Gamma stimulation pulse light source system with dose adjustment according to gaze angle

Abstract

Gamma brain stimulation using light or sound is known to prevent or treat Alzheimer's disease or sleep disorders. A 40 Hz flashing light source has been shown to produce positive effects. To understand the relationship between dosage and efficacy, it is advantageous to know the actual dosage of light entering the subject's eye. A camera is used to detect the subject's gaze angle, distance, pupil diameter, and other factors that affect the light power entering the eye. A target dosage is initially determined by a medical professional to determine the effects of administering the exact same dosage to a population, such as Alzheimer's disease patients. Deviations in gaze angle, distance, and pupil size from the ideal result reduce the effective dosage. Based on these factors, the disclosed system adjusts the actual dosage, such as session duration, so that the final dosage received by the subject is consistent and meets the target dosage.

Description

[Technical Field]

[0001] The present invention relates primarily to optical (or photonic) gamma brain stimulation for treating or preventing certain conditions such as Alzheimer's disease, dementia, or circadian rhythm sleep disorders, and more particularly to a light dosage adjustment system that provides a targeted effective dose of gamma brain stimulation regardless of a subject's gaze angle or other changing visual characteristics. The present invention also applies to other light pulse frequencies, such as beta brain stimulation for sleep disorders. [Background technology]

[0002] Research has shown evidence that stimulating gamma brain waves in mice reduces Alzheimer's-related proteins and slows the neurodegeneration associated with the disease. Gamma brain waves are electrical charges that help connect and process information from all parts of the brain. Similar beneficial effects are thought to occur in humans, and such studies are underway.

[0003] A healthy brain is characterized by rhythmic 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 be reduced in the brains of people with Alzheimer's disease and other neurological or psychiatric disorders.

[0004] Exposure of Alzheimer's model mice to visible wavelength LED light flickering (i.e., blinking) at 40 Hz has been found to stimulate gamma waves, which not only reduces levels of beta-amyloid and tau (a protein associated with Alzheimer's), but also activates microglia, which remove harmful debris. In other words, such flashing causes brain wave oscillations around 40 Hz.

[0005] Further details of the effects of optical gamma brain stimulation are described in published applications WO 2018 / 152255 and U.S. Patent Application Publication No. 2020 / 0269065, both of which are incorporated herein by reference. Many further publications describe such effects.

[0006] Gamma stimulation using sound (e.g., clicks played at 40 Hz) in Alzheimer's model mice has associated beneficial effects.

[0007] The use of light or sound gamma stimulation resulted in stimulated mice performing better on memory tasks, including recognizing objects and swimming through a water maze to find a hidden platform. The researchers also observed changes in activation responses in microglia and astrocytes (cells involved in debris removal) and blood vessels.

[0008] Mice exposed to a combination of light and sound gamma stimulation showed effects that extended beyond the visual and auditory cortex to the prefrontal cortex, a brain region important for planning and completing tasks. Through imaging analysis, the scientists found a specific accumulation of microglia around amyloid deposits and a reduction in amyloid pathology in the stimulated mice. However, the effect was short-lived, diminishing one week after stimulation.

[0009] In a study published in the journal Neuron, MIT researchers tested the effects of long-term treatment in a mouse model of more advanced Alzheimer's disease by exposing it to gamma entrainment with visual stimulation for up to six weeks. Results showed that stimulation increased gamma brain waves in the visual cortex and higher brain regions, including the hippocampus and prefrontal cortex. Continuous stimulation also preserved neuronal and synaptic density in these brain regions, improved performance on memory tasks, and reduced inflammation. The results suggest an overall neuroprotective effect, even in the later stages of neurodegeneration, the researchers report.

[0010] The results of this study add to previous research into gamma stimulation as a possible treatment for Alzheimer's disease in humans.

[0011] Using a series of LED lights that flickered at different rates, researchers found that a single, hour-long treatment with 40 Hz flashing light increased gamma waves and halved beta amyloid levels in the visual cortex of mice with very early stages of Alzheimer's. However, within 24 hours, amyloid levels returned to normal in this brain region, which processes information from the eyes. When the scientists exposed mice with even higher levels of amyloid to the flickering 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 the efficiency of microglia, reducing the number of amyloid plaques and free-floating amyloid.

[0012] As mentioned above, gamma brain stimulation requires repeated treatments, which are very time-consuming for the subject. The optimal dosage of gamma brain stimulation light is determined. The effective dosage of flickering light depends on whether the subject looks directly at the light (maximum exposure) or looks away from the light (minimum exposure). Electroencephalography may be used to detect the progress of treatment, but such testing in the subject's home is impractical. Therefore, accurate measurement of dosage is crucial for tracking treatment.

[0013] It is desirable for subjects to be able to administer their own gamma brain stimulation in their own homes at any time. It is also desirable for the gamma brain stimulation system to be fully automated so that the subject's dosage is optimal. Therefore, there is a need for an automated photic gamma brain stimulation system that provides a pre-programmed optimal dosage to the subject regardless of the subject's gaze angle relative to the light source, eye distance, or pupil size. Summary of the Invention

[0014] An optical (or photonic) gamma brain stimulation system is disclosed that uses one or more light sources, such as white light or blue LEDs, to flicker within the gamma range, such as at a rate of 40 Hz. Gamma brain stimulation rates ranging from 20 Hz to 140 Hz can be effective. While a 50% duty cycle is sufficient, the duty cycle is not critical. The light source output power should be at a comfortable level for the subject, such as the patient or another person viewing it; the exact output power does not appear to be important. Optimal dosages are preprogrammed into the system. The optimal dosage for a particular subject, such as a patient, may be, for example, 9:00 AM, for one consecutive hour each day. By accurately monitoring dosages for many similar subjects, storing the information, and simultaneously testing the subjects for changes in their condition, correlations can be made between dosage and patient improvement.

[0015] Various brain regions, such as the hippocampus, amygdala, prefrontal cortex (PFC), visual cortex (VC), and suprachiasmatic nucleus (SCN), can be stimulated by optogenetic brain stimulation (OPS) therapy. The ability to determine optimal target-effective doses of OPS for these specific brain regions could be useful in treating diseases associated with neurodegeneration. In particular, understanding the minimum dose required to activate the hippocampus and SCN and affect circadian rhythms (often associated with early onset Alzheimer's disease) may enable the individualization / personalization of disease treatment.

[0016] Dose-dependent cytokine activation can be determined within 15 minutes of light exposure, whereas activation of autoimmune cells takes 60 minutes. Therefore, knowing when specific enzyme and transcriptional / translational activation occurs is important in determining the required treatment duration (or dosage), so that treatment can be individualized for each subject.

[0017] To determine a more accurate effective dose, an eye-tracking system detects the subject's gaze angle relative to the light source during a stimulation session. If the subject looks directly at the light source at a specific distance (e.g., 50 cm), the maximum dose is administered. In that case, the administration time may be minimal. If the subject's gaze is directed away from the light source for a period of time during treatment, the non-zero gaze angle is processed using an algorithm to extend the administration time so that the subject receives the appropriate total daily dose.

[0018] 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 dose, and the system dynamically controls the dose time or even the light output power to compensate for eye distance and pupil size.

[0019] The display may inform the subject of the time remaining in treatment and dynamically adjusts according to the subject's gaze, thus encouraging the subject to look directly at the light source to minimize session time.

[0020] The system may be incorporated into desk-supported systems, handheld screens and tablets, smartphones, flat or curved screens, wearable goggles, or other types of flat, curved, circular, or other differently shaped optical screens or light source systems. [Brief explanation of the drawings]

[0021] [Figure 1] 1 illustrates an optical gamma brain stimulator with a dose adjuster, according to one embodiment of the present invention. [Figure 2] 1 shows the various modules in the system. [Figure 3] 1 shows the light detection aspects of the system in more detail. [Figure 4] 1 is a flowchart showing the effect of various factors on gamma brain stimulation dosage. [Figure 5]1 is a flow chart identifying steps in an overview of the system process. Elements numbered the same in various drawings may be the same or equivalent. DETAILED DESCRIPTION OF THE INVENTION

[0022] 1 illustrates a subject, such as subject 10, who has been diagnosed with Alzheimer's disease, or is at risk for developing Alzheimer's disease or a related disorder, or who has been diagnosed with a circadian rhythm sleep disorder, and who may be treated with photic gamma brain stimulation. Subject 10 may also receive or be treated with acoustic gamma brain stimulation.

[0023] The gamma brain stimulation light system 12 is placed approximately 50-100 cm from the subject 10. The system may be supported by a table or desk. In another embodiment, the system comprises goggles worn by the subject 10.

[0024] In one embodiment, pulsed light source 14 uses blue LEDs, white LEDs, or monochromatic LEDs of various different wavelengths. Flickering is barely perceptible at 40 Hz. The LEDs are optionally arranged to form a circular light source 14 with the camera lens 16 at the center. In another embodiment, light source 14 may be more point sources, and camera lens 16 may be adjacent to it. In that case, the line of sight angle is adjusted relative to the lens offset and light source. Alternatively, light source 14 may be a flat, two-dimensional array of LEDs, such as a 20 cm x 20 cm diffuse Lambertian light source.

[0025] The total light dosage for the subject 10 may be determined by a medical professional based on clinical trials and testing. While optimal dosage levels for different types of people, such as patients, are still being studied, a reasonable dosage would be for the subject 10 to look directly at the light source 14 for one hour. Such sessions may occur at the same time each day. The subject 10 may be periodically evaluated by a medical professional to correlate gamma brain stimulation with the effects of Alzheimer's disease or other disorders. Cognitive testing may be performed, as well as tests to determine the presence of specific proteins and other chemicals in the subject's body. Testing may include electroencephalography. For evaluation, it is essential to know exactly how much light was administered to the subject 10.

[0026] The applicants have discovered that the effective dose of neurally entrained light is significantly affected by a combination of gaze angle, eye distance from the light source, and pupil size, and that compensating for any of these factors can help achieve the target dose. The actual dose corresponds to a given brain stimulation session duration, taking into account the specific gaze angle, eye distance, and pupil size during the session. Adjusting the gaze angle is paramount to achieving the target dose.

[0027] The camera 18 (FIG. 2) and lens 16 may be of a conventional type used for eye tracking. Conventional software and processing hardware may also be used to detect gaze angle, eye / face distance, and pupil size. The camera 18 may emit an infrared signal and detect its reflection to determine gaze angle, eye / face distance, and pupil size. Alternatively, the camera 18 may use image processing to calculate gaze angle, eye / face distance, and pupil size. Human calibration may be used to initially establish a baseline, in which the subject 10 is instructed to view 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.

[0028] A target light dosage is first established for subject 10 by a medical professional, and this information is downloaded to system 12, such as via the internet. Given the optical output power and pulse frequency of a known light, the target light dosage is correlated to session duration for a subject with an average pupil size at a particular distance from the light source. As an example, this target dosage assumes that subject 10 has an average pupil size and is looking directly at light source 14 at a distance of 50 cm. However, if subject 10 does not look directly at light source 14, is farther away than 50 cm, or has a pupil smaller than the average pupil size, the actual effective dosage will be less.

[0029] As described with respect to Figures 2-5, gaze angle, eye distance from the light source, and pupil size are automatically detected by a camera and algorithm, and the session duration is extended as necessary to achieve a predetermined target light dose. For example, a gaze angle of 0° corresponds to 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. A gaze angle of 90° results in the subject 10 receiving 0% of the light, and a gaze angle of 45° results in the subject 10 receiving 50% of the light. The correlation between the detected gaze angle and the amount of light received may be linearly estimated between 0 and 100%, or the correlation may be nonlinear based on experimental results.

[0030] The detected distance from the light source has a nonlinear correlation to the actual effective dose, as the effect of the light decreases nonlinearly as the subject 10 moves from 50 cm to 100 cm from the light source. Similarly, pupil size has a nonlinear effect on the actual dose.

[0031] In Figure 2, the subject's eye 20 is assumed to be looking upward at the light source 14. A camera 18 uses the image frame or reflected infrared light to determine 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 looked at by the viewer and 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 also used in a variety of other fields, and such systems are commercially available and inexpensive.

[0032] Gaze detection systems suitable for customization are available from SR Research, Tobii AB, and other companies. A fully customized system can also be created using the Raspberry Pi Camera Module v2 in conjunction with a Raspberry Pi 3 Model B+ single-board computer. Much of the software is commercially available.

[0033] The raw digital data from camera 18 is then processed by a processor running an algorithm within eye-tracking module 22. Such algorithms may consist of publicly available software customized for the present invention. In the present case, the software uses the obtained information about gaze angle, distance, and pupil size to dynamically control the dosage so that subject 10 ultimately receives the target dosage, particularly if the subject is a patient.

[0034] The output of the eye tracking module 22 is then used to adjust the dose controlled by the dose control unit 24. The dose control unit 24 initially receives a target dose from the healthcare professional, which may correlate to a one-hour session. This target session time is then automatically extended based on deviations from the ideal conditions of direct gaze, 50 cm distance, and average pupil size.

[0035] 2 shows a dose control 24 controlling a 40 Hz current pulse power supply 26 to be on for a fixed period of time. The dose control 24 may also control the current flowing to the light source 14.

[0036] The required session time is displayed to the subject 10 on the display screen 28. Thus, the subject 10 knows that the session time has been extended because the subject 10 has looked away from or is more than 50 cm away from the light source 14. The display screen 28 may use data generated by a local system or by a remote system communicating over the internet.

[0037] The memory 30 stores the results of the session so that the medical professional has accurate data regarding dosage.

[0038] The communications hardware 32 may communicate the data to medical personnel and update the system with upcoming session information.

[0039] Figure 3 shows one embodiment of a suitable camera and algorithm in more detail. The algorithm and processor reside in the eye tracking module 22 of Figure 2. The 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. The system is assumed to have been initially calibrated by the subject.

[0040] In Figure 3, faces are detected (block 34), for example, using the Viola-Jones object detection algorithm. The face is a region of interest (ROI). Once a face is detected, the ROI information is communicated to a face alignment block 36, which detects relative distances between facial features for distance estimation (block 38). The calculated distances are then provided in a data package (block 40).

[0041] 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 pupil angle is estimated (block 44). From this, the gaze angle is calculated by 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 the data packaging block 40 before capturing the next frame. The dosage may be adjusted dynamically from frame to frame, or simply near the end of the session.

[0042] If no face is detected, a "user not present" signal is generated and the light source is not powered on.

[0043] The packaged data is applied to the dose control unit 24 of FIG. 2 to adjust the session duration, as previously described.

[0044] FIG. 4 is a flow chart illustrating steps for dynamically controlling dosage.

[0045] In step 50, a 40 Hz flashing light source is turned on to emit a stimulus light 52. The gaze detection system detects the subject's distance, gaze angle, and pupil diameter (step 54) when the subject's eyes receive the light (step 56). The brain then undergoes neural entrainment (i.e., the brain's ability to naturally synchronize its brainwave frequency with the rhythm of periodic external stimuli) (step 58).

[0046] The target duration (step 60) provided by a healthcare professional or other source is correlated with the expected or target dose of light (step 62). Real-time detection (step 64) during the analysis of step 54 is then correlated with the predicted loss of dose due to gaze angle, etc. (step 66). A look-up table may be used to correlate the data with the loss of dose.

[0047] A dose correction step 68 then subtracts the dose loss from the "ideal condition" dose to derive the actual effective dose the subject is receiving. The effective dose information (step 69) is then used to extend the session as needed to achieve the target dose.

[0048] Data obtained from the sessions, and particularly from testing of subjects such as patients, may be used to further understanding the effects of gamma brain stimulation on, for example, Alzheimer's disease.

[0049] 5 is a broader flowchart summarizing certain steps in one method. In step 70, a medical professional or other source communicates to the system an optimal dose of gamma brain stimulation, which may be in the form of a session duration using a known light source.

[0050] In step 72, the light source and eye tracker are activated to begin the session.

[0051] In step 74, the detected gaze angle, eye distance, and pupil diameter are correlated with the reduction in effective dose.

[0052] The session time is extended as required to compensate for the detected gaze angle, eye distance, and pupil diameter in step 76. In another embodiment, the target dose estimates some variation from ideal in the detected gaze angle, eye distance, and pupil diameter, which the system can add or subtract from the session time.

[0053] In step 78, the session data is stored in memory for evaluating the effectiveness of the treatment.

[0054] The communication system transmits the data to a clinic or other medical professional in step 80. The communication system may also receive information such as a target dosage.

[0055] The system may also be used to simply analyze the effects of optogenetic gamma brain stimulation on a group of similar subjects to gather further data for treatment or research. Other flash frequencies besides 40 Hz may prove valuable in further study.

[0056] The present invention is not limited to gamma brain stimulation rates of 20-140 Hz. Light pulses of other frequencies emitted by light source 14 may be beneficial for beta brain waves (beta brain stimulation rates of 13-38 Hz) and circadian function.

[0057] definition The term "gamma brain stimulation" refers to a stimulus, such as a light source, that can alter neuronal gamma activity in the brain.

[0058] The term "subject" means a subject receiving gamma brain stimulation, such as a patient exhibiting symptoms of a brain disease such as Alzheimer's disease, or a subject desiring early gamma brain stimulation, or a test-taker receiving gamma brain stimulation for educational or testing purposes.

[0059] The term "stimulation session" refers to a treatment over time in which a subject is exposed to a brain stimulator and receives a consistent dose of light. A single stimulation session typically lasts for less than a day, but customized sessions can be extended and tailored to span multiple days, weeks, or months.

[0060] The term "stimulation duration" refers to the time of a stimulation session, however, "stimulation duration" is not limited to including the duration of the entire session, as the stimulation session time can be divided into multiple individual durations allowing for "interval" training, such as a 15 minute x 4 = 60 minute session.

[0061] Flashing and blinking are used interchangeably in this application.

[0062] While particular embodiments of the present invention have been shown and described, it will be obvious to those skilled in the art that changes and modifications can be made without departing from this invention in its broader aspects. Therefore, the appended claims are intended to encompass within their scope all such changes and modifications as are within the true spirit and scope of this invention.

Claims

1. a processing system; a light source controlled to flash at a brain stimulation rate between about 13 and 140 Hz; an eye-tracking device that detects the person's eyes and provides first data to the processing system corresponding to the person's gaze angle relative to the light source and the person's distance to the light source; Equipped with the processing system is configured to use the first data to adjust aspects of the brain stimulation session and to receive a target dosage of brain stimulation corresponding to a brain stimulation session time; the first data is used to adjust the duration of the brain stimulation session time so that the person receives the target dose. Human brain stimulation system.

2. The brain stimulation rate is a gamma brain stimulation rate between 20 and 140 Hz. The stimulation system of claim 1 .

3. the first data corresponds to a pupil size of the person; The stimulation system of claim 1 .

4. the processing system is configured to adjust a duration of the brain stimulation session based on the first data. The stimulation system of claim 1 .

5. the processing system is configured to extend the duration of the brain stimulation session based on the first data. The stimulation system of claim 4 .

6. and a display that displays the duration of the brain stimulation session while the brain stimulation session is being adjusted. The stimulation system of claim 1 .

7. the eye-tracking device comprises a camera; The stimulation system of claim 1 .

8. Further provided with memory, second data corresponding to the brain stimulation session is stored in the memory for later retrieval; The stimulation system of claim 1 .

9. The brain stimulation is used to treat the effects of Alzheimer's disease, or to prevent Alzheimer's disease, or to treat a sleep disorder. The stimulation system of claim 1 .

10. further comprising a communication system; the communication system transmitting second data regarding the brain stimulation session for use in determining the effectiveness of the brain stimulation. The stimulation system of claim 1 .

Images