Light therapy device

Abstract

Phototherapy apparatus for emitting therapeutic light, the apparatus comprising: a first set of one or more light sources and a second set of one or more light sources; and a control module configured to control the first and second sets of light sources, wherein the control circuit is configured to control the first set of light sources to generate first light, the first light being periodically varied at a first brain stimulation rate; and to control the second set of light sources to generate second light simultaneously with the first set of light sources generating first light, the second light being periodically varied at a second brain stimulation rate equal to the sum of the first brain stimulation rate and a third brain stimulation rate, the third brain stimulation rate being selected to stimulate nerve oscillations at a beat frequency corresponding to the third brain stimulation rate.

Description

Technical Field

[0001] The present invention relates to a light therapy device, and particularly to a light therapy device for optogenetically induced brain stimulation.

Background Art

[0002] The use of optogenetically induced gamma brain stimulation has been proposed for various therapeutic and / or prophylactic applications and / or cognitive training.

[0003] Research has shown evidence that the stimulation of gamma brain waves in mice reduces Alzheimer's-related proteins and slows down the neurodegeneration associated with the disease. Gamma brain waves are electrical charges that help associate and process information from all parts of the brain. Similar beneficial effects are thought to occur in humans, and such research is ongoing.

[0004] A healthy brain is characterized by rhythm patterns or brain waves that operate at different frequencies. Gamma brain waves oscillate at approximately 20 - 140 Hz, are associated with higher cognitive functions, and are known to decrease in the brains of people with Alzheimer's disease and other neurological or psychiatric disorders.

[0005] Exposure of Alzheimer's model mice to visible wavelength LED light that flashes (i.e., blinks) at 40 Hz has been found to stimulate gamma waves, which not only reduce the levels of beta-amyloid and tau (proteins associated with Alzheimer's), but also activate microglia that remove harmful debris. In other words, such blinking causes brain wave oscillations around 40 Hz.

[0006] WO2018 / 152255 discloses a phototherapy system (e.g., a phototherapy device) for the treatment of Alzheimer's disease, depression, dementia, short-term memory, or for improving learning, motor skills, or cognitive abilities. This prior art photosystem includes a blue light source operating at a frequency in the range of 20–50 Hz (preferably about 40 Hz), thereby allowing human retinal ganglion cells to be exposed to stimulate electroencephalography (gamma oscillations in the human brain). This prior art method uses light with different wavelength components to mask flickering and enhance user comfort.

[0007] Gamma wave stimulation using sound (e.g., a click sound played at 40 Hz) in Alzheimer's model mice has relevant beneficial effects.

[0008] By using light or sound gamma stimulation, stimulated mice performed better on memory tasks, including recognizing objects and navigating a water maze to find hidden platforms. The researchers also observed changes in activation responses in microglia and astrocytes (cells involved in debris removal) as well as in blood vessels.

[0009] Mice exposed to a combination of light and sound gamma stimulation showed effects extending beyond the visual and auditory cortices to the prefrontal cortex (a brain region crucial for task planning and completion). Using image analysis, scientists found a unique clustering effect of microglia around amyloid deposits and a reduction in amyloid pathology in stimulated mice. The effect was short-lived, decreasing after one week post-stimulation.

[0010] In a study published in the journal Neuron, researchers at MIT investigated the long-term effects of gamma synchronization by exposing a mouse model of advanced Alzheimer's disease to visual stimulation for up to six weeks. The results showed that stimulation increased gamma electroencephalograms in the visual cortex and higher brain regions, including the hippocampus and prefrontal cortex. Continued stimulation also maintained neuronal and synaptic density in these brain regions, improved performance on memory tasks, and reduced inflammation. The researchers report that the findings suggest an overall neuroprotective effect even in the later stages of neurodegeneration.

[0011] The results of this study suggest a potential treatment for Alzheimer's disease in humans, furthering previous research on gamma wave stimulation.

[0012] It has been shown that 40Hz light stimulation synchronizes not only with the visual cortex but also with the hippocampus and prefrontal cortex (measurements and validation using human implants).

[0013] Using a series of LED lights flashing at different speeds, researchers discovered that a one-hour treatment with 40Hz flashing light increased gamma waves and halved beta-amyloid levels in the visual cortex of mice in the very early stages of Alzheimer's disease. However, within 24 hours, amyloid levels returned to normal in this brain region that processes information from the eyes. When scientists exposed mice with even higher levels of amyloid to the flashing light for one hour per day for seven days, the number of amyloid plaques and the level of free-floating amyloid decreased. The treatment also increased microglial efficiency and reduced the number of amyloid plaques and free-floating amyloid.

[0014] Thus, repeated treatments are necessary for gamma brain stimulation, and the optimal dose of gamma brain stimulation light can be determined.

[0015] The brain also generates theta waves in the 4-10 Hz range. Theta waves produce theta rhythms, which are neural oscillations in the brain that underlie various aspects of cognition and behavior, including learning, memory, and spatial navigation in many animals. These can be recorded using various electrophysiological methods, such as electroencephalography (EEG), which is recorded from within the brain or from electrodes attached to the scalp.

[0016] At least two types of theta rhythms have been described. Hippocampal theta rhythms are strong oscillations that can be observed in the hippocampus and other brain structures of many mammals, including rodents, rabbits, dogs, cats, bats, and marsupials. Cortical theta rhythms are the low-frequency components of scalp electroencephalograms, usually recorded from humans. Theta rhythms can be quantified using quantitative electroencephalography (qEEG) with commonly available toolboxes such as EEGLAB or Neurophysiological Biomarker Toolbox (NBT).

[0017] In humans, theta rhythm in the hippocampus has been observed and is associated with memory formation and navigation. In addition to being important for hippocampal function, theta rhythm is also important for long-distance communication between brain regions.

[0018] Similar to rats, humans also exhibit theta wave activity in the hippocampus during REM sleep. Humans also primarily exhibit theta wave activity in the cortex during REM sleep. Increased sleepiness is associated with a decrease in alpha wave power and an increase in theta wave power. Meditation has been shown to increase theta wave power.

[0019] In a recent paper in the journal Neuron, Ole Jensen and John Lisman describe a process known as cross-frequency coupling, in which gamma oscillations (40 Hz) and slower theta oscillations (7 Hz) occur in the same brain region and influence each other. Jensen and Lisman suggest that this cross-frequency coupling allows the brain to sequentially represent (encode) multiple pieces of information, and that it can be used to measure the relationship between the phase of theta oscillations and the envelope of gamma power. Therefore, a high coupling value indicates that the gamma amplitude is a strong function of the theta phase. See, for example, https: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3648857 / .

[0020] Recent research suggests that this coding scheme regulates communication between brain regions and is involved not only in memory processes but also in sensory processes.

[0021] Thus, it is believed that if theta and gamma waves generated in the brain are sufficiently strong and occur in the optimal phase, it can have significant benefits for human mental and physical health.

[0022] One problem with optically stimulating the brain with gamma and theta waves is that the flickering of theta light at frequencies of 4-10 Hz can cause extreme discomfort to the user over extended periods and may lead to other neurological problems. However, the flickering of gamma light at a frequency of 40 Hz is barely perceptible to humans. [Overview of the project] [Problems that the invention aims to solve]

[0023] It remains desirable to provide an improved phototherapy device that is versatile, inexpensive to manufacture, user-friendly, and facilitates prolonged exposure for the user. [Means for solving the problem]

[0024] According to one aspect, an embodiment of a phototherapy device for emitting therapeutic light is disclosed herein. The embodiment of the device comprises a first set of one or more light sources and a second set of one or more light sources, and a control module configured to control the first and second sets of light sources, and the control circuit is, controlling the first set of light sources to generate a first light, the first light varying periodically at a first brain stimulation rate, controlling the second set of light sources to generate a second light simultaneously with the first set of light sources generating the first light, the second light varying periodically at a second brain stimulation rate equal to the sum of the first brain stimulation rate and a third brain stimulation rate, and the third brain stimulation rate being configured to be selected to stimulate neural oscillations at a beat frequency corresponding to the third brain stimulation rate.

[0025] Stimulating neural oscillations at a beat frequency corresponding to the difference between the brain stimulation rates of the periodically varying light emitted by each light source enables the stimulation of neural oscillations at many frequencies, including but not limited to frequencies below the critical flicker frequency, without an unpleasant perceptible flicker of the emitted periodically varying light.

[0026] Using the respective sets of light sources to generate the first and second lights enables simple control of the device, for example, enabling the emitted light to have a constant homogeneous visual appearance without unpleasant temporal variations in intensity or color.

[0027] Preferably, the device is configured to generate first and second lights that change periodically such that the periodic fluctuations are substantially imperceptible to a human observer. For this purpose, in some embodiments, the second brain stimulation velocity is higher than the critical flicker frequency (CFF) threshold, and the control module is configured to control one or more second light sources to emit the second light at a changing intensity that changes with the second brain stimulation velocity. In some embodiments, the first brain stimulation velocity is also higher than the critical flicker frequency (CFF) threshold, and the control module is configured to control one or more first light sources to emit the first light at a changing intensity that changes with the first brain stimulation velocity.

[0028] Alternatively, in another embodiment, instead of the light alternating between light and dark, the light can alternate between two different colors at each stimulus frequency. For example, one light source can alternate between XX and YY colors at 47 Hz, and the other light source can alternate between ZZ and KK colors at 40 Hz. This is called heterochromatic flicker. Heterochromatic flicker can be constructed from a combination of multiple waveforms. Such heterochromatic flicker yields good results while reducing noticeable flickering. If the brightness of the two colors is equal (but the hues are different), the flickering should not be perceptible.

[0029] Therefore, in some embodiments, the first brain stimulation rate or both the first and second brain stimulation rates may be lower than the critical flicker frequency. In such or other embodiments, the control module may be configured to control a set of first light sources to alternately generate first and second colored lights at the first brain stimulation rate, wherein the first colored light has a first set of color components, and the second colored light has a second set of color components different from the first set of color components, and the first and second color components are selected such that the alternately generated first and second colored lights are perceptible to a human observer as light having a user-perceptible first fused color, such as white or another suitable color. Similarly, the control module may be configured to control a second set of light sources to alternately generate third and fourth colored lights at the second brain stimulation rate, wherein the third colored light has a third set of color components, and the fourth colored light has a fourth set of color components different from the third set of color components, and the third and fourth color components are selected such that the alternately generated third and fourth colored lights are perceptible to a human observer as light having a second user-perceptible fused color, such as white or another suitable color. Preferably, the first and second fused colors may be selected such that they are perceived as substantially the same color.

[0030] By utilizing the nonlinearity of the brain, particularly the mixed characteristics of 2-wave, 3-wave, and 4-wave waves, other frequency combinations can be generated to stimulate specific dual-frequency combinations for theta-gamma coupling multi-frequency stimulation.

[0031] In another embodiment, the change in light is sinusoidal, and the current to the LED is modulated at a first brain stimulation rate (e.g., 40 Hz) and a second brain stimulation rate (e.g., 47 Hz), respectively. As a result, the brain is stimulated at both the first frequency (e.g., a gamma frequency of, for example, 40 Hz) and the beat frequency corresponding to the third brain stimulation rate (e.g., a theta frequency of, for example, 7 Hz).

[0032] A third brain stimulation frequency may be selected to stimulate neural oscillations in a frequency band of neural oscillations such as the alpha, beta, gamma, theta, or delta frequency band. Furthermore, the first and / or second brain stimulation frequencies may be selected to stimulate neural oscillations in a frequency band of neural oscillations such as the alpha, beta, gamma, theta, or delta frequency band. The neural oscillations stimulated by the first and / or second brain stimulation velocities may be in the same frequency band as the neural oscillations stimulated by the third brain stimulation velocities, or they may be in a different frequency band than the neural oscillations stimulated by the third brain stimulation velocities.

[0033] In some embodiments, the first brain stimulation rate is configured to stimulate nerve oscillations in a predetermined electroencephalogram frequency band, particularly the gamma frequency band, for example, 20 Hz to 140 Hz, preferably 20 Hz to 60 Hz, for example 35 Hz to 45 Hz, for example 39 Hz or 40 Hz, or 45 Hz to 140 Hz, for example 45 Hz to 70 Hz, for example 45 Hz to 55 Hz, for example 50 Hz.

[0034] In some embodiments, the third brain stimulation velocity, i.e., the difference between the second brain stimulation velocity and the first brain stimulation velocity, is between 1 Hz and 140 Hz. In some embodiments, it is, for example, between 1 Hz and 12 Hz, for example between 4 Hz and 12 Hz, for example between 4 Hz and 8 Hz, or between 20 Hz and 140 Hz, for example between 20 Hz and 60 Hz, for example between 35 Hz and 45 Hz.

[0035] In embodiments for stimulating gamma-theta coupling, a first brain stimulation velocity range in the gamma range between 20 Hz and 140 Hz is effective, and a third brain stimulation velocity range in the theta range between 4 Hz and 10 Hz may also be effective. Thus, the flashing frequencies of the two lights differ by only 4 to 10 Hz and are in the range of 20 to 150 Hz.

[0036] As described above, the periodically changing light may be pulsed light or sinusoidal modulated light. In the case of a pulsed system, a duty cycle of 50% is sufficient, but the duty cycle is not critical. In another embodiment, the changing LED light may be substantially sinusoidal. This can be done simply by smoothing the pulse with a low-pass filter.

[0037] In some embodiments, light (photostimulation), skin stimulation, and auditory stimulation, or any combination thereof, may occur simultaneously to stimulate different parts of the brain. In some embodiments, the power supply that pulses the LEDs or produces a sinusoidal light output may further energize electrodes attached to the user's skin to provide electrical or vibratory stimulation, or energize an acoustic system to provide auditory stimulation. Any type of sensory stimulation can affect the brain, generating or amplifying gamma and theta waves within the brain.

[0038] Theta-gamma coupling supports memory processes in the entorhinal-hippocampal network. Low-frequency gamma modulated with theta-gamma may facilitate memory retrieval, while high-frequency gamma modulated with theta may facilitate memory encoding.

[0039] In some embodiments, the device uses flashing light to stimulate theta-gamma coupling of neurons in the user's brain for therapeutic and diagnostic purposes, such as the treatment of Alzheimer's disease or other neurological and psychiatric disorders (i.e., brain network dysfunction).

[0040] In some embodiments, the device may be used to treat or prevent neurodegenerative diseases such as Alzheimer's disease, mild cognitive impairment, multiple sclerosis, and Parkinson's disease. In some embodiments, the device may be used to treat or prevent mental illnesses such as depression, major depressive disorder, or generalized anxiety disorder. In some embodiments, the device may be used to improve the general health of an individual, for example, to promote healthy aging.

[0041] Theta-gamma coupling (TGC) is a form of cross-frequency coupling in the brain in which "high-frequency" gamma (e.g., 30-50 Hz) oscillations are modulated by low-frequency theta (e.g., 4-10 Hz) oscillations.

[0042] Accordingly, in some embodiments, a user-operated optical (or photonic) brain stimulation system is disclosed in which one or more light sources, such as white light or blue light LEDs, are flashed at a specific first brain stimulation rate, for example, a gamma frequency such as 40 Hz, and one or more white light or blue light LEDs are flashed at a second brain stimulation rate, for example, 47 Hz, thereby generating a beat frequency (or subtraction frequency) of, for example, 7 Hz (theta frequency) and a gamma frequency of 40 Hz in the brain. In this way, induced theta-gamma coupling is generated in the brain with little to no perceptible flashing. Since there is no flashing of light at theta frequencies, any flashing that does occur is substantially imperceptible and therefore not bothersome. In some embodiments, for example, as described in Mikkel Pejstrup Agger et al., "Safety, Feasibility, and Potential Clinical Efficacy of 40Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study," Journal of Alzheimer's Disease, 92(2), 653-665. https: / / doi.org / 10.3233 / JAD-221238, when the flickering is adequately masked using, for example, invisible spectral flicker (ISF), at frequencies above approximately 30Hz or 35Hz, the flickering is substantially imperceptible.

[0043] Other embodiments use a first brain stimulation velocity at a gamma frequency, e.g., 40 Hz or 50 Hz, and a second brain stimulation velocity, e.g., 80 Hz or 90 Hz, that produces a beat frequency in the gamma frequency range, e.g., 40 Hz. Below the first stimulation velocity, which can be selected to be at least 50 Hz, e.g., 50 Hz to 60 Hz, e.g., 50 Hz to 55 Hz, there is no flashing of light, so in some embodiments without the use of masking techniques such as ISF, any flashing may remain substantially imperceptible and unobtrusive. Although ISF or another preferred masking technique may still be useful, strobo flicker at frequencies above 50 Hz is not perceived as unpleasant by many subjects.

[0044] In some embodiments, the third brain stimulation rate is substantially equal to the first brain stimulation rate, for example, 20 Hz to 60 Hz, or for example, 35 Hz to 45 Hz, or the third brain stimulation rate and the first brain stimulation rate are within the same frequency band, for example, the gamma frequency band. For example, the first brain stimulation rate may be selected to be 40 Hz to 60 Hz, for example, 45 Hz to 55 Hz, preferably 50 Hz to 60 Hz. The third brain stimulation rate may be selected to be 35 Hz to 45 Hz. Therefore, the first brain stimulation rate is in a frequency range where parvalbumin-positive (PV+) cells are known to exhibit high local electric field potentials during optogenetic stimulation (see, e.g., Jorge J. Palop and Lennart Mucke, "Network abnormalities and interneuron dysfunction in Alzheimer disease," Nature Reviews, Neuroscience, Vol. 17, Dec 2016, pp. 777-792), while producing perceptible flashing, if any, to a lower degree, for most subjects. For this purpose, a first brain stimulation rate of about 50 Hz or slightly higher, e.g., 50 Hz–55 Hz, is preferred. Simultaneously, a third brain stimulation rate of about 40 Hz is also in a frequency range where PV+ cells are known to exhibit high local electric field potentials during optogenetic stimulation, and is a frequency known to halve beta-amyloid levels in the visual cortex of mice in the very early stages of Alzheimer's disease. In general, it may be desirable to increase, preferably maximize, the stimulation of PV+ cells.

[0045] In some embodiments, the first or third brain stimulation rate is selected to correspond to the frequency of electrical oscillations generated in bundles of brain microtubules, particularly in the 38 Hz–40 Hz range, e.g., about 39 Hz. Microtubules are long, cylindrical structures of the cytoskeleton that control cell division, vesicular transport, and cell shape. Microtubules are highly charged and behave as nonlinear electrical transmission lines. Recent studies have determined that bundles of brain microtubules are electrically active and generate electrical oscillations in the 39 Hz range that correlate well with the oscillatory activity observed in neurons and brain function; see, for example, Maria del Rocio Cantero and Horacio F. Cantiello, "Microtubule Electrical Oscillations and Hippocampal Function," J Neurol Neuromedicine (2020) 5(3): 1–5.

[0046] In some embodiments, one or both of the first and second generated lights are white light or light perceptible as white light to a human observer, which has been found to provide a low degree of discomfort even during prolonged exposure. In some embodiments, the color and / or brightness of the first and / or second lights are user-adjustable, thereby allowing the user to adjust the light to achieve a high degree of comfort.

[0047] In some embodiments, the first and second lights have substantially the same perceptible color and / or the same perceptible brightness, thereby providing a low degree of discomfort even during prolonged exposure. For this purpose, the luminous flux exitance of the first and second light source sets may be substantially uniform.

[0048] In some embodiments, the device comprises at least one light-emitting member, e.g., at least one screen, at least one panel, etc. The at least one light-emitting member defines at least one light-emitting surface from which light is emitted. The at least one light-emitting surface may be planar or curved. The light-emitting member may be a diffuser, or otherwise configured to generate diffused light. The at least one light-emitting surface defines a first surface portion and a second surface portion, preferably separate from the first surface portion. The device is configured to emit first light from the first surface portion, particularly from the first surface portion only, and second light from the second surface portion, particularly from the second surface portion only. The first and second surface portions may overlap, but in some embodiments, any overlap is only a small portion of the first and second surface portions, preferably less than, for example, 40%, preferably less than 30%, e.g., less than 20%, e.g., less than 10% of the first and / or second surface portions. In some embodiments, the first and second surface portions are completely separate, i.e., they do not overlap. The first and second surface portions may be adjacent to each other, for example, directly adjacent to each other, or spaced apart from each other. For example, the first and second surface portions may be arranged side by side, or they may be formed as, for example, half of a light-emitting screen or panel. Preferably, the first and second surface portions are arranged horizontally next to each other when the device is in its intended operating position. The first and second surface portions may have different shapes and / or sizes, but it may be preferable that the first and second surface portions have the same size and / or shape to provide uniform stimulation by the first and second lights. Each of the first and second surface portions shall be at least 10 cm 2 For example, at least 20cm 2 For example, at least 50cm 2 For example, at least 100cm 2 For example, at least 200cm 2 It may also be an extended surface having a surface area of ​​. However, a considerably larger surface area, for example up to 500 cm², is also possible. 2It will be understood that embodiments having a surface area of, for example, up to 1 m² or even larger may be used. The extended surface area of ​​the first surface portion may be defined by a single shape, i.e., by a single closed boundary. Similarly, the extended surface area of ​​the second surface portion may be defined by a single shape, i.e., by a single closed boundary.

[0049] In some embodiments, each of the first and second surface portions has 30% to 70% of the surface area of ​​the light-emitting surface, such that the first and second surface portions together have 80% to 100% of the light-emitting surface area.

[0050] For example, a set of first and second light sources and a light-emitting member can form a display screen for an electronic device, such as a tablet, laptop computer, or TV screen. The first and second surface portions may be formed as the left and right portions, or more specifically the left and right halves, of the display area of ​​the display screen, respectively.

[0051] In other embodiments, the light-emitting member may preferably be formed as a planar panel. The first and second surface portions may be formed as respective portions of the light-emitting panel, particularly as each half, such as the left and right portions of the light-emitting panel, particularly as the left and right halves. The light-emitting panel may be a diffuser panel that can be formed as part of the housing of the device. The diffuser panel defines an outward-facing light-emitting surface configured to be seen by the user of the device, and an inward-facing surface opposite to the outward-facing surface. A first set of light sources may be configured to direct first light towards a first surface portion of the inward-facing surface of the diffuser panel, causing the first light to be emitted as first diffused light by the corresponding first surface portion of the outward-facing surface of the diffuser panel. Similarly, a second set of light sources may be configured to direct second light towards a second surface portion of the inward-facing surface of the diffuser panel, causing the second light to be emitted as second diffused light by the corresponding second surface portion of the outward-facing surface of the diffuser panel. The device may include an internal reflector, baffle, or other partition configured to prevent light from the first set of light sources from being emitted through the second surface portion, and to prevent light from the second set of light sources from being emitted through the first surface portion. Thus, the device may be embodied as a lighting fixture comprising a housing, the first and second sets of light sources, and a control circuit.

[0052] Accordingly, in some embodiments, the phototherapy apparatus comprises a housing configured to house a set of first and second light sources, the housing defining a light output panel, in particular a diffuser panel, for outputting the first and second light toward a user, the light output panel defining a first surface portion and a second surface portion distinct from the first surface portion, and the apparatus is configured to output the first light at least primarily through the first surface portion and the second light at least primarily through the second surface portion.

[0053] Preferably, the device is configured to emit first light from a first surface portion with a uniform first luminous flux exitance across the first surface portion, and to emit second light from a second surface portion with a uniform second luminous flux exitance across the second surface portion, preferably a second luminous flux exitance substantially equal to the first luminous flux exitance. Preferably, the first and second luminous flux exitances are uniform enough to provide a light-emitting surface with substantially uniform brightness, or at least enough to be perceived by a human observer without distracting or even bothersome fluctuations in brightness.

[0054] Other types of light sources may be used, but in some embodiments, the first set of light sources comprises a first set of light-emitting diodes (LEDs), and the second set of light sources comprises a second set of light-emitting diodes (LEDs).

[0055] The light source output power should be at a comfortable level for the patient or other subjects observing it, but the exact output power does not seem to be important. The optimal dosage can be pre-programmed into the system. The optimal dosage for a particular subject, such as a patient, might be, for example, one consecutive hour at 9 a.m. every day. By accurately observing the dosages for many similar subjects, memorizing the information, and simultaneously examining the subjects for changes in their condition, a correlation can be established between the dosage and the patient's improvement.

[0056] Various brain regions, including the hippocampus, amygdala, prefrontal cortex (PFC), visual cortex (VC), and suprachiasmatic nucleus (SCN), can be stimulated by photopsychotherapy. The ability to determine the optimal target effective dose of photopsychotherapy for these specific brain regions is beneficial in treating neurodegenerative diseases. In particular, understanding the minimum dose required to activate the hippocampus and SCN and act on circadian rhythms (often associated with the early onset of Alzheimer's disease) can enable the individualization of disease treatment.

[0057] While the dose-dependent activation of cytokines can be examined within 15 minutes of light exposure, the activation of autoimmune cells takes 60 minutes. Therefore, knowing when specific enzymes and transcription / translation activation occur can be useful in determining the required duration (or dosage) of treatment, allowing for individualized treatment for each subject.

[0058] In some embodiments, the apparatus comprises one or more EEG sensors for detecting electroencephalograms and a processing system coupled to detect a first signal corresponding to the electroencephalograms and to control one or more attributes of light generated from a light source to increase one or more predetermined neural oscillations, such as increasing theta-gamma wave coupling in the human brain. The one or more attributes may be selected to include one or more attributes selected from the luminous flux exitance, the modulation degrees of the first and / or second light that change periodically, the first, second and / or third brain stimulation rates, the relative phase between the first and second light that changes periodically, and the session duration. Thus, the light emission may be adaptively adjusted for a particular user to increase the desired effect of phototherapy for that particular user.

[0059] In some embodiments, one or more EEG sensors are configured to detect electrical emissions from at least one of the MEC region and the hippocampal region of the human brain.

[0060] In some embodiments, the phases of gamma and theta waves in the brain as a result of stimulation are measured in real time, for example, by detecting EEG (electroencephalography) signals, by using an implant, or by using other methods for measuring brain activity. Subsequently, the phase of the optical stimulation is controlled (by temporally shifting the stimulation pulses) so that the brain is stimulated at a certain phase so that the theta-gamma coupling of neurons is optimized by a phase feedback mechanism. By actively measuring the phase during treatment and then dynamically adjusting the stimulation using EEG feedback, the stimulation is phase-synchronized to either a natural theta rhythm (which is always present) or an induced theta rhythm (a brain rhythm stimulated by light, sound, touch, electrical / magnetic stimulation, etc.).

[0061] To determine a more accurate effective dose, some embodiments of the device may include a target tracking system configured to detect the subject's gaze angle relative to the light source during a stimulation session.

[0062] Therefore, the phototherapy device may include a processing system and a target tracking device that detects the person's eyes and provides first data to the processing system, the processing system being configured to adjust the mode of the brain stimulation session using the first data.

[0063] In particular, the first data point indicates the angle of a person's line of sight relative to at least the first and / or second set of light sources.

[0064] The maximum dose is administered when the subject is looking directly at the light source at a specific distance (e.g., 50 cm). In this case, the administration time may be minimal. If the subject's gaze is diverted from the light source for any period during treatment, the non-zero gaze angle is processed using an algorithm and the administration time is extended to ensure the subject receives the appropriate total dose for the day.

[0065] The eye-tracker can also determine the distance of the eye from the light source and the diameter of the pupil. These factors also affect the effective dosage, and the system dynamically controls the administration time or even the light output power to compensate for the eye distance and pupil size.

[0066] The device may further include a display that shows the duration of the brain stimulation session as the session is being scheduled. The display may also inform the subject of the remaining time of the treatment, which is dynamically adjusted according to the subject's gaze. Therefore, in order to minimize session time, the subject is encouraged to look directly at the light source.

[0067] The system may be incorporated into a desk-supported system, a portable screen and tablet, a smartphone, a flat or curved screen, wearable goggles, or other types of flat, curved, circular, or other differently shaped optical screens or light source systems.

[0068] The processing system may be configured to adjust the duration of the brain stimulation session based on the first data. In one embodiment, the processing system is configured to extend the duration of the brain stimulation session based on the first data.

[0069] The target tracking device may be equipped with a camera.

[0070] The processing system may be configured to receive a target dose of brain stimulation corresponding to the brain stimulation session duration, and the first data may be used to adjust the duration of the session.

[0071] The device may also be equipped with additional memory, in which second data corresponding to a brain stimulation session is stored for later retrieval.

[0072] In some embodiments, the device further comprises a communication system which transmits second data about the session for use in determining the effectiveness of brain stimulation.

[0073] In one embodiment, a method is disclosed herein for stimulating theta-gamma coupling or other neural oscillatory activity of neurons in the brain using flashing light for therapeutic and diagnostic purposes, such as the treatment of Alzheimer's disease or other neurological and psychiatric disorders (i.e., brain network dysfunction). Theta-gamma coupling (TGC) is a form of cross-frequency coupling in the brain, in which "high-frequency" gamma (e.g., 30-50 Hz) oscillations are modulated by low-frequency theta (e.g., 4-10 Hz) oscillations. The method may use embodiments of the apparatus disclosed herein. [Brief explanation of the drawing]

[0074] [Figure 1] An optical gamma / theta brain stimulator having a dosage adjustment unit, according to one embodiment of the present invention, is shown. [Figure 2] This shows various modules within the system. [Figure 3] The optical detection method of the system is shown in more detail. [Figure 4] This flowchart shows the effects of various factors on gamma / theta brain stimulation dose. [Figure 5] This is a flowchart that identifies the steps in an overview of a system process. [Figure 6] This shows desirable theta-gamma wave coupling in the brain. [Figure 7A] An embodiment of a phototherapy device is shown. [Figure 7B] An embodiment of a phototherapy device is shown. [Figure 8] An example of the light-emitting surface of one embodiment of a phototherapy device is shown. [Figure 9] This shows an experimental apparatus having one embodiment of a phototherapy device. [Figure 10] This shows recorded electroencephalograms during the use of one embodiment of a phototherapy device. [Modes for carrying out the invention]

[0075] Elements numbered the same in various drawings may be the same or equivalent.

[0076] Figure 1 shows subjects such as Subject 10, who have been diagnosed with Alzheimer's disease, are at risk of developing Alzheimer's disease or another brain disorder, or have been diagnosed with a circadian rhythm sleep disorder, and whose disease or disorder may be treated with light-modulated gamma / theta brain stimulation. Subject 10 may also receive or be treated with skin or acoustic gamma / theta brain stimulation.

[0077] The gamma / theta brain stimulation light system 12 is positioned approximately 50-100 cm away from the subject 10. The system may be supported by a table or desk. In another embodiment, the system constitutes goggles worn by the subject 10. In one embodiment, the system uses an apparatus as described below in reference to Figure 7.

[0078] In one embodiment, the pulse light source 14 uses a blue LED, a white LED, or monochromatic LEDs of various different wavelengths.

[0079] One pair of LEDs is excited at 40 Hz (or another first brain stimulation rate, e.g., another gamma frequency), and another pair of LEDs is simultaneously excited at 47 Hz (or another second brain stimulation rate). The combined light perceived by the human brain is 40 Hz, and the beat frequency (subtraction frequency) is 7 Hz (or another third brain stimulation rate, e.g., another theta or gamma frequency). The flickering is barely perceptible at 40 Hz.

[0080] In one embodiment where gamma-theta coupling is intended, frequencies of 40 Hz and 47 Hz are preferred but not essential. The effective gamma brain stimulation velocity range is 20 Hz to 140 Hz, and the effective theta brain stimulation velocity range is 4 Hz to 10 Hz. Therefore, the flashing frequencies of the two lights differ by only 4 to 10 Hz and are in the range of 20 to 150 Hz. As a result, the brain is stimulated at gamma and beta-theta frequencies.

[0081] In this embodiment, only gamma stimulation is intended, and the flashing frequencies of the two lights differ by only 20-150Hz, for example, 35Hz-50Hz, and are in the range of 20-150Hz, for example, 35Hz-55Hz.

[0082] In one embodiment, the LEDs are optionally arranged to form a circular light source 14 with a camera lens 16 in the center. In another embodiment, the light source 14 may be more point light sources, and the camera lens 16 may be adjacent to them. In yet another embodiment, the light source is an extended surface, such as a rectangular surface, and the camera lens 16 may be adjacent to it or embedded in the center of the surface. When the camera is positioned adjacent to the surface, the line of sight angle is adjusted with respect to the lens offset and the light source. Alternatively, the light source 14 may be a flat two-dimensional array of LEDs, such as a 20cm × 20cm diffuse Lambert light source.

[0083] In another embodiment, the LEDs are energized to output light with a sinusoidal amplitude. In this case, the currents energized to the different sets of LEDs are 40Hz and 47Hz, so no flickering is perceived.

[0084] In another embodiment, the LED is energized at 40Hz for a certain period (several seconds), then at 47Hz for several seconds, with the alternation lasting less than six seconds. The brain perceives this as a modulation of the frequency.

[0085] In another embodiment, instead of the light alternating between light and dark, the light can alternate between two different colors at a stimulus frequency, for example, green and red, or blue and yellow. For example, one light source can alternate between XX color and YY color at 47 Hz, while the other light source can alternate between ZZ color and KK color at 40 Hz. This is called heterochromatic flicker or invisible spectral flicker (ISF), as described, for example, in MP Agger et al., "Novel Invisible Spectral Flicker Induces 40Hz Neural Entrainment with Similar Spatial Distribution as 40Hz Stroboscopic Light," J Alzheimers Dis. 2022; 88(1): 335-344, or in Mikkel Pejstrup Agger et al., "Safety, Feasibility, and Potential Clinical Efficacy of 40Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study," Journal of Alzheimer's Disease, 92(2), 653-665. https: / / doi.org / 10.3233 / JAD-221238. Heterochromatic flicker can be constructed using a combination of multiple waveforms. Such heterochromatic flicker yields good results while reducing noticeable blinking. If the brightness of the two colors is equal (but their hues are different), the blinking should not be perceptible.

[0086] The total dose of light administered to subject 10 may be determined by a healthcare professional based on clinical trials and tests. While the optimal dose level for different types of people, such as patients, is still under study, a reasonable dose is for subject 10 to gaze directly at the light source 14 for one hour. Such sessions may be performed at the same time each day. Subject 10 may be periodically evaluated by a healthcare professional to correlate gamma brain stimulation with the effects of Alzheimer's disease or other disorders. Cognitive tests may be performed, as well as tests to determine the presence of certain proteins and other chemicals in the subject's body. Tests may include electroencephalography. For evaluation, it is essential to know exactly how much light was administered to subject 10.

[0087] The applicants have found that the effective dose of neuro-synchronized light is greatly influenced by a combination of gaze angle, eye distance from the light source, and pupil size, and that compensating for any of these factors helps achieve the target dose. The gaze angle is a particularly important parameter when the device emits light from different light-emitting surfaces, for example, in a parallel arrangement. The actual dose corresponds to a certain duration of brain stimulation session, taking into account the specific gaze angle, eye distance, and / or pupil size during the session. Adjusting the gaze angle is crucial for achieving the target dose.

[0088] The camera 18 (Figure 2) and lens 16 may be of conventional types used for eye tracking. Conventional software and processing hardware may also be used to detect the gaze angle, eye / face distance, and pupil size. The camera 18 may emit an infrared signal and detect its reflection to determine the gaze angle, eye / face distance, and pupil size. Alternatively, the camera 18 may use image processing to calculate the gaze angle, eye / face distance, and pupil size. Human calibration may be used to initially establish a baseline, in which case the subject 10 is instructed to look at different areas at different distances to establish baseline data. This baseline data is then stored in memory for later comparison with data collected during the session.

[0089] The target light dose is first established for subject 10 by a healthcare professional, and this information is downloaded to system 12 via the internet or other means. Considering the known light output power and pulse frequency of the light, the target light dose correlates with the session duration for a subject with an average pupil size at a specific distance from the light source. For example, this target dose assumes that subject 10 has an average pupil size and is looking directly at the light source 14 from a distance of 50 cm. However, if subject 10 is not looking directly at the light source 14, is further than 50 cm away, or has pupils smaller than the average pupil size, the actual effective dose will be lower.

[0090] As explained with respect to Figures 2 to 5, the line of sight angle, eye distance from the light source, and pupil size are automatically detected by the camera and algorithm, and the session duration is extended as needed to achieve a predetermined target light dose. For example, a line of sight angle of 0° means looking directly at the light source 14, so a subject 10 with an average pupil size receives 100% of the dose at a distance of 50 cm. At a line of sight angle of 90°, subject 10 receives 0% of the light, and at a line of sight angle of 45°, subject 10 receives 50% of the light. The correlation between the detected line of sight angle and the amount of light received may be estimated linearly between 0 and 100%, or the correlation may be nonlinear based on experimental results.

[0091] As subject 10 moves from 50 cm to 100 cm from the light source, the effect of the light decreases non-linearly; therefore, the detection distance from the light source has a non-linear correlation with the actual effective dose. Similarly, pupil size has a non-linear effect on the actual dose.

[0092] Furthermore, as shown in Figure 1, the EEG feedback system can be used to dynamically optimize the phase of the stimulus pulse to maximize the coupling between the brain's gamma rhythm and theta rhythm. Recent evidence suggests that good memory performance requires the coupling of gamma rhythm (approximately 30–140 Hz) and specific phases of theta cycle in the brain. Theta-gamma coupling is thought to facilitate information transmission throughout the entohippocampal network. By activating gamma-modulated cell aggregates at specific theta phases, dispersed cells may fire more closely in time, allowing the network to produce a stronger output. Depending on the type of gamma rhythm utilized, such mechanisms can facilitate either memory encoding or memory retrieval.

[0093] EEG is typically used to detect abnormalities in brain waves or electrical activity in the brain. During the procedure, electrodes consisting of small metal discs with thin wires attached are either attached to the user's scalp or placed close to the scalp using a headpiece. The electrodes detect the weak electrical emissions resulting from the activity of brain cells.

[0094] Some embodiments of this device instead detect EEG signals from the brain to detect the coupling of gamma and theta rhythms and adjust the phase of the optical stimulation pulse to maximize the coupling.

[0095] In Figure 1, a conventional sensor 17, such as a metal electrode, is placed on or near the scalp of a person. The EEG signal is detected using a conventional EEG detector 19. The sensor 17 is positioned to detect signals from the medial entorhinal cortex (MEC) and the CAI region of the hippocampus. The precise placement of such a sensor 17 will be known to those skilled in the art. The conventional EEG detector 19 then reads two electroencephalograms. The processor 21 then detects the two waves and adjusts the phase of the optical stimulation pulses so that the two detected waves have maximum coupling. This is shown in Figure 6, where the detected MEC and CAI waveforms on the left show the desired strength of theta-gamma coupling due to the appropriate phase adjustment by the processor 21, while the waveforms on the right show weak theta-gamma coupling, as before the phase adjustment. Figure 6 is a copy from https: / / www.semanticscholar.org / paper / Theta%E2%80%93gamma-coupling-in-the entorhinal%E2%80%93hippocampal-Colgin / 4d21566e350ff22f4c03628f5dcaf50fa91430b0. Furthermore, EEG can also measure the "surrogate / indirect" effects of phase coupling using only sensor electrodes. EEG allows for a distinction between "source space" and "sensor space." In source space, phase can be measured in the hippocampus and surrounding regions (source space) using sufficient electrodes, while in sensor space, indirect effects of deep brain phase synchronization can be measured using electrodes, for example, in the frontal or occipital lobe. Therefore, hippocampal measurements in source space are preferably used to detect theta-gamma coupling, but instead, coupling can also be detected using sensor space.

[0096] Figures 2 to 4 relate to achieving a predetermined amount of light stimulation.

[0097] In Figure 2, it is assumed that the subject's eye 20 is looking upwards towards the light source 14. The camera 18 uses the image frame or reflected infrared light to determine the gaze angle, distance, and pupil size. Gaze detection is typically used in conjunction with a display screen to detect which icon on the screen is being viewed by the viewer and to automatically select that icon. Gaze detection is also used in the retail industry to determine where potential customers are looking. Gaze angle detection, including distance detection, is used in various other fields, and such systems are commercially available and inexpensive.

[0098] Customizable gaze detection systems are available from SR Research, Tobi AB, and other companies. Fully customized systems can also be built using a Raspberry Pi Camera Module v2 in conjunction with a Raspberry Pi 3 Model B+ single-board computer. Much of the software is commercially available.

[0099] Next, the raw digital data from camera 18 is processed by a processor that runs an algorithm in the target tracking module 22. Such an algorithm may consist of publicly available software customized for the present invention. In the present invention, particularly when the subject is a patient, the software uses the information obtained about the gaze angle, distance, and pupil size to dynamically control the dosage so that the subject 10 ultimately receives the target dose.

[0100] Next, the output of the target tracking module 22 is used to adjust the dosage controlled by the dosage control unit 24. The dosage control unit 24 first receives a target dosage from the healthcare professional that can correlate with a one-hour session. This target session time is then automatically extended based on deviations from ideal conditions, such as direct gaze, a distance of 50 cm, and average pupil size.

[0101] Figure 2 shows how the dosage control unit 24 controls the 40Hz current pulse power supply and the 47Hz current power supply 26 to be turned on for a certain period of time. The dosage control unit 24 may also control the current applied to the light source 14. This allows the human brain to perceive the 40Hz pulse light and the 7Hz pulse light based on the beat frequency (subtraction frequency). In one embodiment, both the 40Hz power supply and the 47Hz power supply provide current to different sets of LEDs distributed within the light source 14.

[0102] In another embodiment, the current supplied to the light source 14 is a sine wave, and the current is a frequency that is the sum of the gamma frequency and the theta frequency.

[0103] The required session time is displayed to the subject 10 on the display screen 28. Therefore, the subject 10 can see that the session time has been extended because the subject 10's gaze is diverted from the light source 14 or because they are more than 50 cm away from it. The display screen 28 may use data generated by a local system or data generated by a remote system communicating via the internet.

[0104] Memory 30 stores session results so that healthcare professionals can have accurate data regarding dosage. Communication hardware 32 transmits data to healthcare professionals and may update the system with information for the next session.

[0105] Figure 3 shows in more detail one embodiment of a preferred camera and algorithm. The algorithm and processor are located within the target tracking module 22 in Figure 2. Camera 18 captures images of the subject's face and eye position and analyzes the images. In other systems, infrared light is reflected from the subject and the reflected light is processed. This system is assumed to have been initially calibrated by the subject.

[0106] In Figure 3, faces are detected, for example, using the Viola-Jones object detection algorithm (block 34). Faces are regions of interest (ROIs). Once a face is detected, the ROI information is transmitted to face alignment block 36, which detects the relative distance between facial features for distance estimation (block 38). The calculated distances are then provided in a data package (block 40).

[0107] The eyes are also detected and processed by a quantitative fixed threshold algorithm (block 42). This process uses a contrast threshold (binarization) to determine objects such as the iris and pupil. Based on this data, the pupillary angle is estimated (block 44). From this, the line-of-sight angle is calculated using trigonometric functions, and after correcting for the offset of the integrated camera 18 lens relative to the light source (block 46), the resulting angle is transmitted to data packaging block 40 before capturing the next frame. The dosage may be adjusted dynamically for each frame, or simply adjusted near the end of the session.

[0108] If a face is not detected, a "user absent" signal is generated, and the light source is not powered on. The packaged data is applied to the dosage control unit 24 in Figure 2 to adjust the session duration, as described above.

[0109] Figure 4 is a flowchart showing the steps for dynamically controlling the dosage.

[0110] In step 50, a 40Hz / 47Hz flashing light source is turned on to emit a stimulating light 52. The gaze detection system detects the subject's distance, gaze angle, and pupil diameter when the subject's eyes receive the light (step 56) (step 54). The brain then undergoes neural synchronization (i.e., the brain's ability to naturally synchronize its electroencephalogram frequency with the rhythm of a periodic external stimulus) (step 58).

[0111] The target duration provided by a healthcare professional or other provider (step 60) is correlated with the predicted or target dose of light (step 62). Then, the real-time detection during the analysis in step 54 (step 64) is correlated with the predicted dose loss due to line-of-sight angle, etc. (step 66). A lookup table may be used to correlate the data with the dose loss.

[0112] Next, the dose adjustment step 68 subtracts the dose loss from the "ideal condition" dose to derive the actual effective dose received by the subject. Then, using the effective dose information (step 69), the session is extended as needed to achieve the target dose.

[0113] Data obtained from sessions, and in particular from examinations of subjects such as patients, may be used to facilitate the understanding of the effects of gamma brain stimulation on, for example, Alzheimer's disease or other neurological or psychiatric disorders (i.e., brain network dysfunction).

[0114] Figure 5 is a more extensive flowchart summarizing specific steps in one method for achieving the desired dosage and maximizing theta-gamma coupling in the brain. In step 70, a healthcare professional or other provider communicates the optimal dosage of gamma / theta brain stimulation to the system, which may take the form of session duration using a known light source.

[0115] In step 72, the light source and eye tracker are activated, and the session begins.

[0116] In step 74, the detected line-of-sight angle, interocular distance, and pupil diameter are correlated with the reduction in effective dose.

[0117] In step 76, the session time is extended as needed to compensate for the detected gaze angle, interocular distance, and pupil diameter. In another embodiment, the target dose estimates a certain degree of deviation from the ideal for the detected gaze angle, interocular distance, and pupil diameter, and the system may add or subtract this from the session time.

[0118] In parallel with the detection of the effective dose, the phase of optic stimulation is controlled to maximize theta-gamma coupling in the brain. The system for adjusting the phase is described with respect to Figure 1. In step 78, EEG signals from the MEC and CAI regions of the brain are detected using sensors.

[0119] In step 80, the EEG signals are processed, and the phase of the photostimulation system is dynamically adjusted so that the two detected EEG signals have high coupling, as shown on the left side of Figure 6.

[0120] In step 82, the session data is stored in memory to evaluate the effectiveness of the treatment.

[0121] In step 84, the communication system transmits data to the clinic or other healthcare professionals. The communication system can also receive information such as target doses.

[0122] This system may be used for therapeutic purposes, or it may be used solely to analyze the effects of optic gamma / theta brain stimulation on similar populations of people in order to collect further data for research. As mentioned above, other flashing frequencies besides 40Hz and 47Hz may also prove valuable through further research.

[0123] The present invention is not limited to gamma / theta brain stimulation velocities of 20-140 Hz and 4-10 Hz. Other frequency light pulses emitted by the light source 14 may be beneficial for beta electroencephalography (beta brain stimulation velocities of 13-38 Hz) and circadian function. By generating light at a frequency higher than that which causes perceptible flickering, and further generating light by adding a lower frequency to that frequency, the original frequency and the subtracted frequency are perceived within the brain without detecting the flickering.

[0124] In another embodiment, the system is used solely for gamma wave stimulation. For example, the first set of light sources may flash at a frequency of 40 Hz to 60 Hz, and the second set of light sources may flash at a frequency of 74 Hz to 120 Hz.

[0125] In other embodiments, the optical system of Figure 1 is combined with other systems that stimulate other senses, such as touch and hearing. The energization of the LEDs of the light source 14 can also trigger electrical pulses to electrodes attached to a person's skin, delivering a mild shock, and / or the electrical signals may trigger sound pulses. Thus, different areas of the brain are stimulated simultaneously with the exact same gamma and theta waves. This skin and acoustic system is represented by the functional block 86 in Figure 1.

[0126] The phases of gamma and theta waves may also be varied to test results with different phases.

[0127] Figures 7A and 7B show one embodiment of the phototherapy device 12. Figure 7A shows a schematic front view of the device, and Figure 7B shows a schematic configuration diagram of the device.

[0128] The phototherapy device of this embodiment is implemented as a lighting fixture having a housing 121. The housing contains a light-emitting member 125, a set of first light sources 124L, a set of second light sources 124R, and a control circuit 123.

[0129] In this embodiment, the light sources 124L and 124R and the control circuit are mounted on a circuit board 122 or other suitable support member.

[0130] The first set of light sources 124L may comprise one or more arrays of LEDs. Similarly, the second set of light sources 124R may comprise one or more arrays of LEDs. Each array of LEDs includes colored LEDs, such as white LEDs or multiple LEDs of different colors, so that heterochromatic flicker can be produced as described herein.

[0131] The operation of the two light source sets is controlled by the control circuit 123. For this purpose, the control circuit 123 may include a suitable power supply and a suitable driver circuit.

[0132] The light-emitting member 125 is formed as a diffuser panel that can form part of the housing, for example, by forming one side wall of the housing or by being embedded in one side wall of the housing. A first set of light sources 124L is configured so that its light is emitted through a portion 125L of the light-emitting member 125, in this example, the left portion. A second set of light sources 124R is configured so that its light is emitted through another portion 125R of the light-emitting member 125, in this example, the right portion. The two portions 125L and 125R each form half of the total light-emitting surface of the light-emitting member 125. Thus, when the sets of light sources are controlled to blink at different frequencies, the two surface portions blink at these different frequencies. In Figure 7A, the boundary between the two portions 125L and 125R is schematically shown by a dashed line 126. In some embodiments, the two portions may be separated by a visible boundary, but in other embodiments, it will be understood that there may be no visible boundary between the portions.

[0133] In the example shown in Figure 7B, the apparatus includes a light barrier 127 configured to prevent light from the first set of light sources 124L from reaching a second portion of the light-emitting member 125R and to prevent light from the second set of light sources 124R from reaching a first portion of the light-emitting member 125L. In other embodiments, for example, in some embodiments, such a barrier may be omitted because a certain amount of cross-beam light may be acceptable or even desirable, and / or one or more alternative means are employed to direct the light from the set of light sources to a selected portion of the light-emitting member. For example, the light sources may include suitable lenses or other optical elements for selectively directing their light to the corresponding portion of the light-emitting member.

[0134] Embodiments in Figures 7A and 7B further include a camera 18 having a lens 16 positioned centrally within the light-emitting member. The camera is communicatively coupled to a control circuit and used, for example, for line-of-sight angle detection as described herein. In other embodiments, the camera may be located elsewhere, for example, on or otherwise next to the light-emitting member. In some embodiments, the camera may be omitted.

[0135] In the example shown in Figure 7A, the light-emitting element defines a generally rectangular light-emitting surface. It will be understood that other embodiments may have light-emitting surfaces of different shapes, as shown, for example, in Figure 8.

[0136] Figure 8 shows another example of a light-emitting surface 125 in one embodiment of a phototherapy device. In the example of Figure 8, the light-emitting surface is circular or annular and optionally has a camera lens position at the center of the circular or annular light-emitting member, as described in relation to Figure 1, for example. As in the embodiments described above, the light-emitting surface is divided into a first portion 125L and a second portion 125R, the first portion emitting first light that changes at a first brain stimulation rate, and the second first portion emitting second light that changes at a second brain stimulation rate, as described herein.

[0137] Figure 9 shows an experimental apparatus having one embodiment of a phototherapy device. In this example, a phototherapy device was used that had two housings, each housing a set of light sources and each defining its respective light-emitting surface portions 125R and 125L. The light sources were controlled to flash at different brain stimulation speeds. The flashing of each light source was heterochromatic flicker, also known as invisible spectral flicker (ISF). The subjects observed the phototherapy device while their neural vibrations were recorded using an EEG sensor.

[0138] Figure 10 shows the power spectral density of recorded electroencephalograms (EEGs) during use of one embodiment of a phototherapy device. In particular, Figure 10 shows the power spectral density of recorded EEGs during use of the device shown in Figure 9, which operates to emit light that flickers at 40 Hz through one light-emitting surface portion 125L and light that flickers at a different brain stimulation rate through the other light-emitting surface portion 125R. The flickering light emitted through both light-emitting surface portions was ISF light, as described in Mikkel Pejstrup Agger et al., "Safety, Feasibility, and Potential Clinical Efficacy of 40Hz Invisible Spectral Flicker versus Placebo in Patients with Mild-to-Moderate Alzheimer's Disease: A Randomized, Placebo-Controlled, Double-Blinded, Pilot Study," Journal of Alzheimer's Disease, 92(2), 653-665. https: / / doi.org / 10.3233 / JAD-221238. The experiment was repeated with different brain stimulation velocities, namely 32Hz, 40Hz, 44Hz, 45Hz, 46Hz, 47Hz, and 48Hz. Figure 10 shows the power spectral density of each combination of 40Hz flashing and the other brain stimulation velocities. Thus, the combination of 40Hz flashing and 40Hz flashing serves as a comparative example where essentially only a single stimulation frequency of 40Hz is applied. In the other experiments, the difference frequency, and therefore the stimulated beat frequency, changes.

[0139] As can be seen in Figure 10, since all experiments involved 40Hz flashing through one of the light-emitting parts, the recorded power spectral density for all experiments shows a strong peak at 40Hz. The power spectral density also shows peaks at the corresponding other brain stimulation velocities. For example, the blue curve (combination of 40Hz and 32Hz flashing) shows another peak at 32Hz, and the red curve (combination of 40Hz and 45Hz flashing) shows a peak at 45Hz. Furthermore, both combinations with an 8Hz difference frequency, namely the 32Hz and 40Hz combination (blue line) and the 40Hz and 48Hz combination (pink line), show a distinct peak at 8Hz, confirming considerable stimulation of neural oscillations at beta frequencies in the theta range. Neural stimulation at other beat frequencies was also present, but to a lower degree in this particular subject.

[0140] definition The term "gamma / theta brain stimulation" refers to stimuli, such as light sources, that can alter the neuronal gamma and theta activity in the brain.

[0141] The term "subject" refers to individuals who are candidates for gamma / theta brain stimulation, such as patients exhibiting symptoms of brain diseases like Alzheimer's disease, or subjects who desire early gamma / theta brain stimulation, or to examinees who undergo gamma / theta brain stimulation for educational or diagnostic purposes.

[0142] The term "stimulation session" refers to a series of treatments in which a subject is exposed to a brain stimulator and receives a fixed dose of light. A single stimulation session usually takes place within a day, but customized sessions can be extended and individually modified to consist of multiple days, weeks, or months.

[0143] The term "stimulation duration" refers to the duration of a stimulation session, but is not limited to the total duration of the session, as the stimulation session duration can be divided into multiple individual durations that allow for "interval" training, such as a 15-minute x 4 = 60-minute session. "Flashing" and "blinking" are used interchangeably in this application.

[0144] While specific embodiments of the present invention have been shown and described, it will be apparent to those skilled in the art that in broader embodiments, changes and modifications can be made without departing from the invention. Accordingly, the appended claims include, within their scope, all such changes and modifications that fall within the true spirit and scope of the invention.

Claims

1. A phototherapy device for emitting therapeutic light, A set of one or more first light sources and a set of one or more second light sources, A control module configured to control the first and second sets of light sources, Equipped with, The aforementioned control circuit is The first set of light sources is configured to control the first light source to generate a first light, the first light is periodically changed at a first brain stimulation rate, The first set of light sources is configured to control the second set of light sources so that it generates a second light simultaneously with the first set of light sources, the second light source changing periodically at a second brain stimulation rate equal to the sum of the first brain stimulation rate and a third brain stimulation rate, the third brain stimulation rate being selected to stimulate neural oscillations at a beat frequency corresponding to the third brain stimulation rate. Phototherapy device.

2. The aforementioned first brain stimulation rate is between 20 Hz and 140 Hz. The phototherapy apparatus according to claim 1.

3. The first brain stimulation rate is 20 Hz to 50 Hz, for example, 35 Hz to 45 Hz. The phototherapy apparatus according to claim 2.

4. The first brain stimulation rate is 50 Hz to 140 Hz, for example, 50 Hz to 70 Hz. The phototherapy apparatus according to claim 2.

5. The first brain stimulation rate is higher than the critical flicker frequency (CFF) threshold. The control module is configured to control one or more sets of the first light sources to emit light at a varying intensity that changes with the first brain stimulation rate. The phototherapy apparatus according to claim 4.

6. The difference between the second brain stimulation rate and the first brain stimulation rate is between 1 Hz and 140 Hz. A phototherapy apparatus according to any one of the preceding claims.

7. The difference between the second brain stimulation rate and the first brain stimulation rate is between 1 Hz and 10 Hz, for example between 4 Hz and 10 Hz, for example between 4 Hz and 7 Hz. The phototherapy apparatus according to claim 6.

8. The difference between the second brain stimulation rate and the first brain stimulation rate is 20 Hz to 140 Hz, for example, 20 Hz to 60 Hz, for example, 35 Hz to 45 Hz. The phototherapy apparatus according to claim 6.

9. The difference between the second brain stimulation rate and the first brain stimulation rate is substantially equal to the first brain stimulation rate, for example, from 20 Hz to 60 Hz, or for example, from 35 Hz to 45 Hz. The phototherapy apparatus according to claim 8.

10. The first brain stimulation rate is smaller than the critical flicker frequency (CFF) threshold. The control module is configured to control the first set of light sources to alternately generate a first color light and a second color light at the first brain stimulation rate. The first color light has a first set of color components, The second color light has a second set of color components that is different from the first set of color components. The first color light and the second color component are, The alternately generated first and second colored lights are selected so that they can be perceived by a human observer as light having a first user-perceptible fused color, such as white. A phototherapy apparatus according to any one of the preceding claims.

11. The second brain stimulation rate is smaller than the critical flicker frequency (CFF) threshold. The control module is configured to control the second set of light sources to alternately generate third and fourth colored lights at the second brain stimulation rate. The third color light has a third set of color components, The fourth color light has a set of fourth color components that is different from the set of third color components. The third and fourth color components are selected such that the alternately generated third and fourth colored lights are perceptible to a human observer as light having a second user-perceptible fused color, such as white. A phototherapy apparatus according to any one of the preceding claims.

12. One or both of the first and second generated lights are white light. A phototherapy apparatus according to any one of the preceding claims.

13. The color and / or brightness of the first and / or second light are user-adjustable. A phototherapy apparatus according to any one of the preceding claims.

14. The first and second lights have the same perceptible color and / or the same perceptible brightness. A phototherapy apparatus according to any one of the preceding claims.

15. The device comprises a housing configured to accommodate the first and second sets of light sources, The housing defines an optical output panel, particularly a diffuser panel, for outputting the first and second lights toward the user. The optical output panel defines a first panel portion and a second panel portion different from the first panel portion, and the device is configured to output the first light at least mainly through the first panel portion and to output the second light at least mainly through the second panel portion. A phototherapy apparatus according to any one of the preceding claims.

16. The light output panel defines the light output surface area, and each of the first and second panel portions has 30% to 70% of the light output surface area, such that the first and second panel portions together account for 80% to 100% of the light output surface area. The phototherapy apparatus according to claim 15.

17. The first and second panel sections are arranged side by side, The phototherapy apparatus according to claim 15 or 16.

18. The first set of light sources comprises a set of first light-emitting diodes (LEDs), and the second set of light sources comprises a set of second light-emitting diodes (LEDs). A phototherapy apparatus according to any one of the preceding claims.

19. The system further comprises one or more EEG sensors for detecting brain waves, and a processing system coupled to detect a first signal corresponding to the brain waves and to control one or more attributes of the generated light from the light source to increase one or more predetermined neural oscillations, such as increasing the theta-gamma wave coupling in the human brain. A phototherapy apparatus according to any one of the preceding claims.

20. Processing system and, A target tracking device that detects a person's eyes and provides first data to the processing system, Furthermore, The processing system is configured to adjust the mode of the brain stimulation session using the first data. A phototherapy apparatus according to any one of the preceding claims.

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