is complete. For example, the systems may actuate the light source for delivery of the visual stimulus for a set period of time. The set period of time may be programmed such that the visual stimulus is actuated at certain hours of the day. In some embodiments, the system comprises one or more sensors for sensing if a patient is in the room before actuating the light source to deliver the visual stimulus. For example, the one or more sensors may be a motion sensor, a biometric sensor, or the like.

[0203] In some embodiments, the systems may include other forms of sensory stimulation. For example, the system may include a sound source. In some embodiments, the sound source comprises an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus. The sound source may include bone conduction, i.e. direct vibration of the bones in the head, in the same or different frequency as the visual stimulation. The bone conduction may be an integrated headset or headphones. The bone conduction may be a headset / headphones operably connected to the device.

[0204] In particular, the sound source may be configured to generate auditory pulses in a similar frequency to delivered by the light source. The sound source may be integrally formed with the device. The sound source may be operably connected to the system via a wired or wireless connection. The sound source may generate, for example, a click train with a click frequency of e g. 50 to 70 Hz, 51 to 70 Hz, 53 to 70 Hz, 55 to 70 Hz, 55 to 65 Hz and 57 to 63 Hz. The clicks may have a preferred frequency of about 60 Hz. The sound may be generated at a same or different frequency as delivery of the visual stimulus.

[0205] Each click in the click train may preferably have a duration of less than 10 ms, e.g. about 1 ms. Each click in the click train may have a sound pressure level of e.g. about 1 dB to about 85 dB, about 30 dB to about 70 dB, or about 60 dB to about 65 dB. Alternatively or in addition, the sound may be emitted at a volume that varies over a selected period of time. The at least one electroacoustic transducer may include at least one headphone or speaker. The system may include noise-cancelling features for reducing ambient noise. The system may reduce ambient noise using passive noise isolation and / or active noise cancellation.

[0206] In some embodiments, the systems may include a means for tactile stimulation delivered at certain frequencies to correspond with delivery of the visual stimulus. In some embodiments, the systems may comprise a timer connected to the one or more light sources. The timer may enable the light source to emit light for a selected period of time. For example, the visual stimulus may be emitted for at least e.g. 1 min, 5 mins, 10 mins, 20 mins, 30 minutes, 1 hour, 1.5 hours or 2 hours, preferably for at least 1 hour, at least 1.5 hours or at least 2 hours, more preferably 1 to 3 hours. The duration of the exposure of the subject to the visual stimulus and / or the administration of the visual stimulus to the subject may be e.g. 1 to 3 hours, for instance about one hour. The exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated over a time period. For example, the exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated at least once per day over the time period. The time period may include, but is not limited to, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, and / or one month (or longer, such as once daily for the rest of the subject's life). In a particular example, the period of time is 2 hours for 5 consecutive days.

[0207] Systems of the invention may be used for treating a mental disease, disorder, or related symptoms. In non-limiting examples, the mental disease, disorder, or related symptoms may be one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

[0208] Methods for treating a mental disease or disorder

[0209] Aspects of the invention provide methods for treating a mental disease, disorder, or related symptoms thereof in a subject. The methods for treating a mental disease, disorder, or related symptoms include inducing the mechanism of action via one or more stimulation methods. Accordingly, the mechanism of action may be induced by a stimulation modality such as via visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound.

[0210] FIG. 5 illustrates a block diagram of a method 500 for treating a mental disease or disorder in a subject according to one embodiment of the invention. The method includes providing a device 501 comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor, and delivering 503 the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

[0211] In some embodiments, the visual stimulus may be considered to be analogous to the administration of a pharmaceutical composition such as ketamine, in the sense that it involves delivery of photons to a subject as part of a therapeutic method.

[0212] Accordingly, aspects of the invention provide for delivering a visual stimulus at a defined pulse frequency for use in medicine. As described herein, the light pulses typically have a frequency of about 50 to about 70 Hz inclusive. The light pulses or photons may be used to induce entrainment to activate microglia cells to target the PNN in the brain. Thus methods of the invention may be used to treat a disease or condition associated with dysfunction in neuronal plasticity.

[0213] In non-limiting examples, methods of the invention may be used to treat a mental disease, disorder, or related symptoms such as general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, postmenopausal depression, fear based disorders, and sleep disorders.

[0214] Methods of the invention may be used to treat subjects who cannot tolerate ketamine treatment, for example due to side effects associated with this drug. Thus, devices, systems, and methods of the invention may provide a similar effect in treating patients with a mental disease, disorder, or related symptoms as does ketamine, without the side effects of ketamine. Methods, systems, and devices as described herein may be used alone or in combination with pharmaceutical compositions in order to promote neuronal plasticity. For instance, systems of the invention providing light pulses at a frequency of about 50 to about 70 Hz may be applied to a subject in combination with a pharmaceutical composition comprising an active agent, such as ketamine. In such cases, combined use of multiple treatment modalities may provide synergistic effects in treatment, reduced side effects and / or enable a lower dose of an active agent (e g. ketamine) to be used.

[0215] As disclosed in more detail herein, devices of the invention may be configured as a head- worn device with the light source housed within the head-worn device and the visual stimulus is delivered to the user’s eyes while the user wears the device. For example, the head-worn device may be a headset or eyewear that fits a user similarly to a pair of glasses. The device may be configured as reading glasses such that the light source may be housed in a frame of the glasses. The head-worn device, i.e. headset and / or eyewear, may partially cover the user’s face and eyes, for example, similar to a VR headset. In some embodiments, the head-worn device may entirely cover the user’s face and eyes, in the manner of a mask. The head-worn device partially or fully covers the user’ s head in the manner of a helmet.

[0216] Additionally and / or alternatively, devices of the invention may be configured as a tabletop device designed for a user to sit or stand in front of to receive the visual stimulus delivered by the device. In this way, it is not necessary for the user to wear the device to receive the visual stimulus. For example, the device may be built into a display device, for example, a television, cell phone, tablet, and the like. In some embodiments, devices of the invention may be configured for incorporation into room lighting fixtures. The devices of the invention may be configured such that the device may alternate between delivering a defined visual stimulus and providing normal room lighting. Devices of the invention may also be configured to attach to one or more external devices such as a laptop or phone. For example, in some embodiments, the device is configured to attach to one or more of an external cell phone, a tablet a display device, a television, and a headset.

[0217] In general, any suitable light intensity may be used. For example, the light may have an intensity of about 1 x 1018to x 1019photons / cm2 / s, e.g. 2 - 6 x 1018photons / cm2 / s, for example about 4 x 1018photons / cm2 / s. The power and electromagnetic frequency of the light may be selected to achieve the desired light intensity.

[0218] The visual stimulus may be delivered at any desired pulse frequency. In some embodiments, the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz, inclusive. The visual stimulus may be a burst of light, and / or pulsing, flashing or flickering light. The light pulses may have a frequency of at least 51 Hz, at least 52 Hz, at least 55 Hz, at least 57 Hz, or at least 58 Hz. In other embodiments the light pulses have a frequency of up to 70 Hz, up to 68 Hz, up to 65 Hz or up to 63 Hz. Suitable preferred frequency ranges for the light pulses include e.g. about 50 to about 70 Hz, 51 to 70 Hz, 53 to 70 Hz, 55 to 70 Hz, 55 to 65 Hz and 57 to 63 Hz. Most preferably the light pulses have a frequency of about 60 Hz.

[0219] Delivery of the visual stimulus may be at a pre-defined pulse frequency. Delivery of the visual stimulus may be at a varying frequency. Each light pulse may, for example, have a duration of less than 20, less than 15 or less than 10 milliseconds, e.g. about 1 ms, about 5 ms or about 8 ms. For instance the light pulses may have a duration of about 5 to 12 ms or about 6 to 10 ms. For example, in some embodiments, the light pulses have a frequency of about 60 Hz, each light pulse has a duration of about 8.3 ms and the light pulses are separated by an interval of about 8.3 ms (i.e. a dark interval of 8.3 ms with no light).

[0220] The light source may be any source capable of delivering a visual stimulus at defined wavelengths and / or pulse frequencies. In some embodiments, the light source may be one or more of a single point of light and an array of light sources. The light source may be one or more of a light-emitting diode (LED) and an array of LEDs. The device may include a single light source configured to deliver the visual stimulus to both eyes of the patient. The device may include a two light sources configured to deliver the visual stimulus to a respective eye of the patient. As disclosed herein, the wave form of light emitted from the light source may be a repeating pattern of stimulation. The repeating pattern of stimulation may be one or more one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

[0221] The light source may be white light containing all the colors in the color spectrum. In some embodiments, light of a specific color may be used. The light may be any wavelength or range of wavelengths. In some embodiments, light of a specific wavelength or range of wavelengths is used. In some embodiments, the color, the wavelength, and / or the range of wavelengths of the light of the light source used provides a desired strength of or effect on the activation of microglia cells.

[0222] The visual stimulus may be a single point of light or an array of light sources. It will be appreciated that the devices of the invention may employ any light source for generating a visual stimulus at desired wavelengths and / or pulse frequencies. In some embodiments, the light source comprises a pre-defined wavelength range. For example, the light pulses may be in the visible wavelength range, typically the range of what the human eye can detect: 380 to 740 nm. Thus, the light may be of any color. Devices of the invention may include one or more light sources of varying wavelengths such that the visual stimulus may be delivered at different frequencies and wavelengths. In non-limiting embodiments, the light spectrum utilized may range from 440 nm to 770 nm corresponding to daylight wavelengths. In some embodiments, the light intensity may be adjustable to ensure comfort during delivery of the therapy. For example, the light intensity may be adjustable to between 14 and 113 pW.

[0223] In some embodiments of the devices of the invention, the devices include one or more sensors. For example, the device may include a sensor / feedback component such as one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor.

[0224] Referring back to FIG. 5, the method may further include receiving data 505 from the device and / or the one or more sensors, analyzing 507, via one or more algorithms, the received data, and controlling 509 treatment parameters. Controlling may include adjusting one or more of a frequency, duration, and intensity of the visual stimulus.

[0225] For embodiments of the device / system that include an EEG, the EEG may be an EEG array. The device, via the one or more sensors, may allow for real-time feedback on how the device is operating. For example, the one or more sensors may deliver feedback as to whether the visual stimulation is delivered at a desired frequency and / or strength of stimulation. The one or more sensors may be configured to provide feedback to a clinician as to the patient’s improvement or progression before, during, or after treatment. For example, the device may provide feedback to a user and / or a clinician as to whether the patient is correctly using the technology. The device may provide feedback to the user and / or the clinician as to whether the patient is adhering to a treatment regimen using the device.

[0226] Further, the device may include a computing system operably associated with the device. The computing system may comprise a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program. The computer program may be executable by the processor to cause the computing system to receive data from the device and / or the one or more sensors, analyze, via one or more algorithms, the received data, and control one or more of a frequency, duration, and intensity of the visual stimulus.

[0227] As disclosed in more detail herein, the device, via the computing system, may interface with a control system architecture comprising, in non-limiting examples, one or more of a computer, a processor, a network, and / or a graphical user interface (GUI) for controlling one or more user inputs, defining a treatment protocol, controlling and / or monitoring the delivery of the visual stimulus, and displaying one or more outputs from the device. The control system architecture, via the computing system, may generate a stimulus, control emission of the stimulus, monitor emission of the stimulus / results, and / or process feedback regarding the stimulus / results. The control system architecture may provide for detecting and providing feedback regarding delivery of the visual stimulus including, for example, whether microglia cells are activated, changes in the PNN are induced, neuroplasticity is improved, subject sensitivity, cognitive function, physical or chemical changes, stress, safety, etc.

[0228] In some embodiments of the device, the computing system further comprises a user interface operably associated with the computing system, wherein the user interface is provided via a software application accessible using one or more of a computer, a smartphone, and a tablet, wherein the received and analyzed data is displayed on an associated display device via the software application.

[0229] The user interface may allow the user to interact with and control the operation of the device. For example, the device, via the user interface, may include one or more input / output mechanisms, such as a keyboard, knobs, buttons, scroll wheels, or the like, with which a user can interact so as to operate the device. The user interface may be physically connected to the device, may be integrally formed with the device, or may be located remotely. The user interface may be a handheld device, e.g., a smart tablet, a smart phone, or a specialty device produced for the device. User interaction may be implemented on a computer having an I / O device, e.g., a CRT, LCD, LED, or projection device for displaying information to the user and an input or output device such as a keyboard and a pointing device, (e.g., a mouse or a trackball), by which the user may provide input to the computer. In some embodiments, the device may include a display integrated into the device, for example, a display screen as part of a head-worn device or a table-top device. In some embodiments, the device includes a display that is operably associated with the device via, for example, a wired or wireless connection.

[0230] In some embodiments of the device, user interaction with the device may be via a form of sensory feedback, for example, visual feedback, auditory feedback, or tactile feedback, and input from the user may be received in any form, including acoustic, speech, or tactile input.

[0231] As disclosed herein, the device, via the computing system, may provide for monitoring and controlling various aspects or parameters associated with delivery of the visual stimulus. For example, the device may include a communication interface as part of the user interface to provide for communication with the subject, a healthcare provider, a caretaker, a clinical research investigator, a database, a monitoring application, and the like.

[0232] Monitoring and controlling various parameters related to the operation of the device may be performed using any type of computing system or device. The computing system may be integrated into the device such as into a head-worn device or in a standalone device. Alternatively and additionally, the computing system may be operably connected to the device via a wired or wireless connection. The device may be operably connected with, for example, a personal and / or portable computing device, such as a smartphone, tablet, laptop computer, or the like.

[0233] In some embodiments, the computing system may be configured to communicate with and exchange data over a network. The network may represent, for example, a private or nonprivate local area network (LAN), personal area network (PAN), storage area network (SAN), backbone network, global area network (GAN), wide area network (WAN), or collection of any such computer networks such as an intranet, extranet or the Internet (i.e., a global system of interconnected network upon which various applications or service run including, for example, the World Wide Web). In alternative embodiments, the communication path between the user interface and the systems of the invention may be, in whole or in part, a wired connection.

[0234] The network may be any network that carries data. Non-limiting examples of suitable networks that may be used as network include Wi-Fi wireless data communication technology, the internet, private networks, virtual private networks (VPN), public switch telephone networks (PSTN), integrated services digital networks (ISDN), digital subscriber link networks (DSL), various second generation (2G), third generation (3G), fourth generation (4G), fifth generation (5G), and future generations of cellular-based data communication technologies, Bluetooth radio, Near Field Communication (NFC), the most recently published versions of IEEE 802.11 transmission protocol standards, other networks capable of carrying data, and combinations thereof. In some embodiments, the device may utilize any suitable radio communication method (e.g. Bluetooth) to communicate with the user interface, e.g. a mobile device operating a suitable app-

[0235] In some embodiments, the network may be chosen from the internet, at least one wireless network, at least one cellular telephone network, and combinations thereof. As such, the network may include any number of additional devices, such as additional computers, routers, and switches, to facilitate communications. In some embodiments, the network may be or include a single network, and in other embodiments the network may be or include a collection of networks.

[0236] In some embodiments, the device includes a head-worn frame. At least a portion of the head-worn frame may define eyewear such that the light source is housed within a frame of the eyewear. The eyewear may include a virtual reality display configured to display virtual reality content to the subject in conjunction with delivery of the visual stimulus to the subject. The device may be configured as a headset that fits similar to a pair of glasses. The device may be configured to cover the eyes and at least partially cover the face of a user, similar to a virtual reality headset. The device may be configured to fully cover the eyes and face of a user, similar to a mask. The device may be configured to at least partially or fully cover the eyes, face, and head of a user, similar to a helmet.

[0237] In some embodiments of the device configured to fit as a pair of glasses, the light source may be housed in a frame of the glasses. The glasses may be any type of glasses, for example sunglasses, and / or prescription or non-prescription reading glasses such that the delivery of the visual stimulus to the user is incorporated into a user’s daily activities. In this way, treatment may be integrated into a patient’s daily activities. The glasses may be virtual reality glasses or other glasses designed for spatial computing.

[0238] The device may be configured similar to a virtual reality (VR) headset or other spatial computing device. In such embodiments, the light source may be housed at the edges of a display screen, such as a virtual reality (VR) screen. In this way, the glasses, and / or VR headset may be transparent so that the user may see through the device while the head-worn device is worn. Where the device is configured as glasses or a VR headset, a transparent display may allow for a user to use the center of the screen for reading, watching a video, engaging in a virtual therapy session, etc. Accordingly, the head-worn device may comprise one or more lenses and / or display that may be transparent, semi-transparent, opaque, or may partially or completely block external light.

[0239] In some embodiments, the eyewear includes one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject. As discussed in more detail herein, in some embodiments, delivery of the visual stimulus is incorporated into a form of video such that delivery of the visual stimulus may be unnoticeable by the user. In some embodiments, the virtual reality content includes one or more of a virtual therapy session, a wellness application, a brain-training application, a mindfulness application, a video, a meditation application, rehabilitation therapy, functional training, and fitness training. The frame of the head-worn device may be any material suitable for housing the one or more light sources. For example, the frame may be one or more of a metal, alloy, polymer, or other material that is suitably light-weight with the structural strength and flexibility for housing the components of the device.

[0240] Parameters of the delivery of the visual stimulation may be controlled by the system.

[0241] The parameters may include, in non-limiting examples, a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject. For example, the intensity, frequency and / or duration of the light emitted by the light source may be modulated based on whether, for example, 60 Hz activity in the brain is detected. If this activity is not detected or only weak signals are detected, the device may increase the intensity of the light emitted by the light source. Alternatively the device may modulate the frequency of emitted light, e.g. by 1 or 2 Hz within the 50-70 Hz frequency band, in order to identify a suitable frequency for generating 60 Hz activity. If the processor determines that 50-70 Hz activity is detected for a sufficient period of time, the processor may switch off the light source.

[0242] The period of time may be any time period determined to provide increased neuroplasticity via microglia-mediated remodeling of the PNN. For example, the visual stimulus may be emitted for at least e.g. 1 min, 5 mins, 10 mins, 20 mins, 30 minutes, 1 hour, 1.5 hours or 2 hours, preferably for at least 1 hour, at least 1.5 hours or at least 2 hours, more preferably 1 to 3 hours. The duration of the exposure of the subject to the visual stimulus and / or the administration of the visual stimulus to the subject may be e.g. 1 to 3 hours, for instance about one hour. The exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated over a time period. For example, the exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated at least once per day over the time period. The time period may include, but is not limited to, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, and / or one month (or longer, such as once daily for the rest of the subject's life). In a particular example, the period of time is 2 hours for 5 consecutive days.

[0243] Thus, the method may include using the device to constantly, regularly, or intermittently track and analyze the brain activity of the subject. The device may provide a real-time neurofeedback to the user. Therefore in some embodiments, the duration or intensity of the visual stimulus, i.e. flickering light, is adjusted for each subject on a personalized basis. As disclosed herein, the components of the device may be embodied in the same device or in separate linked devices.

[0244] As disclosed herein, the computing system may be operable to receive data from the device and / or one or more sensors and analyze the data via one or more algorithms. In some embodiments, the data includes brain imaging data and / or brain activity data. Thus, the device may provide a feedback loop for automatically adjusting the visual stimulus parameters. For example, based on data received by the EEG and analyzed by the computing system, the device may automatically adjust parameters associated with delivering the visual stimulus such that treatment is personalized for the user. The parameters may be, for example, one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject..

[0245] The algorithms may be one or more supervised or unsupervised machine learning (ML) algorithms such as artificial neural networks, linear discriminant analysis, decision tree / random forest, K-nearest neighbor, naive Bayes, and support vector machine for analyzing EEG data. In some embodiments, the one or more algorithms may include a cross coupling analysis method, wherein low frequency signal data may be received and correlated to high frequency signals, for example signals from the EEG.

[0246] The device may include one or more pressure sensors on the headset to record if the device is being worn correctly and to provide feedback as to whether the patient is adhering to a treatment protocol. In some embodiments, eye tracking sensors may be incorporated to provide feedback as to the patient’s use of the device and the effectiveness of the therapy. In some embodiments, the device may include other sensors, such as heart rate and / or skin temperature sensors. The sensors may be used to provide feedback during a treatment protocol. In some embodiments, the device is operable to communicate with external sensors not part of the device itself.

[0247] In some embodiments, the device includes a display sized and configured for placement on a tabletop. The light source may include an LED array positioned on a front side of the display such that the visual stimulus is delivered to the subject when a subject is positioned facing the front side of the display.

[0248] The device may be configured as a lighting fixture. The lighting fixture may be a floor lamp, a table lamp, a ceiling fixture, a sconce, or the like. The device may be operable to actuate the light source for delivery of the visual stimulus and actuate normal room lighting once delivery of the visual stimulus is complete. For example, the device may actuate the light source for delivery of the visual stimulus for a set period of time. The set period of time may be programmed such that the visual stimulus is actuated at certain hours of the day. In some embodiments, the device comprises one or more sensors for sensing if a patient is in the room before actuating the light source to deliver the visual stimulus. For example, the one or more sensors may be a motion sensor, a biometric sensor, or the like.

[0249] In some embodiments, the device may include other forms of sensory stimulation. For example, the device may include a sound source comprising an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus. In some embodiments, the device may include a means for tactile stimulation delivered at certain frequencies to correspond with delivery of the visual stimulus.

[0250] In some embodiments, the device includes a sound source configured to generate auditory pulses in a similar frequency to delivered by the light source. For instance, the device may comprise an electroacoustic transducer to convert an electrical audio signal into a corresponding sound stimulus. The sound source may include bone conduction, i.e. direct vibration of the bones in the head, in the same or different frequency as the visual stimulation. The bone conduction may be an integrated headset or headphones. The bone conduction may be a headset / headphones operably connected to the device.

[0251] The sound source may generate, for example, a click train with a click frequency of e.g. 50 to 70 Hz, 51 to 70 Hz, 53 to 70 Hz, 55 to 70 Hz, 55 to 65 Hz and 57 to 63 Hz. The clicks may have a preferred frequency of about 60 Hz. The sound may be generated at a same or different frequency as delivery of the visual stimulus.

[0252] Each click in the click train may preferably have a duration of less than 10 ms, e.g. about 1 ms. Each click in the click train may have a sound pressure level of e.g. about 1 dB to about 85 dB, about 30 dB to about 70 dB, or about 60 dB to about 65 dB. Alternatively or in addition, the sound may be emitted at a volume that varies over a selected period of time. The at least one electroacoustic transducer may include at least one headphone or speaker. The device may include noise-cancelling features for reducing ambient noise. The device may reduce ambient noise using passive noise isolation and / or active noise cancellation.

[0253] The sound source may be integrally formed with the device. The sound source may be operably connected to the device via a wired or wireless connection.

[0254] In some embodiments, the device may comprise a timer connected to the one or more light sources. The timer may enable the light source to emit light for a selected period of time. For example, the visual stimulus may be emitted for at least e.g. 1 min, 5 mins, 10 mins, 20 mins, 30 minutes, 1 hour, 1.5 hours or 2 hours, preferably for at least 1 hour, at least 1.5 hours or at least 2 hours, more preferably 1 to 3 hours. The duration of the exposure of the subject to the visual stimulus and / or the administration of the visual stimulus to the subject may be e.g. 1 to 3 hours, for instance about one hour. The exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated over a time period. For example, the exposure of the subject to the stimulus and / or the administration of the stimulus to the subject may be repeated at least once per day over the time period. The time period may include, but is not limited to, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, one week, two weeks, three weeks, and / or one month (or longer, such as once daily for the rest of the subject's life). In a particular example, the period of time is 2 hours for 5 consecutive days.

[0255] In some embodiments of the methods, the visual stimulus may be delivered for two hours per day for five days. In some embodiments, the visual stimulus may be delivered for thirty minutes per day for thirty days. In some embodiments, the visual stimulus is delivered in combination with a pharmaceutical composition.

[0256] As described in detail in the Examples, the devices, systems, and methods of the invention may advantageously provide improvements in cognitive function and alleviation of neuropsychiatric disorders following a relatively short treatment time. Thus in preferred embodiments, a subject may be exposed to the visual stimulus for less than 1 hour, e.g. 10 seconds to 50 minutes, 30 seconds to 30 minutes, 1 minute to 10 minutes, 2 to 8 minutes or about 5 minutes. This duration of exposure may be repeated e.g. up to 4 times daily, e.g. once or twice daily, or 1 to 6 times a week (e.g. once, twice or three times a week). The treatment may continue for e.g. one week, two weeks, three weeks, and / or one month (or longer. In particularly preferred embodiments, the subject is exposed to the stimulus (e.g. light at 60 Hz) for 1 to 10 minutes once daily for one week or more.

[0257] Preferably the visual stimulus is administered to the subject while the subject is awake, that is, while the subject’s eyes are open. In other embodiments, the visual stimulus may be administered while the subject’s eyes are closed and / or is asleep. In some embodiments, the intensity of the visual stimulus is varied during treatment. In this way, the light intensity may be varied over a selected period of time. In preferred embodiments, treatment may be applied in a closed system such that is substantially free from ambient light.

[0258] Systems, devices, and methods of the invention may be used to treat a mental disorder or disease. The mental disorder or disease may be one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, and bipolar disorder.

[0259] In some embodiments, the mental disease, disorder, or related symptoms is depression. Types of depression that may be treated include but are not limited to any of major depressive disorder, single episode, recurrent major depressive disorder-unipolar depression, seasonal affective disorder- winter depression, bipolar mood disorder-bipolar depression, mood disorder due to a general medical condition-with major depressive-like episode, or mood disorder due to a general medical condition-with depressive features, including where those disorders are resistant to treatment in a given patient. In a preferred embodiment, the present invention is used to treat a subject with treatment-resistant depression.

[0260] There are three types of depression generally characterized in the art, major depression, dysthymic disorder, or dysthymia, and depressive disorder not otherwise specified. Major depression is characterized by peak episodes of extreme depression. During a peak episode, the patient may suffer from depressed mood, and markedly diminished interest or pleasure in activities. Other symptoms include significant weight loss or weight gain, decrease or increase in appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive or inappropriate guilt, diminished ability to think or concentrate or indecisiveness, recurrent thoughts of death, suicidal ideation or suicidal attempts. Symptoms last for at least two weeks and cause significant distressor impairment in important areas of functioning.

[0261] Dysthymia is characterized by depressed mood for at least 2 years as well as other symptoms like poor appetite or overeating, insomnia or hypersomnia, low energy or fatigue, low self-esteem, poor concentration or difficulty making decisions and feelings of hopelessness. As is recognized in the field of psychiatric arts, depression may also comprise, and / or may also manifest itself in a variety of forms, including but not limited to, seasonal affective disorder, diurnal mood variations, or depression associated with menopause.

[0262] Depression with seasonal affective pattern or seasonal affective disorder (hereinafter referred to as "SAD") is also known as cabin fever, evening blues, and sun deprivation syndrome. The terms "seasonal affective disorder" or "seasonal pattern specifier" are defined in the DSM-IV as a specifier or adjective that more precisely characterize feature associated with depression. A particular feature of SAD is the regular occurrence of depression in winter. Most of the patients with SAD are characterized by an atypical type of depression in the winter which is associated with mood reactivity (mood brightens in response to actual or potential positive events) as well as weight gain or increase in appetite, hypersomnia, leaden paralysis (heavy, leaden feelings in arms or legs), long-standing pattern of interpersonal rejection sensitivity.

[0263] Psychotic conditions such as schizophrenia and related disorders, for example schizoaffective disorder, are complex and heterogeneous diseases of uncertain etiology. Schizophrenia itself is characterized by fundamental distortions in realms of thinking and perception, cognition and the experience of emotions. The methods, devices and systems described herein may thus be used to treat psychotic disorders, including schizophrenia. Examples of psychotic disorders that can be treated according to the present invention include, but are not limited to, schizophrenia, for example of the paranoid, disorganized, catatonic, undifferentiated, or residual type; schizophreniform disorder; schizoaffective disorder, for example of the delusional type or the depressive type; delusional disorder; brief psychotic disorder; shared psychotic disorder; psychotic disorder due to a general medical condition; substance-induced psychotic disorder, for example psychosis induced by alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants, opioids, or phencyclidine; personality disorder of the paranoid type; personality disorder of the schizoid type; psychotic disorder not otherwise specified.

[0264] Schizophrenia as used herein refers to a disorder that lasts for at least 6 months and includes at least one month of active-phase symptoms (i.e., two [or more] of the following: delusions, hallucinations, disorganized speech, grossly disorganized or catatonic behavior, negative symptoms).

[0265] Schizoaffective disorder is defined as a disorder in which a mood episode and the activephase symptoms of schizophrenia occur together and were preceded or are followed by at least 2 weeks of delusions or hallucinations without prominent mood symptoms.

[0266] Schizophreniform disorder is defined as a disorder characterized by a symptomatic presentation that is equivalent to schizophrenia except for its duration (i.e., the disturbance lasts from 1 to 6 months) and the absence of a requirement that there be a decline in functioning.

[0267] Schizotypical disorder is defined as a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal relationships, eccentric behavior, and mild perceptual distortions.

[0268] Post-Traumatic stress disorder (PTSD) is a disorder that develops in some people who have experienced a shocking, scary, or dangerous event. It is natural to feel afraid during and after a traumatic situation. Fear triggers many split-second changes in the body to help defend against danger or to avoid it.

[0269] Anxiety disorders are extremely common, with a lifetime prevalence of between 5 and 30% in the general population. Patients suffering from anxiety disorders experience excessive worry or fear and often have associated physical symptoms. Examples of anxiety disorders include Post-traumatic stress disorder (PTSD), Generalized anxiety disorder (GAD), social anxiety disorder, panic disorder, and phobias.

[0270] Obsessive Compulsive Disorder (OCD) is a chronic condition characterized by uncontrollable and distressing thoughts (obsessions) of diverse natures, such as contamination, need for symmetry, intrusive thoughts, or rumination, coupled with compulsions that are repetitive behaviors such as hand-washing, checking, counting, and reassurance-seeking. Some OCD patients can benefit from pharmacological therapies such as antidepressants at high doses but even with psychotherapy many struggle to break out of patterns of behavior that severely impact on their quality of life. Imaging studies have shown differences in the frontal cortex and subcortical structures of the brain in patients with OCD.

[0271] In some embodiments, devices, systems and methods of the invention may be used for diagnosing brain disorders such as dementia and / or Alzheimer’s disease.

[0272] In some embodiments, the methods of the invention include obtaining a saliva sample from the patient before and / or after treatment and measuring salivary cortisol and / or C-reactive protein (CRP) levels. Salivary cortisol levels may be utilized as a biomarker as to the therapeutic efficacy of the method. In particular, reduction of cortisol levels measured in saliva over time may indicate the efficacy of the therapy administered to the patient. Saliva samples may be obtained at designated time intervals after delivery of the visual stimulation to account for the strong diurnal variation of salivary cortisol levels. Patients may be instructed to abstain from eating for a minimum amount of time before saliva collection and to avoid dairy products, caffeinated drinks, or acidic beverages a designated time before sampling. Salivary cortisol and C-reactive protein (CRP) levels may be measured using a commercially available protocol such as competitive cortisol ELISA (Invitrogen, Cat. n. #EIAHCOR) and a quantitative CRP sandwich ELISA (Abeam, Cat. n. #ab!08826).

[0273] Methods for promoting and / or improving cognitive function

[0274] Aspects of the invention include methods for promoting and / or improving cognitive function. In some embodiments, methods of the present invention may be used to promote cognitive function in a normal subject. By “normal subject” in this context, it is a meant a subject or patient who is not suffering from a clinical disorder, e.g. a neuropsychiatric disorder. Thus a “normal subject” may refer to a healthy subject. The present invention (e.g. the methods, devices, and systems described herein) may be used in non-therapeutic treatment of such subjects. In some embodiments, the devices, systems, and methods of the present invention may be used to treat subjects experiencing stress or burnout, and chronic stress.

[0275] As disclosed herein, the methods, devices, systems described herein may be used to promote or improve learning, attention, memory, language, executive functions, social cognition and / or visual -spatial abilities.

[0276] Preferably the methods, devices, systems described herein are used to promote or improve executive functions, learning, attention or memory. In some embodiments, the present invention may be used to promote or improve memory, e.g. working memory, episodic memory, recognition memory, reference memory, visual and / or spatial memory, preferably working memory. In one preferred embodiment, the methods of the invention may be used to promote or improve memory preservation and retrieval. In another embodiment, methods of the present invention may be used to promote or improve learning, preferably reversal learning.

[0277] The methods for promoting and / or improving cognitive function include inducing the mechanism of action via one or more stimulation methods. Accordingly, the mechanism of action may be induced by a stimulation modality such as via visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound.

[0278] As disclosed herein, the methods for promoting and / or improving cognitive function in a subject may comprise providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer- readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

[0279] In some embodiments of the method, the visual stimulus may be delivered at a pulse frequency of 50 Hz to 70 Hz inclusive. In some embodiments, a wave form of light emitted from the light source may comprise a repeating pattern of stimulation. Further, the repeating pattern of stimulation may comprise one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave, in some embodiments.

[0280] In some embodiments, light source may be a pre-defined wavelength range.

[0281] As disclosed in detail herein, in some embodiments of the method, the device may comprise one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor. For example, in some embodiments, the method further comprises receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject. Further, in some embodiments, the one or more algorithms may comprise a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals. In particular embodiments, the data may comprise one or more of brain imaging and brain activity recording, wherein the device may be configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0282] In some embodiments, cognitive function may be promoted and / or improved in a subject experiencing one or more of stress, burn-out, chronic stress, accelerated aging, and / or brain injury. For example, in some embodiments of the method, one or more of learning, attention, memory, language, executive functions, social cognition and / or visual-spatial abilities may be improved.

[0283] As disclosed in detail herein, the visual stimulus may be delivered for any period of time. In some embodiments, the visual stimulus may be delivered for two hours per day for five days. In some embodiments, the visual stimulus may be delivered for thirty minutes per day for thirty days.

[0284] In some embodiments, the methods of the invention include obtaining a saliva sample from the patient before and / or after treatment and measuring salivary cortisol and / or C-reactive protein (CRP) levels. Salivary cortisol levels may be utilized as a biomarker as to the therapeutic efficacy of the method. In particular, reduction of cortisol levels measured in saliva over time may indicate the efficacy of the therapy administered to the patient. Saliva samples may be obtained at designated time intervals after delivery of the visual stimulation to account for the strong diurnal variation of salivary cortisol levels. Patients may be instructed to abstain from eating for a minimum amount of time before saliva collection and to avoid dairy products, caffeinated drinks, or acidic beverages a designated time before sampling. Salivary cortisol and C-reactive protein (CRP) levels may be measured using a commercially available protocol such as competitive cortisol ELISA (Invitrogen, Cat. n. #EIAHCOR) and a quantitative CRP sandwich ELISA (Abeam, Cat. n. #ab 108826).

[0285] Without being bound by theory, microglia-mediated remodeling of the PNN as achieved by devices, systems, and methods of the invention promote neuronal plasticity and permit the PNN to reform in an improved configuration which is more permissive to plasticity. Such changes may therefore promote both short and long term improvements in neuronal plasticity.

[0286] Methods for monitoring cognitive function

[0287] Aspects of the invention provide methods for monitoring cognitive function or treating a mental disease, disorder, or related symptoms. As disclosed herein, the methods may include the steps of obtaining a first saliva sample from a subject; measuring a first salivary cortisol level from the first saliva sample; conducting a treatment on the subject that is designed to impact cognitive function or treat a mental disease, disorder, or related symptoms; obtaining a second saliva sample from the subject; measuring a second salivary cortisol level from the second saliva sample; and comparing the second salivary cortisol level to the first salivary cortisol level, wherein a difference between the second salivary cortisol level and the first salivary cortisol level indicates an effect of the treatment.

[0288] Methods for treating stress

[0289] Aspects of the invention provide methods for treating stress in a subject. The methods for treating stress include inducing the mechanism of action via one or more stimulation methods. Accordingly, the mechanism of action may be induced by a stimulation modality such as via visual stimulus, magnetic field exposure, high- and mid-range frequency deep brain stimulation, repetitive magnetic stimulation, alternating stimulation in a high gamma frequency range, direct current stimulation, and focused ultrasound.

[0290] In some embodiments, the methods include the steps of providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitoiy, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

[0291] Stress may be one or more of acute stress, chronic stress, episodic acute stress, or toxic stress. Acute stress may be a short-term stress that may come and go over a relatively short period of time. Acute stress may be experienced on a daily basis. Episodic stress may include acute stress experienced on a regular basis and / or with some regularity or frequency. Chronic stress may be long-term stress that continues for a period of time, including days, weeks, months, and / or years. Toxic stress may be stress that lingers and intensifies. Toxic stress may be associated with strong, frequent, and / or prolonged adversity, for example a sustained traumatic event. Toxic stress may be lasting and serious stress.

[0292] In some embodiments of the method the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

[0293] In some embodiments of the method the wave form of light emitted from the light source comprises a repeating pattern of stimulation. The repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave, in some embodiments.

[0294] In some embodiments, the light source comprises a pre-defined wavelength range.

[0295] In some embodiments of the method, the device further comprises one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor. Further, the method further comprises, receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject, in some embodiments. Is some embodiments, the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals. In some embodiments, the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

[0296] In some embodiments of the method, the stress comprises one or more of burn-out, acute stress, chronic stress, episodic acute stress, and toxic stress. In some embodiments, one or more symptoms associated with stress are improved. In non-limiting examples, the symptom may be one or more of fatigue, depression, anxiety, nightmares, memory loss, distress, sleep disturbances, irritability, difficulty concentrating, exaggerated response to stimuli, and headache. In some embodiments, one or more of learning, attention, memory, language, executive functions, social cognition, visual -spatial abilities, fatigue, depression, anxiety, sleep, mood, distress, irritability, concentration, response to stimuli, headache, and focus is improved.

[0297] In some embodiments of the method, the visual stimulus is delivered for two hours per day for five days. In some embodiments, the visual stimulus is delivered for thirty minutes per day for thirty days.

[0298] In some embodiments of the method, the method further comprises obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level. The saliva sample is obtained at a defined time after delivery of the visual stimulus, in some embodiment. In some embodiments, the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

[0299] Modes of stimulation

[0300] The invention provides devices, systems, and methods for treating a mental disease, disorder, or related symptoms in a subject, improving mental health, promoting or improving cognitive function, and treating stress by stimulating activation of microglia cells via a stimulation modality. While embodiments of the devices, systems, and methods of the invention as disclosed herein may be directed to using a visual stimulus at a defined frequency, the invention recognizes that the mechanism of action may be achieved using other stimulation methods. Accordingly, the devices and methods of the invention may be adapted to accommodate any particular mode of stimulation. For example, the mode of stimulation may be extremely low-frequency (ELF, <300Hz) time-varying magnetic fields (MF). In non-limiting examples, the stimulus may be administered as 60Hz of MF exposure at 1800 pT for 30 minutes. The MF exposure may be produced using an MRI scanner and a 32-channel head coil, such that the magnetic field exposure is produced by the MRI z-gradient coil.

[0301] The mode of stimulation may be deep brain stimulation (DBS). The DBS may be an implanted electrode using electrical stimulation to interrupt brain signals. In some embodiments, the DBS may be provided by varying the pulse frequency. For example, the stimulation may be DBS pulses between 60 and 200 Hz, with 130 Hz as the default stimulation frequency. In some embodiments, the DBS may be provided in the in the subthalamic nucleus (STN).

[0302] The mode of stimulation may be repetitive high-frequency (>1 Hz) transcranial magnetic stimulation (rTMS). Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation technique that uses magnetic pulses to stimulate nerve cells in the brain. A magnetic coil may be placed on the scalp such that the device emits magnetic pulses that penetrate into the brain to stimulate specific brain regions. The transcranial magnetic stimulation may be applied in a paired-pulse sequence. The stimulation may be, in non-limiting examples, 10 Hz, 25 Hz, or 50 Hz. In some embodiments, the stimulation may be at 50 Hz. The 50 Hz rTMS may be applied with a circular coil on the primary motor cortex, for example using a circular 90-mm coil connected to a magnetic stimulator. Stimulation intensity may first be applied at 60% rest motor threshold and 0.5 sec train duration. The intensity may then be increased in 0.5 sec steps to 2 sec, and by 10% steps to 90% RMT. The mode of stimulation may be 50 Hz rTMS at an intensity of 90% RMT for 2 sec.

[0303] The mode of stimulation may be transcranial alternating stimulation (tACS) in a high gamma frequency range. Transcranial alternating current stimulation uses weak, alternating electric currents to modulate brain activity, particularly cortical oscillations, by applying sinusoidal currents to the scalp. tACS involves placing electrodes on the scalp and applying a low-intensity alternating current, which passes through the skull and into the brain. In some embodiments, the method includes applying external electric fields of relatively low amplitudes (minimum estimated cortical electric field of 0.2 mV / mm), if intrinsic frequency was closely matched with the externally applied electric field. In some embodiments, the electrical stimulation may be sinusoidal with a current intensity of 1500 mA. Using this current intensity the maximum current density at the Oz electrode may be 93,75 mA / cm2. In some embodiments, the stimulation is 60 Hz. In some embodiments, the stimulation is 70 Hz.

[0304] The mode of stimulation may be transcranial focused ultrasound stimulation (tFUS). In some embodiments, transcranial ultrasonic waveforms may be generated using an ultrasound neurostimulation system. The ultrasound neurostimulation system may be integrated into devices of the invention. The ultrasound neurostimulation system may be a standalone system. The channel output may be set to deliver a signal to drive a focused ultrasound transducer having, in non-limiting examples, a center frequency of 0.5 MHz, a diameter of 48 mm and a focal length of about 30 mm (the distance from sound passing membrane to focal point). The ultrasound pulse mode may include a pulse width, pulse repetition period, a burst duration, and a burst period. The pulses may have an associated pulse repetition frequency, i.e., the rate of the pulses delivered and may be repeated for a length of time. The duty cycle may be the proportion of each pulse filled with ultrasound cycles (pulse width / burst duration as a percentage value). The burst period may include the burst duration and the burst interval.

[0305] In some embodiments, the stimulus may be delivered at a pulse width of 200 ps, a repetition period of 0.5 ms, a burst duration of 500 ms, a burst period of 2 s, a pulse repetition frequency of 2000 Hz, and a duty cycle of 40%. In some embodiments, the stimulus may be delivered at a pulse width of 400 ps, a repetition period of 20 ms, a burst duration of 500 ms, a burst period of 2 s, a pulse repetitio frequency of 50 Hz, and a duty cycle of 2%.

[0306] In some embodiments, the mode of stimulation may be transcranial direct current stimulation (tDCS). tDCS includes placing electrodes on the scalp, for example over an area of the brain to be targeted, and passing a weak, direct current (typically 1-2 milliamps) through the skin and skull to the brain.

[0307] In some embodiments, bipolar stimulation may be delivered by an electrical stimulator. The electrical stimulator may be integrated into devices of the invention. Bipolar stimulation may be delivered, for example, through a pair of square rubber electrodes (e.g. 4 x 4 cm2), with the anode placed over the placing the anode over the left primary motor cortex and the cathode over the contralateral orbit. The electrodes may be fixed under an EEG cap — only during stimulation — using elastic bands. In some embodiments, the current may be applied for 10 minutes with a current strength of 1 mA.

[0308] Examples

[0309] Example 1: An open label study of light treatment in depressive disorder

[0310] Overview:

[0311] It is an insight of the invention that stimulating the brain using 60Hz light through the eyes may activate a cell type called microglia. When microglia are stimulated at 60Hz they may specifically target a structure in the brain called the perineuronal net (PNN). The microglia essentially “eat” or poke holes in this structure. The PNN can be thought of as a cage that surrounds the neurons in your brain and can make it more difficult for neurons to form new connections between each other. By poking these holes in it we can make it easier to form new connections or to change the structure of old connections. It was not previously known that microglia could have this effect. Thus, the invention provides devices, systems, and methods for increasing neuroplasticity by using microglia mediated remodeling of the PNN. The effect was initially discovered during research into ketamine. It was seen that ketamine induces this 60Hz activity in the brain and has this effect. It was discovered that the effect of ketamine is an electrical effect rather than pharmacological, and that this effect could be replicated to stimulate the same frequency using light to avoid the side effects associated with ketamine.

[0312] Purpose:

[0313] It is proposed to conduct the first proof of concept open-label study examining the safety and therapeutic effects of 60hz light entrainment on depressed human volunteers.

[0314] Background:

[0315] As shown in FIG. 6D, ketamine increases cortical plasticity through the activation of microglia, which disrupt the perineuronal net. As a result, new synaptic connections with the underlying neurons are facilitated. Finally, in vivo electrophysiological recordings of rodents have demonstrated that ketamine infusions stimulate gamma cortical activity (25 to 100 Hz). Consequently, the effects on social defeat and PNN integrity demonstrated in FIG. 6C, FIG. 6D may be replicated via light stimulation at frequencies comparable to those cortical oscillations stimulated by ketamine.

[0316] FIG. 6G demonstrates that cortical entrainment with a 60Hz flashing light, of 2 hours duration (matching the clearance time of ketamine), had the same effects on the microglia and PNN as the drug. By employing the TRAP2 transgenic mouse model, PNN effects were demonstrated which extended beyond the visual cortex, including frontal cortex and hippocampus, which could account for the reversal of the depression model.

[0317] Methods:

[0318] Subjects and measures: 30 depressed drug-naive individuals will be recruited via the Centre of Affective Disorders referral system.

[0319] Main outcome measures:

[0320] Hamilton Depression Rating Scale (HDRS-17), HAM-A. Response is indicated by a 50% reduction in scores. Remission is defined by a score of less than 7 on both scales.

[0321] Secondary outcome measures: Beck Depression Inventory (BDI), WEISS Functional Impairment Scale, Spielberger State Anxiety Scale.

[0322] Screening tools: Mini International Neuropsychiatric Interview (to exclude other Axis I disorders), Alcohol use disorders identification test (AUDIT), Drug Abuse Screen Test (DAST-10), BSI self-rated psychiatric symptoms.

[0323] Inclusion criteria: HDRS score > 16 and BDI score > 19 (Moderate to severe depression)

[0324] Exclusion criteria:

[0325] Comorbid drug and alcohol misuse, history of psychosis, bipolar disorder, photosensitive epilepsy, pregnancy, under anti-inflammatory or clopidogrel treatment.

[0326] Procedure:

[0327] Following the completion of baseline measures, subjects meeting the study criteria will be required to wear a headset providing 60Hz light stimulation for 2 hours per day for 5 days. They will receive treatment under the supervision of a clinical researcher at the Clinical Research Centre, King’s College London. They will repeat all outcome measures at 6, 14 and 28 days. Any adverse events will be recorded.

[0328] Statistical analysis:

[0329] Changes in main and secondary outcome measures will be compared between baseline and follow up using repeated measures t-tests and ANOVA. The significance threshold for changes in secondary outcomes will be corrected for multiple comparisons. The baseline characteristics of participants who improve and those who drop out of the study will be analyzed.

[0330] Example 2: Flickering white light stimulation at 60Hz in healthy human subjects induces robust, widespread, and well-tolerated brain entrainment

[0331] Overview

[0332] Background

[0333] Entrainment induced by flickering white light at a specified frequency shows promise as a novel non-invasive brain stimulation technique. While the effects of 40Hz externally-induced brain entrainment have been described, little is known about 60Hz entrainment in humans. Objectives

[0334] This study aimed to characterize the brain and somatic response of healthy volunteers to 60Hz flickering white light over 3 weeks of stimulation.

[0335] Methods Six healthy volunteers were exposed to 60Hz flickering white light and compared to a sham condition (constant light). Stimulation lasted 3 weeks, with daily 30-minute sessions. Brain entrainment was assessed with an 8-channel EEG setup on days 1, 5 and 19. Salivary cortisol and C-reactive protein levels were measured using ELISA kits on the same days. Side effects and well-being were monitored via questionnaires. Results

[0336] Flickering white light at 60Hz induced a robust brain entrainment, detected not only in the visual cortex but also in parietal, temporal and frontal areas, indicating spreading of entrainment. The pattern of such diffuse activity showed high synchronicity as revealed by phase locking value (PLV). Interestingly, both the normalized PLV and the power of entrainment declined significantly by day 19 compared to day 1. The statistical significance for these differences was assessed using the Kruskal-Wallis test to compare values across multiple days. Post-hoc pairwise comparisons between days were performed using Dunn’s test with Bonferroni correction, revealing highly significant declines in normalized PLV (p < 0.001) and entrainment power (p < 0.05)., indicating neural habituation. No signs of somatic stress or inflammation were observed; in fact, cortisol and CRP levels were unchanged. The rate and type of side effects did not differ across groups and the most common side effect was sleepiness.

[0337] Conclusions

[0338] Externally induced brain entrainment with 60Hz light over 3 weeks is robust, synchronized across brain regions, and leads to neural habituation. 60Hz stimulation might be a new approach for modulating brain activity and inducing neuroplasticity, with implications for the basic understanding of brain physiology as well as treatment of psychiatric disorders. Introduction;

[0339] Neuromodulation refers to a broad range of techniques aimed at modulating diffuse neuronal activity to achieve therapeutic effects. When this modulation is obtained through external energy applied to the brain it is referred to as neurostimulation. Non-invasive brain stimulation (NIBSs) techniques, such as electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), and direct current stimulation (DCS), exert measurable structural and functional effects on the brain. These effects include increased neuroplasticity, changes in brain structure and connectivity, and restoration of brain-derived neurotrophic factor (BDNF) levels. Several NIBSs solutions are FDA-approved for the treatment of various brain diseases, including depression and obsessive-compulsive disorder (OCD), underscoring the therapeutic potential of neuromodul ati on .

[0340] Emerging non-invasive neuromodul atory solutions leverage different energy modalities to modify neuronal excitability and modulate brain activity. These include ultrasounds, such as transcranial focused ultrasound; interference of electric fields, such as temporal interference stimulation; and thermal stimulation using near-infrared lasers.

[0341] A new promising, fully non-invasive NIBS utilizes intermittent sensory stimulation. Brainwaves naturally synchronize with the rhythm of periodic external stimuli, such as flickering lights, speech, music, or tactile stimuli. The synchronization of brainwaves is called entertainment. Synchronization in the gamma range (between 30 and 70Hz) is of particular therapeutic interest, as gamma brainwaves occur naturally when the brain is concentrated and is involved in cognitive and executive functions.

[0342] Multisensory (combined visual and acoustic) external stimulation at 40Hz has been extensively studied in both mouse models and humans. This stimulation has been shown to induce strong and well -tolerated entertainment. Initial findings suggest its potential for treating Alzheimer’s disease (Hajos et al, Front Neurology 2024). In particular, 40Hz stimulation increased connectivity between the precuneus and posterior cingulate cortex in Alzheimer's patients, indicating neuroplastic effects mediated by brain entrainment.

[0343] In contrast, stimulation with 60Hz remains less explored. Given the role of 60Hz in cognitive and executive functions in the healthy brain, and evidence that disruptions in 60Hz rhythms are linked to neurological and psychiatric conditions, this area deserves further investigation. Our previous work demonstrated that visual 60Hz stimulation with intermittent light in mice induces brain entrainment and increases neuroplasticity through the microglia- mediated remodeling of the perineuronal nets (PNNs) (Venturino et al. Cell Reports 2021). However, 60Hz light entrainment in humans has not been extensively studied, particularly regarding the effect of repeated stimulations over time.

[0344] The scope of this pilot study is to characterize the effect of 60Hz light-based stimulation on the healthy human brain. LED-generated, 60Hz pulsed intermittent white light with a square wave modulation was applied to a group of 14 healthy volunteers to study its acute (single session), short (after 5 days), and intermediate (after 3 weeks) effects on brain electrical activity, as measured by electroencephalogram (EEG), compared to sham stimulation (constant light). Salivary levels of biochemical markers -cortisol and c-reactive protein (CRP)- and participant questionnaires were used to monitor the somatic responses. The findings show that 60Hz flickering light stimulation induces robust and widespread brain entrainment, with a high level of synchronization across brain regions. Notably, the entertainment and synchronization adapt over time, suggesting a neuroplastic response induced by 60Hz. The stimulation is well tolerated by healthy individuals.

[0345] Methods:

[0346] Participants. The study involved a cohort of 14 young adults, healthy volunteers (demographics shown in Table 1). The primary exclusion criteria were diagnosis of neurodegenerative or psychiatric diseases, in particular history of seizures or epilepsy, migraine, and tinnitus. Full inclusion and exclusion criteria are listed in Supplementary Table 1 below.

[0347] Supplementary Table 1 The 14 participants were randomized to active stimulation (n=8) or sham (n=6). The groups were balanced in terms of self-identified sex, age, and education, as shown in Table 1. Two participants in the active group dropped out for personal reasons. One completed one week of stimulation, and the other completed 16 days. Both individuals completed the final questionnaire.

[0348] Ethical Approval and Study Design. The study was conducted in accordance with the World Medical Association Helsinki Declaration for human experimentation. All procedures were performed in compliance with relevant laws and have been approved by Lower Austria Ethical Commission (study GS3 -EK-4 / 908-2024 approved on July 1st 2024). All procedures were carried out under medical supervision. Written consent was obtained by study personnel from all participants. After the assessment of eligibility, participants were randomly assigned with equal probability (0.5) to either the active stimulation group (60Hz white light) or the sham group (simulation periods illustrated in FIG. 7B). The study was single-blind, with participants not aware of group assignment; at the end of the study, participants were asked to guess which stimulation they received and on average 60% of them, in both groups, guessed correctly, illustrated in Table 2.

[0349] FIG. 7C illustrates a diagram of the experimental timeline. Participants underwent light stimulation over three weeks, with EEG recordings and saliva sampling conducted on Days 1, 5, and 19 during the stimulation. Participants received either an active stimulus (60Hz flickering light) or a sham stimulus (constant light) for 30 minutes per session. Each participant received 30 minutes of stimulation every day, Monday to Friday, for 3 consecutive weeks (FIG. 7C). On days 1, 5, and 19 an EEG recording was performed during the stimulation and a saliva sample was collected. Side effects were collected daily based on self-report; a final questionnaire was administered at the end of the study to investigate tolerability, side effects, and blinding. All data were pseudonymized and handled according to national and international laws; the privacy rights of human subjects have been observed.

[0350] Prototype Device and features of the li ht used. To deliver intermittent white light stimulation in a controllable and standardized manner, a novel wearable headset derived from Uvex Ultrasonic safety glasses (Manufacturer Part No 9302245) was developed. The device was worn around the face and head, resembling a pair of safety glasses. A strip of LEDs (PowerLED Chromatic LED strip - Manufacturer Part No D0-55-35-1-120-F8-20-FP) was integrated around the ocular component to direct light tangentially to the periphery of the wearer’s eyes. FIG. 7A illustrates an embodiment of the device used. This LED strip has 120 LEDs per meter, and 35cm of this LED strip was used in the headset. The LEDs emitted a square-wave function of white light at a 60Hz band with a duty cycle of 50%. The stimulation frequency was manually measured using an oscilloscope (Keysight Eduxl052A, Manufacturer Part No 302-25- 092) before each data collection to 59.6Hz, corresponding to an acceptable ~0.6% deviation from 60Hz to ensure consistent frequency throughout the recording. The light spectrum ranged from 440 nm to 770 nm, corresponding to daylight wavelengths, measured with (ThorLabs CCS200; as shown in FIG. 10A). Light intensity was adjustable between 14 and 113 pW to ensure a safe and comfortable experience for participants, and the color temperature was matched at 4000K. To minimize electrical noise interference with the EEG setup, the LED strip was enclosed within a copper mesh (Thorlabs, Catalog No. PSY406), and powered using a long shielded cable (RS PRO data cable - Manufacturer Part No 303-95-459), both grounded to the EEG acquisition board, effectively creating a Faraday cage to eliminate electromagnetic emissions from both the powering cable and the LED strip.

[0351] The 60Hz square signal was generated using an Arduino Nano board PWM pin (Arduino, Catalog No. SKU A000005) soldered onto a PCB, connected to the LEDs via a circuit that included a 10K potentiometer (Manufacturer Part No P16NP103MAB15) for intensity modulation and a p-channel MOSFET (Manufacturer Part No IRF9540NPBF) to drive sufficient current to the LEDs. The entire setup was powered using a power bank (Manufacturer Part No 57976 101 111) placed more than Im away from the subject. Additionally, the prototype was equipped with a photoresistor (Manufacturer Part No TS2134-A) to capture the light emitted from the LEDs for synchronization during data processing. The photoresistor was connected to an Arduino Nano board, where its analog signal was converted into a digital signal. This digital signal was then transmitted to one of the digital pins on the acquisition board.

[0352] Light Stimulation Protocol. Participants were seated comfortably on a chair with a headrest to provide additional support and stability. The wearable device was carefully positioned on the participant’s face to ensure both comfort and secure placement. The environment was kept quiet, with dim ambient lighting (as shown in FIG. 10B). The operator activated the controller and adjusted the light intensity based on real-time feedback from the participant to maximize comfort. The light adjustment was performed during the first minute of the stimulation. Volunteers received either 60Hz active stimulation or constant light as a sham condition.

[0353] FIG. 7B illustrates the experimental protocol. On the EEG recording day, the experimental protocol consisted of three distinct periods:

[0354] I. Baseline (No light): A 5-minute initial period without light exposure.

[0355] II. Constant Light Exposure (Constant light): A subsequent 5-minute period of constant light exposure.

[0356] III. Stimulus-Modulated Light Exposure (Stimulus light): A 20-minute final period of stimulus-modulated light exposure, which was either active (60 Hz) or sham (constant light).

[0357] On all non EEG-days, the protocol was simplified to a continuous 30-minute session of stimulus-modulated light exposure. Each participant received 30 minutes of stimulation daily, Monday through Friday, for three consecutive weeks.

[0358] EEG Recording. EEG data were recorded using the Cyton + Daisy Biosensing Boards (OpenBCI; 16 channels at 250Hz sampling rate - PIC32MX250F128B microcontroller) and the OpenBCI EEG Electrode wt electrode Cap Kit (OpenBCI, 19-channel electrode cap), medium size, fitted with sintered wet electrodes (sintered Ag / AgCl coated electrodes) known for their low impedance and stable signal acquisition properties, ensuring high-quality data capture over repeated use. Electrodes were placed according to the internationally recognized 10-20 system, ensuring consistent electrode positioning for comparability across studies. In this study, channels Fpl, Fp2, C3, C5, T5, T6, 01, and 02 targeting key frontal, central, temporal, and occipital regions (as shown in FIG. IOC) were specifically used. A low-impedance electrode gel (OpenBCI 380130) was applied using a syringe with a blunt needle to ensure very low- impedance electrical contact between the scalp and the electrodes. The EEG signals were referenced to the right earlobe to establish a stable baseline for differential measurements. To minimize environmental noise and enhance the signal-to-noise ratio, the EEG system’s bias electrode was connected to the subject’s left wrist. This configuration allowed the differential amplifier to effectively reject common-mode noise by accounting for the bias voltage ( Vb) in signal processing. The amplified EEG signal was obtained using the following equation:

[0359] Here, VEECrepresents the raw EEG signal, ^reference isthe reference signal from the right earlobe, is the bias voltage, and G denotes the gain of the amplifier. By integrating the bias voltage into both signal paths, the system effectively eliminated common-mode interference, yielding a cleaner and more accurate representation of the neural activity for subsequent analysis.

[0360] Data was wirelessly transmitted from the acquisition boards to a computer via the Cyton board’s built-in radio module (over Bluetooth), minimizing cable artifacts and enhancing participant comfort during recording sessions. The board was powered by a rechargeable lithium battery (Manufacturer Part No 304-24-383 - 5V 2A output), providing a stable power supply throughout the experiment. The recordings were performed using the OpenBCI GUI software (version 6.0.0-beta.1 ) on an Apple MacBook Pro computer with an M2 processor and 16GB of RAM. The EEG cap was cleared after each use using a brush to remove the residual gel off the cap’s electrodes, and was soaked in warm water for 15 minutes so that the remaining gel dissolves quickly. To disinfect the cap, it was soaked for up to 30 minutes in a diluted bleach solution containing approximately 100 ppm sodium hypochlorite, then rinsed with clean water and hung to dry completely.

[0361] EEG Data Preprocessing. Since two subjects in the active group dropped out for personal reasons (one in week 1 and one in week 2), only the data from the 6 subjects in this group who completed the study were analyzed. EEG data preprocessing was performed using MATLAB (MathWorks Inc., Natick, MA) and the EEGLAB toolbox. The raw signals were first notch- filtered at 50Hz to remove power line noise, followed by a bandpass filter from 0.5Hz to 80Hz using a butterworth 2nd order filter applied bi-directionally to the signal to retain relevant EEG frequencies. The signals were then averaged and re-referenced to eliminate common noise across electrodes. Then, using the signal captured via the photoresistor, the signals were divided into baseline (5 minutes), constant light (5 minutes), and stimulus light (20 minutes) for further analysis. Then, segments of data containing excessive noise or artifacts were manually inspected and removed. Finally, Independent Component Analysis (ICA) was applied to the preprocessed data to remove ocular and muscle movement artifacts. Subsequent analyses were conducted using the MATLAB EEGLAB toolbox (MATLAB R2024b, and EEGLab v2024.2.1). Additional analysis and visualization were performed with open-source software ElecPhys (https: / / github.com / AminAlam / ElecPhys), selected for its functionality in handling large datasets and advanced signal analysis capabilities.

[0362] EEG Data Analysis - Fast Fourier Transform (FFT), The frequency content of the EEG signals was analyzed using the Fast Fourier Transform (FFT) implemented in MATLAB. The FFT is an efficient algorithm for computing the Discrete Fourier Transform (DFT) of a sequence, which transforms discrete time-domain signals into their frequency-domain representation.

[0363] The DFT of a discrete signal x[n] of length N is defined as: where X[k] is the complex amplitude of the kth frequency component, x[ ] is the timedomain signal, j is the imaginary unit, and N is the number of samples. By applying the FFT, spectral components associated with the 60Hz light stimulation were identified and changes in EEG power spectra across different experimental conditions were assessed.

[0364] EEG Data Analysis - Short-Time Fourier Transform (STFT), Time-frequency analysis was conducted using the Short-Time Fourier Transform (STFT) with a Hamming window of 1- second length and 0.5-second overlap between windows. The STFT provides a way to analyze the frequency content of non-stationary signals over time by applying the Fourier Transform to short, overlapping segments of the signal.

[0365] The STFT of a discrete-time signal x[n] is defined as: where:

[0366] • x[n] is the input signal,

[0367] • w[n] is the window function (in this case, a Hamming window),

[0368] • m is the time index corresponding to the center of the window,

[0369] • a> is the angular frequency,

[0370] • j is the imaginary unit.

[0371] By sliding the window across the signal and computing the Fourier Transform at each position, a time-frequency representation was obtained that allowed for the observation of transient changes in spectral power related to the light stimulation.

[0372] EEG Data Analysis - Phase-Locking Value (PLV), To assess the phase synchronization between EEG channels at the stimulation frequency, the Phase-Locking Value (PLV) was calculated. The EEG signals were filtered around 60Hz (59.4-60Hz) using a 2nd order Butterworth filter applied bidirectionally, ensuring zero-phase distortion. The instantaneous phase of each signal was extracted using the Hilbert transform. The PLV between each pair of channels was computed using the following formula: where 0i(n) and 07(n) are the instantaneous phases of signals i and j at time point n, N is the number of time points, and j is the imaginary unit.

[0373] The PLV values for the constant light and stimulus light conditions were normalized against the PLV of the no-light condition to quantify the relative increase in PLV compared to the baseline. Saliva collection. Saliva samples were obtained from participants on designated days (Day 1, 5 and 19). Saliva samples were collected in 2 ml tubes (SARSTEDT, Cat. n. 72.695.500) following light stimulation, with the exact time of each collection carefully recorded. Participants were instructed to abstain from eating for a minimum of 1 hour before saliva collection and to avoid dairy products, caffeinated drinks, or acidic beverages within 15 minutes of sampling. Immediately following the collection, a Protease Inhibitor Cocktail (Sigma, Cat. n. #P2714) was added to the saliva at a concentration of 1 pL per 1 mL (v / v) of whole saliva, prepared according to the manufacturer’s instructions. Samples were then centrifuged at 2,000 g for 2 minutes to remove larger debris. The supernatant was aliquoted into 2 ml tubes, labeled with the participant ID code, date, and indication of pre- or post-stimulation. Finally, samples were flash-frozen and stored at -70°C for subsequent analysis.

[0374] Cortisol and CRP ELISAs and Analysis. Salivary cortisol and C-reactive protein (CRP) levels were measured using a competitive cortisol ELISA (Invitrogen, Cat. n. #EIAHCOR) and a quantitative CRP sandwich ELISA (Abeam, Cat. n. #ab 108826). Samples with high viscosity, excessive debris, or mucus contamination were excluded from the analysis. To account for the strong diurnal variation of salivary cortisol levels, only samples collected within approximately the same time of the day (within Ih) were included in the cortisol analysis. Samples collected more than 1 hour apart were excluded. Ultimately, cortisol levels were analyzed in 9 participants (5 sham and 4 active), while CRP levels were analyzed in 10 participants (5 sham and 5 active). The colorimetric reactions for both assays were measured using a (Synergy Hlplate reader) set to 450 nm, following the manufacturer's protocols. CRP and cortisol concentrations were calculated using AssayFit Pro version 5.3.2 online analysis software. Relative fold changes in cortisol levels over the course of the study were determined by normalizing each time point to baseline (Day 1) cortisol levels.

[0375] Safety and tolerability measures. To assess tolerability and gather general feedback on the stimulation, participants completed a final questionnaire at the end of the study. The questionnaire contained statements about the general experience, which participants rated on a scale from 0 (not at all) to 5 (absolutely). The questionnaire also contained a question to check participant blinding by asking them to identify the light frequency they received. Adverse events were recorded daily based on participants’ self-reports throughout the study.

[0376] Statistical Analysis. Statistical comparisons between two groups were made using the two-sided Wilcoxon rank-sum U test due to the non-normal distribution of some data groups (tested using Shapiro-Wilk test). Wilcoxon rank-sum test was also used to analyze ordinal questionnaire data. Proportions were tested with Fisher's exact test. Significance was determined at p<0.05 . Repeated measures over time were analyzed with two-way ANOVA. Statistical analyses were performed using MATLAB and GraphPad (versions 5 and 10.4). An exploratory analysis of results by sex was not performed due to the low number of subjects per group.

[0377] Statistical Analysis EEG. Statistical analyses were performed using MATLAB to assess group differences and identify significant patterns in the data. Different statistical tests were applied depending on the nature of the data and the comparisons being made, with a focus on nonparametric methods due to violations of normality as determined by the Shapiro-Wilk test.

[0378] 1) Inter-group comparisons (Control vs. Active groups):

[0379] To compare the Control and Active groups within each light condition and for each day, the Wilcoxon rank-sum test (also known as Mann-Whitney U test) was used. This test was chosen because it is a non-parametric method that does not assume normality and is appropriate for independent group comparisons. The rank-sum test evaluates whether the distributions of the two groups differ significantly. For each day within each light condition, the test provided p- values indicating whether there were significant differences between the Control and Active groups.

[0380] 2) Intra-group comparisons across multiple days:

[0381] To evaluate differences across multiple days within each group (Control or Active) for a given light condition, the Kruskal-Wallis test was applied. This test is a non-parametric alternative to one-way ANOVA and is suitable for comparing more than two groups (in this case, days) when the assumption of normality is violated. The Kruskal-Wallis test assesses whether there are statistically significant differences in the distributions of the dependent variable across the days. 3) Post-hoc pairwise comparisons:

[0382] When the Kruskal-Wallis test indicated significant differences (p < 0.05), post-hoc pairwise comparisons were conducted using Dunn’s test with Bonferroni correction. This step was necessary to determine which specific pairs of days differed significantly. Dunn’s test adjusts for the increased risk of Type I errors when performing multiple comparisons, ensuring the results remain reliable.

[0383] Results:

[0384] Experimental setup to study 60Hz brain entrainment

[0385] The primary goal was to assess whether 60Hz light stimulation would elicit brain entrainment in healthy volunteers, as previously described in animal models and documented in humans at other frequencies, such as 40Hz.

[0386] To address this, 60Hz flickering light was administered to a group of 8 volunteers (referred to as active' group) and compared their response to a parallel group of 6 volunteers who received constant, non-flickering light (referred to as sham). The two groups were balanced in terms of self-reported sex, age, and years of education as shown in Table 1 of FIG. 19 A.

[0387] Table 1 summarizes the main characteristics of the study participants. Sex was selfreported. Data were analyzed using a t-test for years of education, a Wilcoxon U test for age and Fisher's exact test for proportions. No statistically significant differences were observed across groups.

[0388] FIG. 7A illustrates a wearable headset according to one embodiment. FIG. 7A shows the schematic of the experimental setup showing a wearable device (adapted from a Uvex mask equipped with LED lights) designed to be compatible with an EEG cap. For the stimulation, a prototype wearable headset derived from safety glasses, lined with a strip of LEDs was used. The intensity and frequency of the LEDs were controlled by an external controller operated by study personnel (as shown in FIG. 7A, and FIG. 10B). Importantly, to minimize electrical noise from the wearable device, a mini Faraday cage during stimulation was employed. The stimulation lasted for 3 weeks, with participants undergoing one session per day from Monday to Friday. On most days, participants received 30 min of stimulus light, according to their group allocation. Brain entrainment was investigated using an 8-channel EEG setup during the stimulation on days 1,5 and 19. The 8-channel system was chosen to cover a wider range of frequency spectrum due to a higher sampling rate.

[0389] FIG. 7B illustrates simulation periods. FIG. 7B shows that each EEG session included control phases and one stimulus phase: no light and constant light, followed by the stimulus light. On EEG recording days, the stimulation followed a three-step experimental paradigm as illustrated in FIG. 7B. Each subject sequentially underwent: (I.) an initial habituation phase of 5 minutes with no light, (II.) 5 minutes of constant light, and (III.) 20 minutes of stimulus light. For the sham group, the stimulus light (III.) consisted of non-flickering, constant light, while for the active group, it consisted of 60 Hz flickering light. The inclusion of the no-light condition and constant light condition served as critical controls to establish a robust baseline for interpreting the effects of stimulus light. The no-light condition was included to assess the participants’ baseline brain activity without any external visual stimulation, ensuring that any subsequent changes were attributable to light stimulation rather than inherent variability in brain activity. The constant light condition allowed for the isolation of general effects of light exposure independent of the flickering characteristics of the stimulus light. By comparing these conditions, the general effects of light exposure from the specific entrainment effects induced by flickering light in the active group were distinguished. This approach provided a comprehensive framework to evaluate the specificity of brain entrainment to the 60Hz flicker.

[0390] 60Hz light induces brain entrainment

[0391] The occurrence and characteristics of brain entrainment at 60Hz using different EEG signal analysis techniques were investigated. First, a Fast Fourier Transform (FFT) analysis to investigate the frequency component of the EEG signal was performed. If entrainment occurs, a peak at the administered frequency was expected to be observed.

[0392] Indeed, the FFT analysis of EEG data from participants in the active group demonstrated a clear and distinct peak at 60Hz during the stimulus-modulated light exposure on day 1.

[0393] FIG. 7D illustrates a distinct peak at 60Hz during the stimulus-modulated light exposure on day 1, Day 5, and Day 19. This peak was absent in the baseline period and in all conditions for the sham group (FIG. 7D, gray line, and FIG. 10D gray line). FIG. 7D shows Scalp EEG power spectral density (PSD) averaged across all channels for participants in each group. The gray bar indicates the 50Hz line noise, which was notch-fdtered. FIG. 7E illustrates topographic maps showing normalized changes in 60Hz PSD (relative to baseline) averaged across participants of each group.

[0394] FIG. 7E and FIG. 7F illustrate the quantification of normalized entrainment power at 60Hz. The quantification of normalized entrainment power at 60Hz across individual channels confirms that the entrainment at 60Hz in the active group affected most channels in all subjects. FIG. 7F shows the normalized power in the active group on Day 1 across channels was significantly higher than in sham groups. FIG.7F shows that significant differences in normalized changes in 60Hz PSD values were observed across all channel pairs between the active and sham groups on days 1, 5, and 19. Statistical significance for these inter-group comparisons was assessed using the Wilcoxon rank-sum test. Furthermore, within the active group, significant differences in normalized PSD were detected between Day 1 vs. Day 5 and Day 1 vs. Day 19, accounting for repeated measurements. These intra-group comparisons across days were evaluated using the Kruskal -Wallis test, followed by post-hoc pairwise comparisons performed using Dunn’s test with Bonferroni correction. The normality of the data was assessed using the Shapiro-Wilk test, and non-parametric methods were applied due to deviations from normality. In this figure, different channels are shape-coded. Only significant differences are indicated, with * indicating p < 0.05 and *** indicating p < 0.001. Detailed p-values are provided in

[0395] Supplementary Table 2A below.

[0396] Supplementary Table 2A (EEG FIG. 7F)

[0397] As shown in FIG. 7F (with shape code per each subject) and FIG. 10H, while some variability was observed across subjects, most subjects responded at day 1.

[0398] FIG. 7G illustrates Short-Time Fourier Transform (STFT) of a representative active group participant, demonstrating visible 60Hz entrainment during light stimulation, as indicated by the arrow. Importantly, Time-frequency analysis using STFT revealed a consistent band of activity at 60Hz throughout the 20-minute stimulus in the active group (FIG. 7G). This sustained 60Hz activity was absent during the baseline period in the same participants and in the sham group (also shown in FIG. 101). The continuous presence of the 60Hz band over time strongly supports the effectiveness of the light stimulation in entraining neural oscillations at the desired frequency.

[0399] When analyzing the effect over time, a noticeable decrease in 60Hz power on days 5 and 19 as compared to day 1 was observed, as illustrated in FIGs. 7D, 7E, and 7F. By day 19, the power in the active group was significantly reduced compared to day 1 in the same group, as illustrated in FIG. 7F. Overall, these results indicate that 60Hz light entrainment facilitates brain entrainment, with the oscillations observed across multiple brain regions and a gradual decrease in power over time.

[0400] The 60Hz light entrainment is widespread and synchronized

[0401] Having confirmed the occurrence of brain entrainment, its spatial distribution was assessed. Topographical maps of EEG power at 60Hz showed a global increase in power across most electrodes on Day 1 of stimulation in the active group, as shown in FIG. 7E and FIG. 10E. This increase was observed across frontal, parietal, temporal, and occipital regions, indicating widespread neural entrainment indicating that the activity is not limited to the visual cortex, but reaches also frontal areas of the brain. Given the widespread pattern of brain activation, phaselocking value (PLV) analysis was performed to determine whether the 60Hz brain entrainment observed across regions exhibited synchronization or consistent phase relationships. On Day 1, strong phase synchronization was evident between most channel pairs in the active stimulation group, as illustrated in FIG. 8B, and FIG. 1 IB, suggesting coherent neural activity induced by the light stimulation.

[0402] Statistical analysis confirmed robust and significant increase in PLV in the active group compared to the sham as illustrated in FIG. 8 A and FIG. 11 A.

[0403] Synchronization of Brain Activity During 60Hz Entrainment.

[0404] FIG. 8 A and FIG. 8B illustrate synchronization of brain activity during 60Hz entrainment. Phase-Locking Value (PLV) analysis was performed to evaluate whether 60Hz brain entrainment in the active group led to synchronization or consistent phase relationships across brain regions. Each PLV matrix was normalized to its corresponding baseline PLV matrix to highlight stimulation-induced changes. FIG. 8A shows significant differences in normalized PLV were observed across all channel pairs between the active and sham groups on Days 1, 5, and 19. Additionally, within the active group, significant differences in normalized PLV were detected between Day 1 vs. Day 5 and Day 1 vs. Day 19, accounting for repeated measurements. Statistical significance for these inter-group comparisons was assessed using the Wilcoxon ranksum test. Furthermore, within the active group, significant differences in normalized PLV were detected between Day 1 vs. Day 5 and Day 1 vs. Day 19, accounting for repeated measurements. These intra-group comparisons across days were evaluated using the Kruskal-Wallis test, followed by post-hoc pairwise comparisons performed using Dunn’s test with Bonferroni correction. Normality of the data was assessed using the Shapiro-Wilk test, and non-parametric methods were employed due to deviations from normality. FIG. 8B shows PLV matrices for the active and sham groups across experimental days. Each element in the matrix represents the PLV value for specific pairs of EEG channels, with diagonal elements showing a value of 1, indicating PLV between identical signals. Significant differences are indicated, with * indicating p < 0.05 and *** indicating p < 0.001. Detailed p-values are provided in Supplementary Table 2B below.

[0405] Supplementary Table 2B (EEG FIGS. 8A. 8B)

[0406]

[0407] Similar to the observed changes in the power of entertainment, a significant effect of time on the topographic distribution of power was detected, with reductions observed on Day 5 and Day 19. Topographically, the power decline did not follow a consistent pattern, suggesting a habituation effect or neural adaptation to repeated stimulations over time, as previously shown with other sensory modalities.

[0408] Consistent with these findings, PLV values significantly decreased from Day 5 until Day 19 in the active group, as shown in FIG. 8A. This reduction in PLV over time suggests a decline in neural synchrony at the stimulation frequency with repeated exposures.

[0409] Effects on cortisol and CRP measured in saliva

[0410] Given the robust and widespread brain entrainment observed in the participants, whether this effect was accompanied by any sign of somatic response, including stress or inflammatory response was investigated. To address this, salivary cortisol and C-reactive protein (CRP) levels as markers of stress and systemic inflammation following 60Hz flickering light stimulation were measured. Cortisol levels were presented as relative values, normalized to Day 1 levels to account for sample variability. Although no statistically significant differences were observed between sham and active participants in response to 60 Hz stimulation at day 5 or day 19

[0411] FIG. 9A illustrates that active participants exhibited a surprising and notable trend toward reduced cortisol levels over the course of the stimulation. Thus, the reduction of cortisol levels measured in saliva may be used as a biomarker for the disclosed therapy’s efficacy.

[0412] FIG. 9B illustrates that, similarly, no significant differences were observed in the levels of CRP on Day 1, 5 and 19, when comparing active and sham groups. These findings suggest that 60Hz stimulation, even over a three-week period, does not induce a detectable stress or inflammatory response.

[0413] Systemic effects of 60Hz entrainment.

[0414] FIG. 9A and FIG. 9B show molecular marker analysis for stress and inflammatory responses in saliva following 60Hz light stimulation. FIG. 9A illustrates competitive ELISA quantification of salivary cortisol levels, normalized to baseline (Day 1). Cortisol levels were measured after 1 week (Day 5) of stimulation and after 3 weeks of long-term stimulation (Day 19) in the active (turquoise) and sham (gray) group (active: n = 4; sham: n = 5). Data are presented as scatter dot plots showing mean ± standard deviation (SD). Statistical significance was determined using two-way ANOVA with multiple comparisons, followed by the Shapiro- Wilk test, ns (not significant). FIG. 9B shows quantification of CRP levels in saliva, measured on Day 1, Day 5, and Day 19 of the study. Participants received either active (turquoise) or sham (gray) stimulation (active: n = 5; sham: n = 5). Data are presented as scatter dot plots showing mean ± standard deviation (SD). Statistical significance was determined using Kruskal-Wallis test multiple comparisons.

[0415] FIG. 9C shows day by day record of side effects during the stimulation. No statistically significant differences were observed, as illustrated in Table 2.

[0416] Tolerability

[0417] Brain entrainment using white light is generally safe and well tolerated by subjects with only minor side effects such as headaches and eye strain. The study was designed to minimize the discomfort experienced by subjects, by using an LED-generated light whose spectrum largely overlaps with daylight and at a very low intensity which subjects could adjust according to their preference (between 14 and 113 pW ). However, tolerability of 60Hz brain entrainment over prolonged periods has not been previously studied. This seems relevant since the protocol induced a pattern of continuous and robust 60Hz activity over 3 weeks, which is different from what is observed in daily life and might be linked to discomfort. Therefore the occurrence of somatic complaints and the general tolerability of the procedure were investigated using questionnaires, self-reporting of side effects, and free comments from participants. Questionnaire data (in which participants were asked to rate sentences in a scale from 0 - not at all- to 5 - absolutely), as well as side effects occurrence and dropouts, were compared statistically between the active and sham groups. The results of this analysis are shown in Table 2 of FIG. 19B and in FIG. 9C.

[0418] Table 2 shows the analysis of data collected from questionnaires and self-reports to assess tolerability and safety of 60Hz stimulation (active) as compared to stimulation with constant light (sham). Participants rated statements on a scale from 0 (‘ not at all’) to 5 (‘absolutely’). Both light stimulation conditions, sham and active, were well tolerated and induced only minor side effects. Discrete data were analyzed using the Mann-Whitney-Wilcoxon U test, while all other data were analyzed with Fisher’s exact test. No statistically significant differences were observed between the groups.

[0419] Out of the 14 participants in the study, none found the stimulation, whether sham or active, unpleasant. The stimulation was rated as highly tolerable with an average score of 4.5 in the sham group, 4.8 in the active group. All participants indicated a willingness to undergo the procedure again, with an average score of 3.5 in the sham and 4.0 in the active group. Side effects were recorded in both groups at similar rates and were generally minor. Consistent with findings from other brain entrainment studies using 40Hz, , the most common side effect was sleepiness, reported by 66.7% of the sham group and 62.5% of the active group, followed by dry eyes. Interestingly, the number of reported side effects declined over time in both groups. By week 3, only one subject in the active group reported a side effect (see FIG. 9C). Overall, the stimulation appeared to be well tolerated and safe, with no unexpected adverse events recorded.

[0420] Discussion Technical considerations

[0421] While several studies have investigated the effect of 40Hz brain entrainment, 60Hz entrainment is relatively less explored. Given the role of high gamma oscillations in cognitive functions, their alterations in several neurological and psychiatric diseases, and the preclinical effects of 60Hz on neuroplasticity (Venturino et al 2021), 60Hz brain entrainment is a topic of high interest. One study showed successful and widespread entrainment with acute 60Hz visual stimulation, but the effect of prolonged stimulation has not been tested. A few studies have used transcranial alternating current stimulation (tACS) at 60Hz in healthy volunteers and showed entrainment, but the effect of visual stimulation has not been tested. The effects on subjects’ somatic response and well-being have not been systematically recorded in most studies.

[0422] The scarcity of studies on 60Hz entrainment might be due to inherent technical challenges in working with this specific frequency. First of all, with a standard 16-channel, the sampling rate is 62.5Hz, which is not sufficient for reliable measures in the 60Hz region. Second, at least in the United States, a 60Hz EEG signal overlaps with electrical noise (the US has a voltage of 110 V and a frequency of 60Hz), making it hard to analyze. The disclosed protocol has overcome these challenges; by using an 8-channel EEG setup, a wider range of frequency spectrum is covered due to a higher sampling rate. With this system, at around 60Hz may be confidently measured. Being based in Europe, the protocol worked with a voltage of 220 V at 50Hz, therefore the electrical noise could be easily filtered out and did not interfere with the analysis. Another technical aspect that makes this type of work challenging is the interference between the electrical noise of the flickering LEDs and the EEG recording. To overcome this issue, the LED stripe is incased in a mini Faraday cage. This resulted in a clear reduction of electrical noise (data not shown). The fact that the 60Hz entrainment signal in EEG declines over time in each subject, while the LED light was always active throughout the 3 weeks, demonstrates that the device was successful in removing noise and that the observed signal is driven by brain activity.

[0423] 60 Hz brain entrainment power

[0424] This is the first study that combines in-depth EEG signal analysis over 3 weeks and biochemical / quality of life responses in healthy volunteers receiving light-induced brain entrainment. The presence of the 60Hz peak in the PSD of active group participants confirmed that the disclosed intermittent light stimulation effectively entrained neural activity at the stimulation frequency. This finding aligns with previous studies demonstrating frequency-specific entrainment using acute stimulation with visual stimuli, as well as rhythmic sensory stimulation, particularly at gamma frequencies such as 40 Hz.

[0425] Further analysis of the EEG signal confirmed that the response in the active group was robust and not driven only by a few individuals or a few channels. As shown in FIG. 7F, most channels were entrained. FIG. 7F and FIG. 10H show the subject-specific response; while there was considerable variability across individuals, overall the response was seen across subjects. In each person, the entrainment was sustained over the 20min as shown in the STFT analysis, as shown in FIG. 7G.

[0426] 60 Hz brain entrainment topographic distribution

[0427] The topographical distribution of the entrainment was next investigated. Interestingly, a focal neural activation limited to the visual cortex (the primary target of visual stimulation) was not observed but rather an activity that spread to the rest of the cortex, including the parietal cortex, and reaching the frontal cortex was observed. Similar spreading has been observed with other entrainment modalities such as 40Hz light and transcranial electrical stimulation. Such a diffuse pattern of brain activity could be driven by synaptic connections or traveling cortical waves. Indeed, gamma entrainment has been shown to induce traveling waves connecting the occipital / parietal regions to the frontal region of the cortex through the temporal region.

[0428] In addition, it was found that the brain activation pattern is not random but is highly synchronized, as revealed by our the PLV analysis. This finding is consistent with reports that flickering simulations increase phase connectivity between brain regions. Without being limited to any particular theory or mechanism of action, while the mechanism underlying such connectivity effect is not known, it is believed to involve functional neuroplastic changes.

[0429] Effect of time

[0430] In line with the idea of neuroplastic changes occurring with 60Hz stimulation, a neural adaptation to the entrainment over time, namely after 5 and 15 days of stimulation (corresponding to Day 19) was observed. The results indicate that the response is highest on Day 1 during the very first stimulation, still present at Day 5 but lower, and further reduced at Day 19. All features of the 60Hz entrainment that were analyzed (the normalized entrainment power (FIG. 7F), the topographic distribution (FIG. 7E) and the PLV analysis (FIG. 8A and FIG. 8B) showed a similar pattern.

[0431] The reduction in entrainment power as well as PLV over time suggests a neural adaptation to the repeated stimulations over time. Similar adaptation has been previously described with repeated acoustic stimulations as well as with 40Hz combined visual and auditory entrainment. The adaptation is not surprising based on neurophysiology, and is related to homeostatic plasticity. Briefly, repeated stimulations will first stimulate Hebbian plasticity and the formation of new connections (quick response in minutes / hours); this is followed, at a slower timescale (days) by homeostatic plasticity which removes connections to assure stability. Without being bound by any particular theory or mechanism of action, it is intriguing to observe that, in animal experiments, 60Hz was shown by our group to promote juvenile-like neuroplasticity via remodeling of the PNN (venturino et al and unpublished). PNN remodeling might be the molecular underpinning of the functional synaptic changes observed in healthy volunteers receiving 60Hz flickering light; this hypothesis remains to be investigated.

[0432] Somatic response

[0433] In preclinical models 60Hz was shown to activate microglial cells, who were in turn driving the PNN remodeling (venturino et al), suggesting a potential effect on the immune system. This was investigated by measuring CRP in saliva samples of participants; importantly, 60Hz in humans does not appear to elicit a strong immune response, as CRP levels appeared not statistically different across groups, (as shown in FIG.9B). Similarly, the strong brain activity response we observed was not accompanied by any sign of stress, as measured by cortisol levels (as shown in FIG. 9A), and was overall well tolerated by the participants (as shown in FIG. 9C. Based on the literature (mostly on 40Hz stimulations), w only minor side effects were expected, including eye strain and sleepiness. Indeed, the vast majority of participants reported some side effects (as shown in Table 2), but all of them, in both sham and active groups, were minor and did not require medical assistance. The responses the participants gave to the questionnaire confirmed that the stimulation (both active and sham) was well tolerated and all would have done it; the two dropouts were due to personal reasons, and none was stimulation-related. Since this was a particularly young and healthy research cohort, it remains to be assessed whether the 60Hz effect is the same in a more heterogenous population. However these results confirm that the EEG changes we have encased observed were not confounded by stress or discomfort caused by the stimulation itself. Data for cortisol levels is shown in Supplementary Table 2C below.

[0434] Supplementary Table 2C

[0435]

[0436] Data for C-reactive protein (CRP) levels is shown in Supplementary Table 2D below.

[0437] Supplementary Table 2D

[0438]

[0439]

[0440] Supplementary experimental set up and control conditions to assess 60Hz-induced brain entrainment: FIG. 10A illustrates a graph showing the light spectrum of the LEDs ranging from 440 nm to 770 nm, similar to daylight wavelengths.

[0441] FIG. 10B illustrates an experimental setup on EEG Days: subjects were seated on a chair during the stimulation.

[0442] FIG. 10C illustrates the location of the 8 EEG channels utilized in the study, mapped according to the 10-20 electrode placement system.

[0443] FIG. 10D shows scalp EEG power spectral density (PSD) averaged across all channels for participants in each group under (I.) No light and (II.) Constant light conditions. The gray bar indicates the 50 Hz line noise, which was notch-filtered.

[0444] FIG. 10E shows topographic maps showing normalized changes in 60Hz PSD (relative to baseline) averaged across participants of each group under (I.) No light and (II.) Constant light conditions.

[0445] FIG. 10F and FIG. 10G illustrate that statistical significance for these inter-group comparisons. Statistical significance was assessed using the Wilcoxon rank-sum test. Furthermore, within the active group, significant differences in normalized PSD were detected between Day 1 vs. Day 5 and Day 1 vs. Day 19, accounting for repeated measurements. These intra-group comparisons across days were evaluated using the Kruskal-Wallis test, followed by post-hoc pairwise comparisons performed using Dunn’s test with Bonferroni correction. The normality of the data was assessed using the Shapiro-Wilk test, and non-parametric methods were applied due to deviations from normality. In this figure, different channels are shape-coded. Only significant differences are indicated, with * indicating p < 0.05 and *** indicating p < 0.001.

[0446] FIG. 10H displays the average PSD of all channels for each subject in both groups over days 1, 5, and 19, represented as individual lines. The thick line indicates the group average across all channels and subjects. Data were recorded during light stimulation, with 60Hz flickering light for the active group and constant light for the sham group.

[0447] FIG. 101 illustrates Short-Time Fourier Transform (STFT) of a representative sham group participant, demonstrating no visible 60Hz entrainment during light stimulation, as indicated by the turquoise arrow.

[0448] Supplementary assessment of synchronization of brain activity during 60Hz entrainment during no light and constant light stimulus FIG. 11A illustrates that no significant differences in normalized PLV were observed across all channel pairs between the active and sham groups under (I.) No light and (II.) Constant light conditions on Days 1, 5, and 19. Inter-group comparisons were assessed using the Wilcoxon rank-sum test. Intra-group comparisons across days were evaluated using the Kruskal- Wallis test, followed by post-hoc pairwise comparisons performed using Dunn’s test with Bonferroni correction. Normality of the data was assessed using the Shapiro-Wilk test, and nonparametric methods were employed due to deviations from normality.

[0449] FIG. 1 IB shows PLV matrices for the active and sham groups across experimental days under (I.) No light and (II.) Constant light conditions. Each element in the matrix represents the PLV value for specific pairs of EEG channels, with diagonal elements showing a value of 1, indicating PLV between identical signals. Significant differences are indicated, with ** indicating p < 0.01 and *** indicating p < 0.001.

[0450] Conclusions

[0451] Externally induced brain entrainment with 60Hz light over 3 weeks is robust, synchronized across brain regions, and leads to neural habituation, with no major side effects. Several FDA-approved drugs for psychiatric conditions, including SSRIs and ketamine, boost neuroplasticity, promote the remodeling of extracellular matrix, and induce gamma activity (ref). Externally induced 60Hz entrainment might therefore be a new approach for modulating brain activity and inducing neuroplasticity, with implications for our basic understanding of brain physiology as well as treatment of psychiatric disorders. Since light is a non-invasive, easily implementable, and cheap methodology, this warrants further investigation.

[0452] Example 3: A feasibility, open label study of intermittent light treatment in major depressive disorder

[0453] Introduction:

[0454] Depression is the most common mood disorder worldwide, with an estimated 20 million U.S. adults affected in 2019. Current pharmacological treatments do not work for all patients, often have significant side effects and in some cases require medical monitoring. Non-invasive brain stimulation (NIBS) techniques are emerging as a promising therapeutic alternative, offering fewer side effects. It is an insight of the invention that intermittent light stimulation at 60Hz promotes juvenile-like neuroplasticity and ameliorates depressive-like symptoms in animal models (Venturino et al 20211 and unpublished). Daily 30min sessions of 60Hz in healthy volunteers were well tolerated for 3 weeks (unpublished). Intermittent white light at 60Hz might therefore be a novel NIBS for treatment of depression; however, intermittent light at 60Hz has not yet been evaluated in depressed patients in clinical trials.

[0455] Major Depressive Depression and Current Treatments

[0456] Major Depressive Disorder (MDD) involves one or more major depressive episodes lasting at least two weeks, marked by a depressed mood or loss of interest or pleasure in nearly all daily activities. Further symptoms include fatigue, sleep disturbances, changes in body weight, and impaired cognition2 . MDD can be highly debilitating, leading to severe impairments that limit an individual's ability to carry out major life activities.

[0457] Depression is the most prevalent mood disorder globally. In 2019 an estimated 20 million adults in the United States (7.8% of the adult population) experienced at least one major depressive episode2. The US economic burden of MDD was estimated to be $333.7 billion in 2019, including direct medical costs, workplace productivity losses, and suicide-related costs3. Depression is currently treated using psychotherapy, medications and brain stimulation, either alone or in combination.

[0458] Current pharmacological treatments do not work for all patients, often have significant side effects and in some cases require medical monitoring. Selective Serotonin Reuptake Inhibitors (SSRIs) are among the most used first-line treatments for MDD. Their efficacy is generally moderate to weak; for example, the STAR*D study 5 found that the SSRI citalopram had approximately a 30% remission rate and a 50% response rate. These effects only occur in a subset of patients (about 40-45% in community practice), typically take about two weeks to manifest, and require long-term use. SSRIs are also associated with high rates of side effects, a risk of relapse, and societal stigma. Intravenous ketamine, an anesthetic drug acting on the NMDA glutamate receptor, has been employed off-label to treat treatment-resistant depression (TRD)6. Recently, esketamine, the S-enantiomer of ketamine, has been approved by the FDA as a rapid-acting nasal spray formulation for TRD, showing up to 69% response rate and a remission rate of 52%7. Both ketamine and esketamine must be administered and monitored in a clinical setting due to their psychiatric and cardiac side effects, particularly dissociation. In addition to pharmacological treatments, brain stimulation is emerging as a promising option for MDD and TRD. Due to encouraging data on the effectiveness and acceptability of these new methods, neurostimulation techniques have been included in international guidelines, received FDA approval and are increasingly used in clinical practice. Brain stimulation broadly refers to the modulation of the brain's electrical activity through an external source of energy, such as electrical (like electroconvulsive therapy, ECT) or magnetic (like in transcranial magnetic stimulation, TMS)9. ECT and TMS are FDA-approved treatments for depression but have some limitations. Both require medical supervision in a hospital setting and are not universally effective for all patients.

[0459] Intermittent white light at a specified frequency is starting to be investigated as an alternative, non-invasive brain stimulation technique. 40Hz intermittent white light is so far the most investigated; 40Hz combined visual and auditory stimulation shows promise for the treatment of Alzheimer's disease. In animal models, 40Hz stimulation promotes amyloid plaques clearance and improves memory.

[0460] Preliminary results with 60Hz intermittent white light. The inventors have been investigating the effect of 60Hz intermittent white light stimulation in animal models, and have discovered its potential for the treatment of depression. Further studies in healthy volunteers showed so far good safety and tolerability. The following preliminary results are relevant for this investigation:

[0461] 1. FIG. 12, panels A-E illustrate that 60Hz intermittent white light induces robust and widespread increased neuronal activity in mice, associated with microglia-mediated remodeling of perineuronal nets (PNN) in brain regions relevant to depression. FIG. 12 Panel A illustrates in-vivo power spectrum density in primary visual (VI) with constant (left) and 60Hz intermittent (right) white light demonstrates robust 60Hz entrainment to external stimuli (red arrow). Panel B illustrates preliminary quantification following 60Hz visual entrainment using TRAP reporter tg mice (n=3) reveals significantly increased neuronal activation in depression-relevant brain regions such as entorhinal cortex (ENT) and frontal cortex (FC), beyond visual cortex (VS). The perineuronal net (PNN) is a specialized extracellular matrix deposited around inhibitory neurons during development and limiting neuronal plasticity in adulthood. Panel C illustrates that 60Hz but not 8Hz or 40Hz intermittent white light stimulation (2h / day, 5 days), induced strong removal of perineuronal nets. The effect is mediated by microglial cells as their depletion with PLX5622 abolishes the effect, as shown in panel D. Panel E shows confocal micrographs illustrate microglia cell (iba 1) phagocyting elements of the PNN (WFA) in phagolysosomes (CD68 stained).

[0462] 2. FIG. 13, panels A and B illustrate that 60Hz intermittent white light treatment is well tolerated by wild type mice, with no indication of weight loss or reduced water / food intake. In a model of social defeat, the intervention increased elevated plus maze locomotion, indicating anti-stress effects. Panel A illustrates the quantification of weight gain, and food and water consumption in wild type mice (n=4 males and n=4 females). The results indicate no effect of 60Hz intermittent light stimulation (2h / day, 5 days) on animal wellbeing as compared to control (constant light). Panel B shows that mice (n=16 per group) were subjected to social defeat model of stress / depression. Following this paradigm, their stress level was investigated with the elevated plus maze. Stressed mice receiving 60Hz intermittent whit light (2h / day, 5 days) spent significantly more time in the open arms compared to mice exposed to constant light (control), indicating reduced stress levels. Further, the distance moved of the treated mice was comparable to that of mice who have not been socially defeated.

[0463] 3. 60Hz intermittent white light application is well-tolerated by healthy volunteers and induces robust and widespread brain entrainment. As illustrated in FIG. 14, panels A-C, a cohort of healthy volunteers (n=12, 6 active, 6 sham) were recruited for studying the effect of 60Hz intermittent light on EEG after acute (same day), short (5 days), and intermediate (3 weeks) stimulation. The experimental design and schedule procedures are shown in panel A. EEG, saliva sampling (before, B, and after, A, stimulation) and a questionnaire participants were asked to rate various sentences / features in a scale from 0 (“not at all”) to 5 (“absolutely”). The stimulation was overall very well tolerated, as illustrated in panel B. The average EEG response in participants (n=3) receiving 60Hz intermittent light (normalized power of 60Hz component) shows robust and widespread entrainment, as shown in panel C. In this study, an open label clinical trial at the Institute of Psychiatry of the Hospital das Clinicas, Faculty of Medicine, USP, is proposed to evaluate the safety and efficacy of 60Hz intermittent white light, administered once a day for 2 weeks, in patients with MDD.

[0464] Hypotheses

[0465] Without being bound by any theory or mechanism of action, the below hypotheses are proposed.

[0466] Primary Hypothesis:

[0467] 1. Intermittent white light at 60Hz is safe and well tolerated by MDD patients over two weeks of daily treatment.

[0468] Secondary Hypotheses:

[0469] 1. Intermittent white light at 60Hz improves depressive symptoms over 2 weeks of treatment, as measured by changes from baseline, response (50% reduction) and remission (score < 7) in the HDRS scale at day 12 and day 40.

[0470] 2. Intermittent white light at 60Hz improves depressive symptoms over 2 weeks of treatment, as measured by changes from baseline, response (50% reduction) and remission (score < 10) in the MADRS scale at day 12 and day 40.

[0471] 3. Intermittent white light at 60Hz improves depressive symptoms over 2 weeks of treatment, as measured by changes from baseline, response (50% reduction) and remission (score < 10) in the BDI scale at day 12 and day 40.

[0472] 4. Intermittent white light at 60Hz improves anxiety symptoms over 2 weeks of treatment, as measured by changes from baseline, response (50% reduction) and remission (score < 7) in the HAM-anxiety scale at day 12 and day 40.

[0473] Additional / Exploratory Hypotheses

[0474] 1. Intermittent white light at 60Hz improves depressive symptoms over 1 weeks of treatment, as measured by changes from baseline in the MADRS, HDRS, BDI, HAM-A scale at day 5.

[0475] 2. Intermittent white light at 60Hz improves depressive symptoms over 4 weeks of treatment, as measured by changes from baseline in the MADRS, HDRS, BDI, HAM-A scale at day 26.

[0476] 3. Intermittent white light at 60Hz improve retina cells responses as measured at day 40. Rationale

[0477] Intermittent white light at 60Hz acts by inducing brain entrainment, which causes microglia activation and remodeling of the perineuronal net (PNN). This effect induces juvenilelike plasticity and ameliorates depressive like symptoms in animal models (Venturino et al.l and unpublished). Its safety profile is good, based on literature and in house studies with healthy volunteers; however, its safety and tolerability has not yet been tested in depressed patients. If our hypothesis is confirmed, this non-invasive treatment will be well tolerated and possibly effective in a population of MDD patients, paving the way for future studies to test the clinical efficacy of 60Hz intermittent light.

[0478] General Objective

[0479] The general objective is to evaluate the safety and efficacy of 60Hz intermittent white light in improving depressive symptoms over 2 weeks of treatment using an open-label clinical trial.

[0480] Specific Objectives

[0481] According to the study design mentioned above, the below are evaluated:

[0482] 1. The safety, acceptability, and tolerability profile of the technique.

[0483] 2. The improvement in depressive symptoms according to changes from baseline in various well established clinical scales including MADRS, BDI and HDRS

[0484] 3. The improvement in depressive symptoms in terms of response and remission.

[0485] 4. The improvement in anxiety symptoms according to Hamilton Anxiety Rate scale (HAM-A)

[0486] Methods:

[0487] The open-label, monocenter study investigates the safety and tolerability of a prototype developed device of the systems and methods of the invention, in the management of individuals with moderate to severe depression. The trial will last 6 weeks in total, comprising 5 sessions per week in the first 2 weeks, 1 time a day (total of 10 sessions, with 30min of stimulation with 60Hz white light) and two follow-ups after 4 and 6 weeks. Thirty patients aged between 18 and 59 years with a diagnosis of current moderate or severe major depressive episode (HDRS-17 > 16) and an antidepressant pharmacological regimen that is stable for at least 6 weeks, will be selected. The primary outcome will be safety and tolerability of the device. Clinical improvement as measured by the change in the HDRS-17, HAM anxiety, BDI and MADRS scores from baseline will be secondary outcomes.

[0488] Expected results:

[0489] The results are expected to introduce a new therapeutic modality into clinical practice. Materials and Methods Study Design

[0490] The study design is an open-label clinical trial, therefore no randomization nor blinding is needed. One person, designated solely to administer the 60Hz light sessions, will carry out the procedure and will not be involved in assessments or with the evaluators. Participants will receive 10 consecutive days (excluding weekends and holidays) of stimulation once a day (30min per session) and will return at 4 and 6 weeks for clinical outcome assessment.

[0491] Sample

[0492] Patients aged 18 to 65 years with an initial HDRS score of 16 or higher and a confirmed diagnosis of Major Depressive Disorder (MDD) by the MINI18, will be included. The Hamilton Depression Rating Scale (HDRS-17) is a 17-item scale widely used to assess the severity of depression and the response to treatment, especially in NIBS studies. The 17 items cover: depressed mood, feelings of guilt, suicide, initial insomnia, middle insomnia, terminal insomnia, work and activities, psychomotor retardation, psychomotor agitation, psychic anxiety, somatic anxiety, loss of appetite, general somatic symptoms, libido, hypochondria, weight loss, and criticism of the morbid state. Eight items are scored from 0 to 2 points and 9 items are scored from 0 to 4 points, with a maximum score of 50 points. Standardized scores are: 7 to 17 points - mild depression; 18 to 25 points - moderate depression; 26 points - severe depression.

[0493] Exclusion criteria will include: other mental disorders (alcohol or drug dependence; bipolar affective disorder; obsessive-compulsive disorder; attention deficit hyperactivity disorder; personality disorders; psychotic disorders; and dementias); presence of severe neurological or medical conditions; severe suicidal ideation; presence of psychotic symptoms; severe depression characterized by HDRS scores greater than 28 points; and manic symptoms evidenced by more than 8 points on the Young Mania Rating Scale (YMRS 17), and rapidcycling bipolar disorder. The YMRS is an 11 -item scale used to assess the severity of manic symptoms. The 11 items cover: expansive or elevated mood, increased energy and motor activity, sexual interest, reduced need for sleep, irritability, speech, thought form, thought content, aggressive behavior, appearance, and criticism of the morbid state. Seven items are scored from 0 to 4 points and 4 items are scored from 0 to 8 points, with a maximum score of 60. Standardized scores are: 15 to 20 points - hypomania; 21 points - mania.

[0494] Additionally, specific contraindications for 60 Hz light treatment include: history of epilepsy or migraine, photosensitivity, tinnitus, retinal diseases or cataract, regular use of antiinflammatory drugs and clopidogrel (which might interfere with the microglia activation), autoimmune disorder.

[0495] Patients on antidepressants or other psychotropic drugs must have stable doses for 6 weeks. Also, any clinical worsening, such as psychotic symptoms, an HDRS score increase to more than 28 points, and severe suicidal ideation during the clinical trial period, will result in exclusion and referring the patient for urgent psychiatric treatment if necessary.

[0496] Recruitment strategies include referrals from other physicians, patients from specialized mood disorder clinics, and spontaneous demand through social media, institutional websites, local radio, and newspapers. A pre-screening using REDCap link ensures that patients who come for in-person screening do not meet the exclusion criteria mentioned above. No financial aid or other benefits, such as transportation or meals, will be provided for participation in this study. Interventions

[0497] Following the completion of screening measures, subjects meeting the study criteria will enter the study. They be required to wear the Syntropic prototype (See Appendix 1 for details), a safety goggle fitted with a stripe of LED, providing 60Hz light stimulation, for 30min per day for 10 days, excluding the weekend. All prototypes will be labelled ‘For clinical investigation use only’ on any packaging as well on the device itself. Syntropic Medical will provide detailed written instructions on the correct use of the prototype. It will also provide technical support. A trained professional from the research team will administer the sessions.

[0498] Safety and Tolerability

[0499] Safety and tolerability will be assessed through clinical evaluations based on the relevance of reported side effects. Adverse effects related to intermittent light stimulation are mostly dry eye / eye strain, sleepiness and headache (see Appendix 2 for more details); all effects will be recorded with a questionnaire. Symptoms indicative of manic / hypomanic episodes will be assessed using the YMRS17.Also, safety will be accesses through a complete ophthalmological evaluation at baseline and 6 weeks assessment. The ophthalmological evaluation includes a best-corrected visual acuity measurement, refraction, slit-lamp biomicroscopy, gonioscopy, intraocular pressure measurement, dilated funduscopic examination using a 78D lens and, retinography scan and an OCT. Number of stimulation-related dropouts will be recorded.

[0500] Clinical Evaluation

[0501] Screening

[0502] Demographic and clinical information will be systematically collected (age, sex, education, socioeconomic status, clinical comorbidities, duration of illness, prior use of antidepressants and other psychoactive drugs). We will also investigate habits or addictions, personal and family psychiatric history, and the presentation / course of the current illness. Previous psychiatric treatments will be assessed, and stability of any ongoing psychiatric treatment will be required to minimize confounding factors. The Brazilian Portuguese version of the Mini International Neuropsychiatric Interview (MINH 8) will be used for initial evaluation of all participants. Additional clinical information, laboratory tests, and imaging studies will be obtained from hospital records or requested based on clinical judgment. The screening procedure will be as follows:

[0503] Clinical scales

[0504] Eligible patients with a major depressive episode (DSM-5), but clinically stable, will proceed into the study according to the study protocol, which includes the following: Secondary outcomes

[0505] 1. Hamilton Depression Rating Scale (HDRS-17) -> Changes from baseline after 10 days of treatment (corresponding to day 12) and at follow up after 6 weeks (day 40)

[0506] 2. HDRS-17 response (50% reduction) at day 12 and day 40

[0507] 3. HDRS-17 remission (<7) at day 12 and day 40 4. Montgomery-Asberg Depression Rating Scale (MADRS) -> Changes from baseline after 10 days of treatment (corresponding to day 12) and at follow up after 6 weeks (day 40)

[0508] 5. MADRS response (50% reduction) at day 12 and day 40

[0509] 6. MADRS remission (<10) at day 12 and day 40

[0510] 7. Back Depression Inventory Scale (BDI) -> Changes from baseline after 10 days of treatment (corresponding to day 12) and at follow up after 6 weeks (day 40)

[0511] 8. BDI response (50% reduction) at day 12 and day 40

[0512] 9. BDI remission (<10) at day 12 and day 40

[0513] 10. Hamilton Anxiety Rating Scale (HAM- A) -> Changes from baseline after 10 days of treatment (corresponding to day 12) and at follow up after 6 weeks (day 40)

[0514] 11. HAM-A response (50% reduction) at day 12 and day 40

[0515] 12. HAM-A remission (<7) at day 12 and day 40 Exploratory outcomes

[0516] 1. Hamilton Depression Rating Scale (HDRS-17) -> Changes from baseline at day 5, 26

[0517] 2. Montgomery-Asberg Depression Rating Scale (MADRS) -> Changes from baseline at day 5, 26

[0518] 3. Hamilton Anxiety Rating Scale (HAM-A) -> Changes from baseline at day 5, 26

[0519] 4. Electroretinogram - to evaluate retina cells responses using portable hand-held RETeval system.

[0520] FIG. 20 illustrates the schedule of procedures.

[0521] Statistical Analysis

[0522] To estimate a sample size we used two approaches. First, a power analysis was based on the effect size obtained in preclinical experiments (doubling the standard deviation and halving the effect size for extra safety). With a reduction in elevated plus maze locomotion index of 25%, a power of 80% and alpha below 0.05, we calculated a sample of 24 per group. This is also similar to the sample size used in previous feasibility study with 40Hz for Alzheimer' sl9 (n=16). Considering an attrition rate of approximately 10-20%, the final estimated sample size is 30 patients.

[0523] Changes in main, secondary and exploratory outcome measures will be compared between baseline and follow up using repeated measures t-tests and ANOVA. The significance threshold for changes in secondary outcomes will be corrected for multiple comparisons. We will analyze the baseline characteristics of participants who improve and those who drop out of the study, and the reasons for drop out will be recorded.

[0524] Ethical Considerations

[0525] The study will be conducted in accordance with all requirements of the Research Ethics Committee and based on the recommendations established in the Declaration of Helsinki (1964), with amendments in Tokyo (1975), Venice (1983), and Hong Kong (1989). Potential benefits of participation include psychiatric and psychological evaluation, improvement in depression, standard clinical treatment, and appropriate referrals at any time during the study. 60 Hz intermittent white light has so far shown to be safe and well tolerated, with few adverse effects (see above and Appendix 2 for more infos). All applications will be conducted in a hospital setting with a physician present. Patients will be assessed over 6 weeks to quickly identify any clinical deterioration and provide early intervention.

[0526] All hospital procedures will follow health recommendations to prevent COVID-19 transmission, including appropriate mask use by participants and professionals, as well as hand and surface cleaning with suitable materials. Data collection will begin only after project approval by the Research Ethics Committee and after each volunteer signs the informed consent form. The study will also be prospectively registered at clinicaltrials.gov. All procedures described pose minimal risk. If a volunteer shows significant suicidal risk, they will be excluded from the study, and standard procedures for managing such patients will be followed (i.e., if outpatient management is possible, the patient will be referred with a family member for treatment; if not, psychiatric consultations will be provided until treatment is available; if outpatient treatment is not feasible and hospitalization is necessary, contact will be made with the regional psychiatric emergency service for such cases). Data will be collected, analyzed, and published in a manner that preserves individual anonymity.

[0527] Criteria for Study Withdrawal

[0528] Participants who complete at least one session of 60Hz intermittent white light and wish to withdraw can do so by withdrawing their consent to participate in the research, regardless of the reason provided. Patients will have access to their data, and any treatments they receive within the institution will not be affected by their withdrawal. Patients will be withdrawn from the study if they meet any of the following criteria: (1) Missing 2 consecutive visits or missing 3 or more non-consecutive visits during the study. (2) Experiencing serious clinical or psychiatric events (at the clinician's discretion) during the study: these criteria will be assessed on a case-by- case basis according to the clinical evaluation of the attending physician. Examples of serious clinical events: neurological deficits, cardiovascular deficits, endocrine decompensation, loss of consciousness, syncope. Examples of serious psychiatric events: suicidal ideation, suicide attempt, self-harm, aggression, severe anxiety, psychosis. (3) Severe side effects during the study: these criteria will be assessed on a case-by-case basis according to the clinical evaluation of the attending physician. Examples of severe side effects: severe or frequent headaches, severe dizziness, and severe nausea. (4) Severe adverse events during the study: these criteria will be continuously monitored throughout the study and include: occurrence of seizures; suicidal risk (item 3 of the HDRS-17 with 3 points and clinical evaluation); HDRS increase to more than 28 points, manic episode confirmed by YMRS, occurrence of psychotic symptoms. Patients who withdraw from the study will be referred back to the psychiatrist who referred them to the study for appropriate follow-up and medication management of the illness.

[0529] Device description

[0530] The device is composed of the following parts:

[0531] 1. Ocular component (Eye mask and head strap)

[0532] 2. Microcontroller with potentiometer

[0533] 3. Power unit

[0534] Only the ocular component comes into direct contact with the participant.

[0535] FIG. 15, panel A illustrates one embodiment of the device used in the study. The ocular component is a wearable headset derived from Uvex safety masks, worn around the face and head, much like a pair of safety glasses. The light stimulation is delivered by 2 strips of LEDs placed on the top and on the bottom of the mask which directs the light tangentially to the periphery of the wearer's eyes, as illustrated in a detailed view of the LEDs position in the device of FIG. 15, panel B.

[0536] The LEDs are controlled with an Arduino microcontroller and powered with a small battery pack.

[0537] The microcontroller pulse generator generates the 60 Hz signal. The 60 Hz square signal, with a period of 8.3 ms, is generated by an Arduino Nano board (SKU A000005) soldered on a breadboard which is then connected to the LEDs. The circuit integrated a potentiometer to modulate the light intensity. The Arduino is inserted into custom-made aluminum box to reduce electrical noise.

[0538] The power unit consists of an external power bank (Varta, mod. n. 57975) of 5000 mA / h that delivers 5 Volts via USB connection.

[0539] The study includes a consideration of possible adverse events. Possible adverse events could include seizures, migraine, headache, eye discomfort and retinal damage, electrical shock, and mechanical hazard. Throughout the study, patients will be monitored during stimulation and any adverse events will be collected with questionnaires. Even though light-induced seizures are a rare possibility, individuals with a history of epilepsy will be excluded to minimize the risk. Our age inclusion (older than 18) also reduces the chances of photosensitive epilepsy which is more common in adolescents. Photosensitivity can trigger a migraine attack, which is considered a critical adverse event whose risk needs to be minimized. In general, visual stimulation that is epileptogenic is also migrainogenic. The study uses a high gamma range of frequencies which are not expected to be epileptogenic. As such, a rare incidence of photogenic migraines is expected. However, to mitigate this risk, individuals with a history of migraine will be excluded. Medical -grade 10,000 lux light boxes are used for a variety of indications and are considered safe. The device uses around 7001ux, so much lower intensity. Eye discomfort is a likely minor adverse event that will be minimized; eye drops will be readily available to participants if needed. Retinal damage is not expected as the device uses low intensity (700 lux), diffuse white light (all wavelengths), not directed into the eye but is shone above and below the eyes. To further mitigate risk individuals with known history of retinal disease will be excluded. There could be risk of electrical shock if the user was to come into contact with any uncovered wires or electrical circuits in the device. Control measures implemented as part of the device mitigate such risks. These control measures include the use of insulated wires and an appropriate casing to isolate the control board. The device has been designed with compliance to relevant electrical safety standards and regulations, such as IEC 60601 for medical electrical equipment. Compliance with standards helps to ensure that appropriate safety measures are incorporated into the device. The ocular component, head strap and connector are all derived from an off-the-shelf Uvex eye mask manufactured by the Uvex Group. Product specifications from the Uvex Group guarantee high mechanical strength and structural reliability for these components. In addition, the provision of clear instructions to users on the proper use of the device to minimize the risk of structural failures and ensure safe operation will be implemented.

[0540] Some skin redness and pressure marking under the ocular frame is normal, and will typically subside within approximately an hour of the end of use. Skin irritation might be experienced beneath the mask frame padding. In this case, the mask frame should NOT be reapplied directly to the irritated skin. A thin hypoallergenic mask protector will be provided for placement over the user’s face before reapplying the device in this situation.

[0541] As discussed above in detail, major adverse events are not anticipated and expect the procedure to be overall comfortable and of short duration for the participants. Patients’ wellbeing will be monitored and comfort or medical assistance will be provided should this become necessary in a very unlikely event. There are no anticipated risks in terms of data safety or other ethical considerations, as data will be handled according to national and international laws. The benefit of the study is represented, for the participants, in the possibility of having an improvement in their symptoms.. Based on the overall very low risk profile and high scientific interest of the results, we think the benefit / risk ratio favors benefits.

[0542] Study Protocol and Directions for Device Use

[0543] Stimulation Program

[0544] The stimulation program consists of 15 sessions during a 3-week period. The number of sessions each patient will do per week is restricted to a maximum of 5, with each patient taking part in only 1 session per day over the 3-week period. Each session contains 30 minutes of stimulation, plus a few minutes of preparation time.

[0545] Example 4: Device Description

[0546] The example provides a detailed overview of the design and functionality of one embodiment of the systems / devices of the invention. By outlining design specifications, materials, component assemblies, and functionality, this example aims to provide detailed understanding of the device architecture and operational mechanisms, according to the embodiment.

[0547] The device has been classified by an independent regulatory expert as a class Ila Medical Device. The device is intended for use in adults (24-65 years old). The device does not require any special training before use. The device is a non-invasive, wearable device designed to deliver 60-Hz or constant light stimulation to the visual cortex and other brain regions associated with learning and memory. Without being bound by any theory or mechanism of action, the stimulation aims to modulate neural plasticity by targeting perineuronal nets (PNNs) through light entrainment. The device is non-sterile and reusable across multiple users.

[0548] FIG. 16 illustrates one embodiment of a system of the invention. As disclosed herein, the system may consist of three core components:

[0549] 1) Ocular Frame, denoted as “1 ” in FIG. 16 This component houses both the LED light strip and a printed circuit board (PCB). It is secured to the user’s face using a flexible, adjustable head strap for comfort. The PCB, integrated within the frame, delivers either a constant voltage or a 60-Hz flickering signal to the LED strip. It contains a microcontroller and supporting electronic components, enabling precise control of light output.

[0550] 2) Device Controller, denoted as “2 ” in FIG. 16: The controller communicates wirelessly with the Ocular Frame via Bluetooth Low Energy (BLE v5). It serves as the central unit for managing the light stimulation parameters and session control.

[0551] 3) Light Source, denoted as “3 ” in FIG. 16: Integrated into the Ocular Frame, the LED strip provides the light stimuli necessary for entrainment. The light characteristics — such as intensity, duration, and flicker frequency — are controlled via pulse-width modulation (PWM) generated by the microcontroller integrated inside the Ocular Frame.

[0552] The system includes a companion User APP, which allows a user to. establish a BLE connection with the Ocular Frame, configure stimulation intensity, and initiate and monitor stimulation sessions.

[0553] The Ocular Frame, also referred to as a head-worn frame, is configured to be secured on the patient's head during use to safely deliver light to the patient. Inside, a PCB provides safe control over the light delivery, enabling tunable light intensity output. The composition and material may be a vacuum cast headset with facial interface comprising detachable foam cushion for user comfort. The Ocular Frame may include a Printed Circuit Board (embedded inside). The material may be an ABS like resin. The Ocular Frame is in direct contact with the wearer's face during use (i.e. facial skin around eye and nose area). Duration of contact may be less than 1 hour. The device controller is configured to safely provide sufficient power to the Ocular Frame for the whole duration of the stimulation session and to enable interaction with the user App’s features via a touchscreen, providing intuitive navigation, visual feedback, and interactive controls for seamless operation. The device Controller contains internal electronics and a re- chargeable battery. Charged via USB-C charging cable. The device controller may have no contact with the wearer during use.

[0554] The light source is configured to safely deliver the light stimulation to the patient. The composition and material may be a LED strip with copper base circuit surrounded by polyimide (PI) overlay with a double sided adhesive (3m 200MP) used to secure strip in place. The light source has no direct contact with the wearer during use.

[0555] Technical specifications of the device are listed in Table 3 below.

[0556] Table 3: List of device performance specifications.

[0557] Power and Electrical Information

[0558] Current Supply: The device controller provides a stable current supply to the LEDs when properly charged (above 25%) and connected to the ocular frame. No additional current measurement is required during operation. This device does not require current monitoring like transcranial direct current stimulation (tDCS) devices.

[0559] Power Compatibility: The device controller charger is compatible with both 110V and 220V electrical systems without requiring a transformer. Users may need a plug adapter depending on regional outlet configurations. The device controller can be charged using standard USB chargers.

[0560] Battery Life: A fully charged device controller (100%) will support approximately 4 stimulation sessions (30 minutes each) under normal conditions. Performance may vary slightly based on environmental factors such as temperature and humidity.

[0561] Alternative Power Sources: Use only the provided cables with this device. Alternative cables may compromise device performance, safety, and study protocol validity.

[0562] Operational Guidelines

[0563] Device Durability: Handle all components with care during operation and transport. If the ocular frame housing becomes damaged but internal circuitry remains intact, the device will continue to function. Severe impact damage to internal components will render the controller non-functional and require replacement.

[0564] Bluetooth Connectivity: The device maintains a typical Bluetooth range of 10-15 meters (30-50 feet) between the ocular frame and the device controller. Range may vary depending on environmental conditions and interference.

[0565] Connection Safety: The stimulation will automatically stop if Bluetooth connection is lost between the controller and mobile phone. This serves as a safety feature to prevent unmonitored stimulation. Pre-Session Protocol: Complete the full checklist in the mobile application before each stimulation session. This mandatory step ensures all setup requirements are properly met and serves as an important safety and quality control measure for the study.

[0566] FIG. 17 illustrates a system 1700 according to one embodiment of the invention. Panel A illustrates an Ocular Frame with a USB-C port indicated by the white arrow. The Ocular Fram includes a head strap with padding to position the device on a head of the subject. Panel B illustrates a device controller connected to the Ocular Frame via a USB-C connection indicated by the white arrow. Panel C illustrates a kill-switch integrated with the USB-C cable. Panel D illustrates a toggle to adjust the head strap position.

[0567] FIG. 18 illustrates device set-up via a user interface according to one embodiment of the invention.

[0568] Device Set-up may include the steps of:

[0569] 1. Ensuring the device controller is charged fully before use.

[0570] 2. Removing the prototype, including ocular frame and device controller from its case.

[0571] 3. Connecting the device controller to the ocular frame using the provided USB-C cable. This is done before placing the device on the head.

[0572] 4. Turning on the switch on the USB-C cable.

[0573] 5. Turning on the device controller and loading the mobile app (user interface).

[0574] 6. Turning on Bluetooth and location services on the mobile phone (if not already on, a message will appear guiding you through the steps to enable them).

[0575] 7. Making one final check that charge levels on the device are sufficient before starting.

[0576] As illustrated in FIG. 18, the user App may include a passcode entry screen Panel a), and a passcode error screen, Panel b) if a previously used PASSCODE is entered. The App may display a DEVICE SCAN SCREEN upon successful PASSCODE entry, as illustrated in Panel c). When an Ocular Frame is found, the screen may show a device scan screen with the available device, as illustrated in Panel d). Panel e) illustrates a stimulation session control screen, while Panel f) illustrates a stimulation session screen during active stimulus application.

[0577] The stimulation session may be performed via the following instructions: 1 . Sit down comfortably in a dim-lit and silent room.

[0578] 2. Follow the instructions above to set up the device.

[0579] 3. Place the ocular frame on head, and make sure that the placement is comfortable. If not, readjust using the toggle on the back of the head strap until it’s comfortably positioned on head.

[0580] 4. On the mobile app, i.e. user interface, enter a passcode. This passcode may be provided to the user daily by the clinician. Each passcode allows the user to use the stimulation for 30 minutes in a 1-hour time frame (1 hour starting from entering the passcode).

[0581] 5. Enter the provided passcode into the user app on the device controller. If an already used passcode is entered, it will not work.

[0582] 6. Upon successful passcode entry, the user is redirected to the ‘Device Scan’ page. At this step, press on the “SCAN” button (located on bottom left).

[0583] 7. Once the Ocular Frame shows up the user will click on ‘CONNECT’ .

[0584] 8. Upon successful connection, the user is redirected to the ‘Stimulation Session Screen’. In this screen, stimulation is started by pressing the Start button indicated by the “ H” symbol. During the session, use the “Stop” button indicated by the “B” symbol to stop the stimulation.

[0585] 9. Adjust light intensity if needed using the slider control feature.

[0586] 10. At the end of the 30 minutes, switch off the device, remove the device from the head and decouple the connected components.

[0587] 11. Recharge the device (i.e., mobile phone) if below 50% charge and put it back in its case for storage.

[0588] Charging the Device

[0589] The device may be charged by connecting the device controller to the provided charger adapter using a USB-C cable, and connect the adapter to the plug. When the mobile phone is fully charged, the battery status indicator will show 100%.

[0590] Cleaning the Device The device can be cleaned using common alcohol cleaning / disinfectant wipes. It is recommended to clean the device before and after use. The device may be cleaned using the following procedure for correct cleaning of the device:

[0591] 1. Ensure the stimulation is off.

[0592] 2. Unplug the ocular frame from the Device Controller.

[0593] 3. Wipe gently only the wearable components such as the exterior of the ocular frame, facial cushion and head strap. DO NOT pour or spray alcohol directly on the devices.

[0594] 4. Allow the cleaned surfaces to fully dry before reuse or storage.

[0595] Storage and Maintenance of the Device

[0596] The device and all components of the device may be stored in a provided storage case when no longer required during use for clinical and / or research purposes. Users should wear the device while seated or lying down. The device should be turned off after use. The device should be fully charged before placing it back into its storage case after each use.

[0597] Incorporation by Reference

[0598] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

[0599] Equivalents

[0600] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

1. Claims1. A device for treating a brain-related disease, disorder, or related symptoms in a subject, the device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, wherein the visual stimulus induces entrainment thereby activating microglia cells to target the perineuronal net (PNN) in the brain of the subject to thereby cause remodeling of the PNN.

2. The device of claim 1, wherein the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

3. The device of claim 1, wherein the light source comprises one or more of a single point of light and an array of light sources.

4. The device of claim 3, wherein the light source comprises one or more of a light-emitting diode (LED) and an array of LEDs.

5. The device of claim 1, wherein a wave form of light emitted from the light source comprises a repeating pattern of stimulation.

6. The device of claim 5, wherein the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

7. The device of claim 1, wherein the light source comprises a pre-defined wavelength range.

8. The device of claim 1, further comprising: one or more sensors; and a computing system operably associated with the device comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor to cause the computing system to: receive data from the device and / or the one or more sensors; analyze, via one or more algorithms, the received data; andcontrol one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus.

9. The device of claim 8, wherein the one or more sensors comprises one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor.

10. The device of claim 9, wherein the device comprises a head-worn frame, wherein at least a portion of the frame defines eyewear such that the light source is housed within a frame of the eyewear.

11. The device of claim 10, wherein the eyewear comprises a one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject.

12. The device of claim 8, wherein the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

13. The device of claim 8, wherein the computing system further comprises a user interface operably associated with the computing system, wherein the user interface is provided via a software application accessible using one or more of a computer, a smartphone, and a tablet, wherein the received and analyzed data is displayed on an associated display device via the software application.

14. The device of claim 1, further comprising a sound source comprising an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus.

15. The device of claim 1, wherein the device comprises a display sized and configured for placement on a tabletop, wherein the light source comprises an LED array positioned on a front side of the display such that the visual stimulus is delivered to the subject when a subject is positioned facing the front side of the display.

16. The device of claim 1, wherein the device is configured as a lighting fixture, wherein the device is operable to actuate the light source for delivery of the visual stimulus and actuate normal room lighting once delivery of the visual stimulus is complete.

17. The device of claim 1, wherein the device is configured for attachment to one or more of a cell phone, a tablet, a display device, a television, and a headset.

18. The device of claim 1, wherein the mental disease, disorder, or related symptoms is one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

19. A system for treating a mental disease, disorder, or related symptoms in a subject, the system comprising: a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, wherein the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN; one or more sensors operably associated with the device; and a computing system operably coupled to the device, the computing system comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor to cause the computing system to: receive data from the device and / or the one or more sensors;analyze, via one or more algorithms, the received data; and control one or more of a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

20. The system of claim 19, wherein the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

21. The system of claim 19, wherein the light source comprises one or more of a single point of light and an array of light sources.

22. The system of claim 19, wherein a wave form of light emitted from the light source comprises a repeating pattern of stimulation.

23. The system of claim 22, wherein the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

24. The system of claim 19, wherein the light source comprises a pre-defined wavelength range.

25. The system of claim 19, wherein the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals.

26. The system of claim 19, wherein the device comprises a head-worn frame, wherein at least a portion of the frame defines eyewear such that the light source is housed within a frame of the eyewear.

27. The system of claim 26, wherein the one or more sensors comprises one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, an eye-tracking sensor.

28. The system of claim 26, wherein the sensor is an EEG array and the system automatically controls the delivery of the visual stimulus based on feedback from the EEG array.

29. The system of claim 26, wherein the eyewear comprises a one or more of a virtual reality (VR) display, an augmented reality (AR) display, and a mixed reality (MR) display, wherein the display is configured to display VR, AR, and / or MR content to the subject in conjunction with delivery of the visual stimulus to the subject.

30. The system of claim 29, wherein the virtual reality content comprises one or more of a virtual therapy session, a wellness application, a brain-training application, a mindfulness application, a video, a meditation application, rehabilitation therapy, functional training, and fitness training.

31. The system of claim 19, wherein the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

32. The system of claim 19, further comprising a sound source.

33. The system of claim 32, wherein the sound source comprises one or more of an electroacoustic transducer configured to convert an electrical audio signal into a corresponding auditory stimulus in a same or different frequency as the light source, and one or more speakers configured to deliver the auditory stimulus.

34. The system of claim 32, wherein the sound source comprises bone conduction in a same or different frequency as the light source.

35. The system of claim 19, wherein the computing system further comprises a user interface operably associated with the computing system, wherein the user interface is provided via a software application accessible using one or more of a computer, a smartphone, and a tablet, wherein the received and analyzed data is displayed on an associated display device via the software application.

36. The system of claim 19, wherein the mental disease, disorder, or related symptoms is one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

37. A method for treating a mental disease, disorder, or related symptoms in a subject, the method comprising: providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

38. The method of claim 37, wherein the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

39. The method of claim 37, wherein a wave form of light emitted from the light source comprises a repeating pattern of stimulation.

40. The method of claim 39, wherein the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

41. The method of claim 37, wherein the light source comprises a pre-defined wavelength range.

42. The method of claim 37, wherein the device further comprises one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor.

43. The method of claim 42, further comprising: receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

44. The method of claim 43, wherein the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals.

45. The method of claim 43, wherein the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

46. The method of claim 37, wherein the mental disease, disorder, or related symptoms is one or more of general depression, resistant depression, postpartum depression, perinatal depression, post-traumatic stress disorder, anxiety, traumatic brain injury, stroke, seasonal affective disorder (SAD), age-related cognitive decline, mild cognitive impairment, brain fog, schizophrenia, bipolar disorder, post-stroke depression, delirium, post-menopausal depression, fear based disorders, and sleep disorders.

47. The method of claim 37, wherein the mental disease or disorder is depression.

48. The method of claim 37, wherein the visual stimulus is delivered for two hours per day for five days.

49. The method of claim 37, wherein the visual stimulus is delivered for thirty minutes per day for thirty days.

50. The method of claim 37, wherein delivery of the visual stimulus is combined with a pharmaceutical compound treatment.

51. The method of claim 37, further comprising obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level.

52. The method of claim 51, wherein the saliva sample is obtained at a defined time after delivery of the visual stimulus.

53. The method of claim 51, wherein the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

54. A method for promoting and / or improving cognitive function in a subject, the method comprising: providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

55. The method of claim 54, wherein the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

56. The method of claim 54, wherein a wave form of light emitted from the light source comprises a repeating pattern of stimulation.

57. The method of claim 56, wherein the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

58. The method of claim 54, wherein the light source comprises a pre-defined wavelength range.

59. The method of claim 54, wherein the device further comprises one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor.

60. The method of claim 59, further comprising: receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

61. The method of claim 60, wherein the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals.

62. The method of claim 60, wherein the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

63. The method of claim 54, wherein cognitive function is promoted and / or improved in a subject experiencing one or more of stress, burn-out, chronic stress, accelerated aging, brain injury.

64. The method of claim 63, wherein one or more of learning, attention, memory, language, executive functions, social cognition and / or visual-spatial abilities is improved.

65. The method of claim 54, wherein the visual stimulus is delivered for two hours per day for five days.

66. The method of claim 54, wherein the visual stimulus is delivered for thirty minutes per day for thirty days.

67. The method of claim 54, further comprising obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level.

68. The method of claim 67, wherein the saliva sample is obtained at a defined time after delivery of the visual stimulus.

69. The method of claim 67, wherein the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

70. A method for monitoring cognitive function or treating a mental disease, disorder, or related symptoms, the method comprising: obtaining a first saliva sample from a subject; measuring a first salivary cortisol level from the first saliva sample; conducting a treatment on the subject that is designed to impact cognitive function or treat a mental disease, disorder, or related symptoms; obtaining a second saliva sample from the subject; measuring a second salivary cortisol level from the second saliva sample; and comparing the second salivary cortisol level to the first salivary cortisol level, wherein a difference between the second salivary cortisol level and the first salivary cortisol level indicates an effect of the treatment.

71. A method for treating stress in a subject, the method comprising:providing a device comprising at least one light source configured to deliver to the subject a visual stimulus at a defined frequency, and a computing system operably associated with the device, the computing system comprising a non-transitory, computer-readable storage medium coupled to a processor and encoded with a computer program executable by the processor; and delivering the visual stimulus to the subject for a defined period of time such that the visual stimulus induces entrainment to thereby activate microglia cells to target the perineuronal net (PNN) in the brain of the subject thereby causing remodeling of the PNN in the brain of the subject.

72. The method of claim 71, wherein the visual stimulus is delivered at a pulse frequency of 50 Hz to 70 Hz inclusive.

73. The method of claim 71, wherein a wave form of light emitted from the light source comprises a repeating pattern of stimulation.

74. The method of claim 73, wherein the repeating pattern of stimulation comprises one or more of a square wave, a sine wave, a rectangular wave, a sawtooth wave, and a triangle wave.

75. The method of claim 71, wherein the light source comprises a pre-defined wavelength range.

76. The method of claim 71, wherein the device further comprises one or more sensors comprising one or more of a pressure sensor, a temperature sensor, a heartrate sensor, an electroencephalography (EEG) array, and an eye-tracking sensor.

77. The method of claim 76, further comprising: receiving data from the device and / or the one or more sensors; analyzing, via one or more algorithms, the received data; and controlling a frequency of visual stimulus, a duration of visual stimulus, an intensity of the visual stimulus, a wavelength, a wavelength color, a duty cycle, a position of the light stimulus, and a direction of the light stimulus delivered to the subject.

78. The method of claim 77, wherein the one or more algorithms comprises a cross coupling analysis method, wherein low frequency signal data is received and correlated to high frequency signals.

79. The method of claim 77, wherein the data comprises one or more of brain imaging and brain activity recording, wherein the device is configured to control the delivery of the visual stimulus based on the data received and analyzed.

80. The method of claim 71, wherein stress comprises one or more of burn-out, acute stress, chronic stress, episodic acute stress, and toxic stress.

81. The method of claim 71, wherein the visual stimulus is delivered for two hours per day for five days.

82. The method of claim 71, wherein the visual stimulus is delivered for thirty minutes per day for thirty days.

83. The method of claim 71, further comprising obtaining a saliva sample from the patient before and / or after treatment and measuring a salivary cortisol level.

84. The method of claim 83, wherein the saliva sample is obtained at a defined time after delivery of the visual stimulus.

85. The method of claim 83, wherein the salivary cortisol level over a defined time interval indicates an efficacy of the delivery of the visual stimulus.

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