Light treatment equipment for treating Alzheimer's disease and related diseases thereof

Abstract

The invention relates to light treatment equipment for treating Alzheimer's disease and related diseases. The light treatment equipment comprises a bearing mechanism and an array of near-infrared irradiation units. The apparatus emits near-infrared light into the accommodation space, the irradiation of the emitted near-infrared light to the subject head in the event that the subject head is in place satisfies a synergistic irradiation condition of an irradiation surface area ratio and an irradiation power level with respect to a reference head cover surface area, the surface area of the reference head cover part is the outer surface area of the surface of the head of the object in a total boundary line, the total boundary line passes through anterior auricular points on two sides along the eyebrow bone from an interbrow point, backwards surrounds and passes through electrode positions O1, OZ and O2 of an occipital bone protrusion and a 10-10 international standard lead system to be converged, and the proportion of the irradiation surface area can be as low as 30% and also can be as high as 65% or above. The equipment can realize robust and continuous remarkable curative effects on AD and related diseases of a treated object.

Description

[0001] This application is a divisional application of Chinese invention patent application No. 202480003895.6, filed on October 16, 2024, entitled "A phototherapy device for treating Alzheimer's disease and related conditions". Technical Field

[0002] This application belongs to the technical field of phototherapy devices for brain and cognitive diseases, and particularly relates to a phototherapy device for treating Alzheimer's disease and related conditions. Background Technology

[0003] Alzheimer's disease (AD) is a chronic, progressive neurodegenerative disease that primarily affects older adults, especially those over 60. It is characterized by memory loss, loss of social and occupational function, executive function decline, speech and motor deficits, personality changes, and behavioral and psychological disturbances. The disease can progress over 8-10 years and is currently incurable, placing a heavy burden on families and society.

[0004] Currently, the pathogenesis of Alzheimer's disease (AD) is not fully understood, but the most widely accepted mechanism is as follows: abnormal processing of amyloid precursor protein (APP) produces β-amyloid protein (Aβ), which aggregates to form amyloid plaques; abnormal phosphorylation of Tau protein forms neurofibrillary tangles (NFTs), and the accumulation of these tangles in the brain leads to damage and dysfunction of nerve cells; furthermore, intracellular NFTs and extracellular Aβ deposition form senile plaques, resulting in increased oxidative stress, increased neuroinflammation, and mitochondrial dysfunction, which in turn leads to neuronal dysfunction and synapse loss, ultimately resulting in neuronal death.

[0005] Long-term clinical practice has shown that using drugs, such as cholinesterase inhibitors, memantine, and the recently developed lencanezumab (a humanized monoclonal antibody that can reduce β-amyloid protein deposition in the brain), in combination with conventional treatment, usually only improves mild cognitive impairment (MCI) or mild AD, and also has the problem of frequent gastrointestinal adverse reactions.

[0006] In recent years, photobiological modulation (PBM) has been introduced to treat Alzheimer's disease (AD). PBM involves applying red or near-infrared light with wavelengths ranging from 600 to 1100 nm to the head, which penetrates the scalp and skull to act on brain tissue. Through various mechanisms of action, such as increasing Aβ clearance, reducing abnormal Tau protein aggregation, improving metabolism and mitochondrial function, increasing cerebral blood flow, and improving antioxidant stress and anti-inflammatory capabilities, it can treat AD non-invasively.

[0007] However, the irradiation parameters of existing photobiological modulation devices (also referred to as phototherapy devices in this article) are vaguely defined, inconsistent, and widely differing. For example, although the optical power density of near-infrared light (unit: mW / cm²) is mentioned... 2 The light power density is used as an irradiation parameter, but the location of its effect is sometimes immediately adjacent to the LED's emitting surface (see Farzad Salehpour et al., Rapid Reversal of Cognitive Decline, Olfactory Dysfunction, and Quality of Life Using Multi-Modality Photobiomodulation Therapy: Case Report, PhotobiomodulPhotomed Laser Surg. 2019 Mar;37(3):159-167), sometimes a few centimeters inward from the inner wall of the head cap (see Liang Chen et al., A Pilot Study of Near-Infrared Light Treatment for Alzheimer's Disease, Journal of Alzheimer's Disease 91 (2023) 191–201), and sometimes at the depth below the dura mater (see US8308784B2). Even considering only the immediate emitting surface of the LED, for photobiomodulation devices with different structures, the actual dose delivered to intracranial tissues can vary significantly even with the same light power density at that surface. As shown in Figure 1(a), the LED light panel is disposed inside the shell of the headgear, at a predetermined distance from the subject's head, and at this distance there are intervals that cause light attenuation; as shown in Figure 2(a), several LED light panels are combined into an irradiation unit, and the irradiation unit is placed close to the subject's head; as shown in Figure 2(b), the LED light panel is suspended at a greater distance from the subject's head in the air. Clearly, in these three phototherapy devices, even if the adjacent emitting surfaces of each LED have the same light power density, the dose that penetrates the scalp and skull and reaches the brain tissue varies considerably.

[0008] Furthermore, irradiation parameters defined at locations within the body are not practical for controlling the irradiation of phototherapy devices. For example, it is impractical to invasively measure the light power density at a depth of several centimeters below the dura mater every time a phototherapy device is used, as mentioned above.

[0009] Currently, manufacturers and researchers of near-infrared light therapy equipment, as mentioned above, typically only measure and list the light power density at different locations, resulting in significant variations in the light power density used. For example, US9993659B2 describes a light power density of approximately 1400 mW / cm² at the luminescent surface. 2 Approximately 4200 mW / cm 2 The optical power density is 31 mW / cm² at the luminescent surface, while Farzad Salehpour et al., Rapid Reversal of Cognitive Decline, Olfactory Dysfunction, and Quality of Life Using Multi-Modality Photobiomodulation Therapy: Case Report, Photobiomodul Photomed Laser Surg. 2019 Mar;37(3):159-167, recorded 31 mW / cm² at the luminescent surface. 2 The light power densities of these two devices differ by 40-140 times, yet both claim therapeutic effects on Alzheimer's disease (AD). It is perplexing to determine the appropriate light power density at what location to achieve a good therapeutic effect on AD. Does simply specifying the light power density at a particular location necessarily guarantee a good therapeutic effect on AD? Although manufacturers and researchers of near-infrared light therapy devices list power (in watts) at various locations (e.g., the emitting surface of an LED), the relationship between power and the AD treatment effect on the subject is unclear. Specifically, some of the power they use refers to the luminous power of the lamp panel, while others refer to the luminous power at the brain tissue. It is unclear whether duty cycle (time-averaged luminous power or peak luminous power) has been factored in, and the orders of magnitude differ significantly. Furthermore, US8308784B2 explicitly states that "for a selected wavelength, the power density (light intensity or power per unit area, W / cm²)..." 2 Or energy density (energy per unit area, measured in J / cm²) 2 The light energy delivered to the tissue (or power density multiplied by exposure time) is an important factor in determining the relative efficacy of phototherapy, but efficacy is not directly related to the total power or total energy delivered to the tissue (see paragraph

[0192] of its specification). Is it really true that the therapeutic efficacy of near-infrared light therapy devices for AD in subjects is not directly related to the total power or total energy delivered to the tissue? In summary, existing technologies provide conflicting and even contradictory information regarding the required dosage for near-infrared light therapy devices, which hinders the promotion and development of near-infrared light therapy devices and methods. Summary of the Invention

[0010] This application is made to address the aforementioned problems existing in the prior art. This application aims to provide a phototherapy device for treating Alzheimer's disease and related symptoms. This phototherapy device is not limited by its specific structure, nor is it limited to whether the near-infrared irradiation unit is a common LED or a low-energy laser diode. As long as uniform synergistic irradiation conditions are met, robust and sustained significant therapeutic effects on AD and related symptoms can be achieved in the treated patient.

[0011] According to a first embodiment, this application provides a phototherapy device for treating Alzheimer's disease and related conditions. The phototherapy device includes a support mechanism and an array of near-infrared irradiation units. The support mechanism is configured to form a receiving space for a subject's head and supports the array of near-infrared irradiation units. The array of near-infrared irradiation units is configured to emit near-infrared light into the receiving space, such that, with the subject's head positioned in the receiving space, the emitted near-infrared light irradiates the subject's head to meet synergistic irradiation conditions of irradiated surface area ratio and irradiation power level. Wherein, the irradiated surface area ratio is the ratio of the irradiated surface area to the surface area of ​​a reference head cover, and the reference head cover surface area is the outer surface area of ​​the subject's head within the total boundary line. Furthermore, the total boundary line starts from the glabella of the subject's head, runs along the brow bone, passes the preauricular points on both sides, and then circles backward, passing between the occipital protuberance and the electrode positions O1, OZ, and O2 of the 10-10 international standard lead system, where it converges. The irradiated surface area ratio can be as low as 30% (which can be called a localized concentrated stimulation scheme) or as high as 65% or more (which can be called a multi-zone balanced stimulation scheme).

[0012] In this application, "irradiation to the head of the subject" refers to the thin outer irradiated surface that comes into contact with the hair (or scalp where there is no hair) of the subject's head. Energy irradiation to this thin outer irradiated surface means that energy is transferred to the head, which includes hair, scalp, skull, and brain tissue. Furthermore, after absorption by the hair and attenuation by the scalp and skull, the energy that can reach the cortex or even deeper parts of the brain tissue is related to the attenuation along the transmission path.

[0013] In this application, the term "time-average optical power density" refers to the optical power density averaged over time. For example, the "time-average optical power density" of a target site refers to the optical power density at that target site averaged over time. As another example, the "time-average optical power density" of a target portion refers to the "time-average optical power density" representing a location on that target portion. Specifically, the "time-average optical power density" of the target portion is 30-60 mW / cm². 2 This means that the time-averaged optical power density at various representative positions on the target surface, such as, but not limited to, the position corresponding to the center of the lamp panel, is 30-60 mW / cm². 2It fluctuates within a certain range.

[0014] The so-called "spatiotemporal average optical power density" of the target region is intended to represent the time-averaged optical power density relative to the surface area of ​​the target region, that is, the optical power density after performing averaging operations relative to both surface area and time.

[0015] Provided that the emitted near-infrared light irradiates the head of the subject in accordance with the synergistic irradiation conditions of irradiated surface area ratio and irradiation power level—for example, but not limited to, for thick black hair wearing a light-guided comb as described in the applicant's patent application PCT / CN2021 / 126700, or for thick light-colored hair without a light-guided comb, or for sparse black hair with or without the light-guided comb—sufficient near-infrared light of sufficient power can be delivered to sufficient areas of brain tissue per unit time. The irradiated surface area ratio of the localized stimulation scheme can be as low as 30% and as high as 65% or more to constitute a multi-zone balanced stimulation scheme. Within this range, the irradiated surface area ratio and the synergistically matched irradiation power level can achieve the "modulation" and "excitation" of a sufficient proportion of cell populations. After being "modulated" and "excited," the sufficient proportion of cell populations not only exhibits a change in response that inhibits AD, but can also transmit and diffuse this change in response to other cell populations along the AD development trajectory, thereby achieving a comprehensive AD inhibition effect throughout the entire brain. In this way, it can not only significantly reduce the accumulation of Aβ plaques in the neocortex and significantly reduce the abnormal accumulation of tau protein in the neocortex, hippocampus and even limbic cortex, but also inhibit and reduce AD-specific lesions in cell populations throughout the brain, thereby effectively inhibiting the progression of AD.

[0016] In some embodiments, suitable synergistic irradiation conditions can be provided for localized concentrated stimulation protocols and multi-zone balanced stimulation protocols.

[0017] Specifically, the localized concentrated stimulation scheme has a smaller irradiated surface area ratio than the multi-zone equalization stimulation scheme, and the matched irradiation power level is also higher. For example, as a localized concentrated stimulation scheme, a spatiotemporal average optical power density of 117 mW / cm² is required when the irradiated surface area ratio is 30% to 40%. 2 The above; and when the irradiated surface area is between 40% and 65%, the spatiotemporal average optical power density irradiated onto the object's head is 110 mW / cm². 2 In this way, the limitations of local cell populations can be overcome, and the cell populations can be fully "modulated" and "stimulated," transmitting and diffusing the inhibitory response to AD to other cell populations in a wider area along the AD development trajectory.

[0018] Multi-region balanced stimulation protocols require an average synergistic dose of 2750 W*% to 14100 W*%. This average synergistic dose is the product of the percentage of irradiated surface area and the average total power, expressed in watts per percent. For example, if the irradiated surface area ratio is 65%, then the percentage is 65, and the average synergistic dose is the average total power multiplied by 65 W*%. As the affected cell populations become more widely distributed, such as across multiple brain regions and functional networks, delivering the aforementioned average synergistic dose can appropriately "modulate" and "stimulate" the cell populations, transmitting and diffusing the inhibitory response to AD to other cell populations across a broad area along the AD development trajectory.

[0019] Compared with existing technologies, the beneficial effects of the embodiments of this application are as follows. This phototherapy device is not limited by specific structures, nor is it limited to whether the near-infrared irradiation unit is a common LED or a low-energy laser diode. It ensures that the irradiation of the near-infrared light onto the subject's head meets the synergistic irradiation conditions of the irradiated surface area ratio and the irradiation power level. That is, it delivers a sufficient composite dose of irradiation power and irradiated surface area ratio after time-averaged delivery to the subject's head, thereby embedding the population response characteristics of cell subpopulations and the mechanism of action of brain functional networks, as well as the characteristics of AD progression across the entire brain. By irradiating the subject's head with a sufficient composite dose of near-infrared light, whether using a localized concentrated stimulation scheme or a multi-zone balanced stimulation scheme, it is possible to "modulate" and "excite" a sufficient proportion of cell populations. After being "modulated" and "excited," the sufficient proportion of cell populations not only exhibits a change in response that inhibits AD, but can also transmit and diffuse this change in response to other cell populations along the AD development trajectory, thereby achieving a comprehensive AD inhibition effect across the entire brain. In this way, not only can the aggregation of Aβ plaques in the neocortex be significantly reduced, and the abnormal aggregation of tau protein in the neocortex, hippocampus, and even limbic cortex be significantly reduced, but AD-specific lesions in cell populations throughout the whole brain can also be inhibited and reduced, thereby effectively inhibiting the progression of AD. The inhibitory effect of the phototherapy device of this application on the progression of AD has also been confirmed in clinical trials. The subjects not only showed a significant improvement in cognitive level during the phototherapy period, but also continued to trigger the inhibitory effect in the sustained period after the phototherapy was stopped. This not only maintained the inhibitory effect on AD to a certain extent, but also continued to promote the inhibitory effect on AD. Cognitive level was maintained or improved without any deterioration or regression (details will be provided below).

[0020] It should be understood that the foregoing general description and the following detailed description are exemplary and illustrative only, and are not intended to limit the invention.

[0021] The overview of various implementations or examples of the technology described in this invention is not a complete disclosure of the full scope or all features of the disclosed technology. Attached Figure Description

[0022] In drawings that are not necessarily drawn to scale, the same reference numerals may describe similar parts in different views. The same reference numerals with or without letter suffixes may indicate different instances of similar parts. The drawings generally illustrate various embodiments by way of example rather than limitation and, together with the description and claims, serve to explain embodiments of the invention. Where appropriate, the same reference numerals are used in all drawings to refer to the same or similar parts. Such embodiments are illustrative and not intended to be exhaustive or exclusive embodiments of the apparatus or method.

[0023] Figure 1(a) shows a schematic diagram of a phototherapy device according to a first embodiment of this application; Figure 1(b) shows a schematic diagram of the structure of the headgear of the phototherapy device according to the first embodiment of this application.

[0024] Figure 2(a) shows a schematic diagram of a phototherapy device according to a second embodiment of the present application; Figure 2(b) shows a schematic diagram of a phototherapy device according to a third embodiment of this application.

[0025] Figures 3(a)-3(f) show schematic diagrams of the reference head model of the patient population according to embodiments of this application.

[0026] Figure 4(a) shows a front view of a reference head model as an example of a subject head according to the fourth embodiment of this application. The electrode positions of the 10-10 international standard lead system, the overall boundary line of the reference head, and the boundary lines between the upper front part of the skull, the left side of the skull, and the right side of the skull are shown on the subject head.

[0027] Figure 4(b) shows a left-side view of a reference head model as an example of an object head according to the fourth embodiment of this application. The object head shows the electrode positions of the 10-10 international standard lead system, the overall boundary line of the reference head, and the boundary lines between the upper front part of the skull, the left side of the skull, the top of the skull, and the back part of the skull.

[0028] Figure 4(c) shows a right-side view of a reference head model as an example of an object head according to the fourth embodiment of this application. The object head shows the electrode positions of the 10-10 international standard lead system, the overall boundary line of the reference head, and the boundary lines between the upper front part of the skull, the right side of the skull, the top of the skull, and the back part of the skull.

[0029] Figure 4(d) shows a top view of a reference head model as an example of an object head according to the fourth embodiment of this application. The object head shows the electrode positions of the 10-10 international standard lead system, the overall boundary line of the reference head, and the boundary lines between the upper front part of the skull, the top of the skull, the left side of the skull, the right side of the skull, and the back part of the skull.

[0030] Figure 4(e) shows a rear view of a reference head model as an example of an object head according to the fourth embodiment of this application. The object head shows the electrode positions of the 10-10 international standard lead system, the overall boundary line of the reference head, and the boundary lines between the top of the skull, the left side of the skull, the right side of the skull, and the back of the skull.

[0031] Figure 5(a) shows a schematic diagram of the upper front part of a reference head model, which serves as an example of an object head, according to the fifth embodiment of this application.

[0032] Figure 5(b) shows a schematic diagram of the upper front part of a reference head model, which serves as an example of an object head, according to the sixth embodiment of this application.

[0033] Figure 5(c) shows a schematic diagram of the upper front part of a reference head model, which serves as an example of an object head, according to the seventh embodiment of this application.

[0034] Figure 6(a) shows an example diagram of the irradiation area according to the eighth embodiment of this application.

[0035] Figure 6(b) shows an example diagram of the irradiation area according to the ninth embodiment of this application.

[0036] Figure 6(c) shows an example diagram of the irradiation area according to the tenth embodiment of this application.

[0037] Figure 6(d) shows an example diagram of the irradiation area according to the eleventh embodiment of this application.

[0038] Figure 7 A bottom view of the headgear of the phototherapy device according to the twelfth embodiment of this application is shown.

[0039] Figure 8 A schematic diagram of the arrangement structure of the lamp panel according to the thirteenth embodiment of the present invention is shown.

[0040] Figure 9 A schematic diagram of the arrangement structure of the lamp panel frame according to the fourteenth embodiment of the present invention is shown.

[0041] Figure 10 A schematic diagram illustrating the process of conducting a clinical trial on AD patients using a phototherapy device according to an embodiment of this application is shown.

[0042] Figure 11(a) shows the changes in ADAS-Cog scale scores of the control group before, during and after near-infrared phototherapy.

[0043] Figure 11(b) shows the changes in ADAS-Cog scale scores of the experimental group before, during and after near-infrared phototherapy.

[0044] Figure 12(a) shows the changes in MMSE scores of the control group before, during and after near-infrared phototherapy.

[0045] Figure 12(b) shows the changes in MMSE scores of the experimental group before, during and after near-infrared phototherapy. Detailed Implementation

[0046] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention without creative effort are within the scope of protection of the present invention.

[0047] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning understood by one of ordinary skill in the art to which this invention pertains. The terms "first," "second," and similar terms used in this invention do not indicate any order, quantity, or importance, but are merely used to distinguish different components. Terms such as "comprising" or "including" mean that the element or object preceding the word encompasses the elements or objects listed following the word and their equivalents, without excluding other elements or objects. Terms such as "connected" or "linked" are not limited to physical or mechanical connections, but can include electrical connections, whether direct or indirect. Terms such as "upper," "lower," "left," and "right" are used only to indicate relative positional relationships; when the absolute position of the described object changes, the relative positional relationship may also change accordingly.

[0048] To keep the following description of the embodiments of the present invention clear and concise, detailed descriptions of known functions and known components are omitted.

[0049] This application aims to provide a phototherapy device for treating Alzheimer's disease and related conditions. The phrase "for treating Alzheimer's disease and related conditions" in this application signifies its ability to alleviate, inhibit, terminate, or even reverse the progression of Alzheimer's disease and related conditions. "Related conditions" refer to pathological or physiological phenomena associated with Alzheimer's disease that exist in the patient before the onset of obvious clinical symptoms of AD and have a certain probability of developing into AD. The term "progression" of Alzheimer's disease and related conditions encompasses both the onset of clinical symptoms of AD and their subsequent development, and the occurrence of pathological or physiological phenomena associated with AD that have a certain probability of developing into AD before the onset of obvious clinical symptoms of AD. In other words, the phrase "for treating Alzheimer's disease and related conditions" in this application includes treating Alzheimer's disease at various stages (from MCI to severe dementia) and also includes treating other conditions associated with Alzheimer's disease. Specifically, according to the 2018 diagnostic criteria for Alzheimer's disease (AD) from the National Institute on Aging and the Alzheimer's Association (NIA-AA), based on the levels of β-amyloid (Aβ) and tau in the brain or cerebrospinal fluid, as well as the results of cranial MRI and FDG-PET scans, biomarkers can be categorized into four classes, further classifying cognitive function into six levels. Level 1 is characterized by normal objective cognitive neuropsychological tests, no subjective cognitive complaints, no neurobehavioral symptoms, no informed reports of cognitive decline or neurobehavioral symptoms, and no follow-up test evidence of cognitive decline. Level 2 includes subjective cognitive decline (SCD), objective mild cognitive decline (Obj-SCD), and neurobehavioral symptoms; Levels 1 and 2 are collectively referred to as the preclinical stage. Level 3 is characterized by abnormal or impaired objective cognitive tests, but not reaching dementia, i.e., MCI. Levels 4-6 represent mild, moderate, and severe dementia, respectively. Positive biomarker test results at any stage within these six levels can be considered part of the Alzheimer's disease course as defined in this application. Furthermore, for individuals who carry genes associated with the risk of Alzheimer's disease but whose current test results are negative for Aβ, such as APOEε4, ABCA7, CLU, CR1, PICALM, PLD3, and TREM2, even if their cognitive function is at level 1, implementing medical interventions to reduce their risk of developing Alzheimer's disease or slowing down their progression to Alzheimer's disease can also be considered as "associated conditions for the treatment of Alzheimer's disease" in this application.

[0050] The phototherapy device includes a support structure 101 and an array 102 of near-infrared irradiation units. The support structure 101 is configured to form a receiving space for the head 103 of the object and to support the array 102 of near-infrared irradiation units. The array 102 of near-infrared irradiation units is configured to emit near-infrared light into the receiving space. The support structure 101 and the array 102 of near-infrared irradiation units can be configured in various ways as needed, for example, see Figures 1(a), 2(a), and 2(b), which will be described in detail below, but the structure of the phototherapy device is not limited to these.

[0051] With the object head 103 positioned within the receiving space, the emitted near-infrared light irradiates the object head, satisfying the synergistic irradiation conditions of the irradiated surface area ratio and the irradiation power level. The irradiated surface area ratio is the ratio of the irradiated surface area to the surface area of ​​the reference head cover 401. The term "positioned" in this application refers to the desired therapeutic positioning of the object head 103 within the phototherapy device, i.e., having the desired spatial position and orientation. Typically, the phototherapy device can be activated when the object head 103 is "positioned." For example, when positioned, the center of gravity of the object head 103 can be aligned with the center of the receiving space, and the central axes in the front-back direction can be aligned with each other. Alternatively, when positioned, the object head 103 can be centered within the receiving space, with substantially equal front-back distances from the front and rear walls of the receiving space, and substantially equal left-right distances from the left and right walls of the receiving space. For example, taking the phototherapy headgear shown in Figure 1(a) as an example, when in place, the brow bone of the subject's head 103 can be aligned with the front edge of the headgear, and the subject's head 103 is located in the center of the headgear, so that the front and rear sides are basically the same distance from the irradiation surface of the inner shell, and the left and right sides are also basically the same distance from the irradiation surface of the inner shell.

[0052] The surface area of ​​the reference scalp is the outer surface area of ​​the subject's head within the total boundary line 400. The total boundary line 400 starts from the glabella of the subject's head, runs along the brow bone, passes the points in front of the ears on both sides, and then circles backward, passing the occipital protuberance and converging between the electrode positions O1, OZ, and O2 of the 10-10 international standard lead system, as shown in Figures 4(a), 4(b), 4(c), and 4(e). The irradiated surface area ratio can be as low as 30% (this can be called a localized concentrated stimulation scheme) or as high as 65% or more (this can be called a multi-zone balanced stimulation scheme).

[0053] Through clinical trials, including case studies and experiments with a specific target population, the inventors have creatively discovered that the effectiveness of treating Alzheimer's disease and related symptoms by irradiating the brain with near-infrared light of the same wavelength is not solely determined by light power density. The irradiation power level reaching brain tissue and the proportion of irradiated surface area are both important factors, and they determine the effect synergistically. Furthermore, the energy attenuation of near-infrared light after passing through the skull can be measured. For example, see Jagdeo JR et al., Transcranial red and near infrared light transmission in a cadaveric model. PLoS One 2012;7:e47460, at a depth of 10 mm (approximate thickness of the cadaver's skull and its intact soft tissue), the penetration percentage of 830 nm LED light is 0.9% for the temporal lobe, 2.1% for the frontal lobe, and 11.7% for the occipital lobe. In addition, the light absorption and attenuation caused by hair of various thicknesses, amounts, and colors can also be measured. In other words, considering the attenuation along the transmission path from the irradiation emission surface to the target brain tissue, by ensuring that the emitted near-infrared light irradiates the subject's head in a synergistic irradiation condition of irradiated surface area ratio and irradiation power level, sufficient near-infrared light with a unit time power can be delivered to a sufficient area of ​​the subject's head. This, in turn, delivers sufficient near-infrared light with a unit time power, even after attenuation along the propagation path, to a sufficient area of ​​the brain tissue, thereby achieving optimized treatment effects for Alzheimer's disease and related symptoms. The optimization of treatment effects has also been confirmed through clinical trials (detailed below). The phototherapy device of this application has indeed demonstrated excellent "endurance" in suppressing the progression of AD. Specifically, the subjects not only experienced a significant improvement in cognitive level during the phototherapy period, but their cognitive level also remained or improved for a sustained period after phototherapy was stopped, and the subjects experienced no adverse reactions. The main mechanism of action of this finding is estimated as follows, but the exact mechanism needs further experimental confirmation.

[0054] Alzheimer's disease (AD) is a global brain disease, and its pathological changes are not limited to a specific area of ​​the brain, but gradually spread from some areas to the whole brain, affecting multiple brain regions and neural networks. For example, the accumulation of Aβ in the brain follows a specific spatial trajectory, starting from the default mode network (DMN) area and gradually spreading to other lower-order sensory-motor areas.

[0055] Furthermore, single-cell transcriptomics studies have revealed cell type-specific changes in AD, meaning that different cell populations exhibit distinct population responses associated with AD. These cell populations include, but are not limited to, astrocytes, microglia, oligodendrocytes, neurons, vascular cells, peripheral glial cells, and the extracellular matrix. Specifically, astrocyte subsets have been found to be associated with cognitive decline, playing a role in regulating the effects of tau protein on cognitive function. Different microglia subsets are involved in the pathogenesis of AD; some subsets drive Aβ protein lesions, while others regulate the effects of Aβ protein on tau protein lesions. Specific responses of oligodendrocytes in AD are associated with disease progression, such as subset-specific transcriptional changes. AD affects specific neuronal subsets, such as those in the hippocampus and cerebral cortex, which are closely associated with AD. Vascular cells, including endothelial cells and perivascular cells, play a role in vascular lesions in Alzheimer's disease (AD). Peripheral glial cells, associated with APOE expression, play a role in the neurodegenerative changes of AD. Changes in the extracellular matrix are also associated with the progression of AD, affecting intercellular interactions and signal transduction.

[0056] As long as the emitted near-infrared light irradiates the subject's head in a synergistic manner with the irradiation surface area ratio and irradiation power level, sufficient near-infrared light with adequate power can be delivered to adequate areas of brain tissue per unit time. The irradiation surface area ratio of localized concentrated stimulation protocols can be as low as 30%, while the irradiation surface area ratio of multi-zone balanced stimulation protocols can be as high as 65% or more. The irradiation power level, synergistically matched with the irradiation surface area ratios within these ranges, can achieve the "modulation" and "excitation" of a sufficient proportion of cell populations. After being "modulated" and "excited," the sufficient proportion of cell populations not only exhibits a change in response that inhibits AD, but can also transmit and diffuse this change in response to other cell populations along the AD development trajectory, thereby achieving a comprehensive AD inhibition effect throughout the entire brain. In this way, it can not only significantly reduce the accumulation of Aβ plaques in the neocortex and significantly reduce the abnormal aggregation of tau protein in the neocortex, hippocampus, and even the limbic cortex, but also inhibit and reduce AD-specific lesions in cell populations throughout the entire brain, thereby effectively inhibiting the progression of AD and its related symptoms. Furthermore, during the period following the cessation of phototherapy, a series of biochemical reactions caused by photoradiation continued to trigger the inhibitory effect, not only maintaining the inhibitory effect on AD to a certain extent, but also continuing to advance the inhibitory effect on AD without any degradation or regression.

[0057] In some embodiments, suitable synergistic irradiation conditions can be provided for localized concentrated stimulation protocols and multi-zone balanced stimulation protocols.

[0058] Specifically, the localized concentrated stimulation scheme has a smaller irradiated surface area ratio than the multi-zone equalization stimulation scheme, and the matched irradiation power level is also higher. For example, as a localized concentrated stimulation scheme, a spatiotemporal average optical power density of 117 mW / cm² is required when the irradiated surface area ratio is 30% to 40%. 2 The above; and when the irradiated surface area is between 40% and 65%, the spatiotemporal average optical power density irradiated onto the object's head is 110 mW / cm². 2 That's all. In this way, it's possible to overcome the limitations of local cell populations, fully "modulate" and "stimulate" cell populations, and transmit and diffuse the inhibitory response to AD to other cell populations in a wider region along the AD development trajectory. Please note that the description of the % range in this application is defined as follows: "Between A% and B%" is intended to include percentages between A% and B%, but excludes neither A% nor B%. "A% to B%" is intended to include percentages between A% and B%, and includes both A% and B% endpoints.

[0059] Multi-zone balanced stimulation protocols require an average synergistic dose ranging from 2750 W*% to 14100 W*%, where the average synergistic dose is the product of the irradiated surface area ratio and the average total power, expressed in watts per percent. As the affected cell populations become more widely distributed, such as across multiple brain regions and functional networks, delivering the aforementioned average synergistic dose can appropriately "modulate" and "excite" the cell populations, transmitting and diffusing the inhibitory response to other cell populations across a broad area along the AD development trajectory. Note that for various synergistic irradiation conditions with varying irradiated surface area ratios and power levels, the spatiotemporal average optical power density irradiated onto the subject's head is approximately 230 mW / cm². 2 The following measures are taken to avoid thermal damage to tissue cells.

[0060] The phototherapy device and its headgear 100 according to the first embodiment of this application are shown in FIG1(a). The support structure 101 is constructed as a headgear, which maintains an appropriate gap when the subject's head 103 is accommodated therein, allowing the subject's head 103 to move. This loose and open headgear design does not restrict the patient's head and is especially friendly to elderly people who are emotionally agitated, anxious, resistant, or even afraid of enclosed or crowded spaces, which can significantly improve the treatment compliance of AD patients. The array 102 of near-infrared irradiation units can form a lamp panel and be assembled and fixed inside the headgear.

[0061] The phototherapy device may also include a user terminal 19 configured for user interaction. The user terminal 19 may be configured with a computer storage medium storing executable instructions. When these instructions are executed by a processor, various interactive steps with the user can be implemented. The storage medium may include read-only memory (ROM), flash memory, random access memory (RAM), dynamic random access memory (DRAM) such as synchronous DRAM (SDRAM) or Rambus DRAM, static memory (e.g., flash memory, static random access memory), etc., and may store computer-executable instructions in any format. In some embodiments, the user terminal 19 is also used to receive confirmation from the user regarding the proposed infrared phototherapy plan; upon receiving confirmation, irradiation is performed according to the confirmed infrared phototherapy plan.

[0062] Specifically, the controller (not shown) controlling the irradiation can be located on the user terminal 19, on the head-mounted device 100, or on a host machine different from the user terminal 19 and the head-mounted device 100. The controller can be implemented by various processors and can be a processing device including one or more general-purpose processing units, such as a microprocessor, central processing unit (CPU), graphics processing unit (GPU), etc., or one or more special-purpose processing devices, such as application-specific integrated circuits (ASICs), field-programmable gate arrays (FPGAs), digital signal processors (DSPs), system-on-a-chip (SoCs), etc. Preferably, most of the computation and processing is concentrated on the user terminal 19 to reduce the computational load and hardware / software costs of the head-mounted device. The head-mounted device 100 is suspended from the support 20 via an elastic member 21. The support 20 has a three-section free-pivoting structure, facilitating flexible adjustment of the position of the head-mounted device 100. In some embodiments, the phototherapy device also carries a cooler 23 to introduce cool air into the phototherapy device to achieve sufficient and comfortable cooling around the subject's head 103, for example, stabilizing the temperature at around 43 degrees Celsius, or even around 41 degrees Celsius.

[0063] Figure 1(b) illustrates an exemplary structure of this loose-fitting headgear 100. As shown in Figure 1(b), the headgear 100 is implemented as a headgear, which includes an outer shell 1, a middle shell 2, and an inner shell 3 arranged sequentially from the outside to the inside. A lamp plate receiving cavity 4 is formed between the outer shell 1 and the middle shell 2, which is provided with multiple lamp plates 5 (corresponding to the array 102 of near-infrared irradiation units in Figure 1(a)). A cooling air cavity 6 is formed between the middle shell 2 and the inner shell 3, and the inner shell 3 encloses inward to form a receiving space. The inner shell 3 is provided with multiple ventilation holes 7 so that the cooling air through the cooling air cavity 6 can enter the receiving space through the ventilation holes 7. Ventilation holes 7 can be opened on a first region of the inner shell 3 near the top of the head and a second region below the first region. The second region is provided with multiple ventilation hole units layered from top to bottom, wherein the upper ventilation hole units and the lower ventilation hole units are arranged differently to cool down different areas of the patient's head and improve the synchronicity and uniformity of cooling. During phototherapy, patients experience a more even temperature distribution and greater comfort throughout their head.

[0064] As can be seen, the inner shell 3 is the shell closest to the patient's head when the patient wears it. A cold air cavity 6 is formed between the middle shell 2 and the inner shell 3. The inner shell 3 and the middle shell 2 are designed to be light-transmitting. In this way, the near-infrared light emitted by the lamp panel 5 (e.g., wavelength in the range of 800-850nm) can pass through the light-transmitting middle shell 2 and the inner shell 3 in sequence and enter the receiving space to irradiate the patient's head with a sufficient dose.

[0065] In some embodiments, the inner shell 3 includes a first region near the top of the head and a second region located below the first region. Ventilation holes 7 can be provided on the first and second regions. As shown in Figure 1(b), the middle shell 2 has a cold air inlet 8 communicating with the cold air chamber 6. A ring of ventilation holes can be provided at least around the outer edge of the first region, allowing for a cavity to be reserved at the top of the head for a protective pad. After entering the cold air chamber 6 through the cold air inlet 8, the cold air passes through the ventilation holes 7 and is then blown towards the patient's head, ensuring a good cooling experience for the area around and top of the patient's head. Furthermore, the above structure allows the cold air to flow from above to below the patient's head, which is beneficial for improving the heat exchange efficiency and temperature uniformity within the containment space.

[0066] In this embodiment, the cold air inlet 8 of the cold air chamber 6 is located in the first region, and is closer to the rear of the inner shell 3 than to the front of the inner shell 3. The front of the inner shell 3 corresponds to the forehead of the headgear, and the rear of the inner shell 3 corresponds to the back of the head. This prevents the forehead area from becoming too cold, while the back of the head, which absorbs more light energy due to its large hair volume and generates more heat, also experiences a stronger cooling effect, thus improving the patient's comfort during phototherapy. This is merely an example; in some embodiments, the cold air inlet 8 maintains a similar distance from both the front end (i.e., the front edge of the inner shell 3) and the rear end (i.e., the rear edge of the inner shell 3) to avoid uneven or untimely cooling caused by significant differences in distance.

[0067] In some embodiments, to distribute the cold air more evenly into the accommodating space, the headgear may include multiple cold air inlets 8, which are distributed at different locations within the inner shell. The location of the cold air inlets 8 can be designed and adjusted according to the specific headgear structure and the arrangement of the phototherapy lamp panel.

[0068] In some embodiments, the second region is provided with multiple vent units layered from top to bottom. The upper vent unit 701 and the lower vent unit 703 are arranged differently, while the upper vent unit 701 and the middle vent unit 702 are arranged in the same way. For example, the number of vents in a single lower vent unit 703 is less than the number of vents in a single upper vent unit 701 or middle vent unit 702. As another example, adjacent upper vent units 701 are provided with vents 7 with a relatively lower vent density compared to the upper vent unit 701. This arrangement allows the upper vent units 701 and middle vent units 702 to release more cold air compared to the lower vent unit 703.

[0069] In some embodiments, the upper vent unit 701 and the middle vent unit 702 may each be composed of vents 7 evenly distributed in the inner ring and vents 7 evenly distributed in the outer ring. For example, the inner ring may have 6 vents 7 evenly distributed and the outer ring may have 6 vents 7 evenly distributed. The lower vent unit 703 may consist of only one ring of vents 7 evenly distributed, for example, only 6 vents 7 evenly distributed.

[0070] The refrigeration unit 23 shown in Figure 1(a), together with the cold air inlet 8, cold air chamber 6, vent 7, and the connection between the containment space and the external environment in Figure 1(b), constitute a cooling mechanism. Using this cooling mechanism, when the average total irradiation power of the object head 103 reaches 27.5-120W and the single continuous irradiation time reaches 30 minutes, the temperature of the air in the space adjacent to but not in contact with the object head 103 does not exceed 41°C. In other words, the temperature of the surrounding air immersed in the object head 103 does not exceed 41°C.

[0071] In some embodiments, the vent 7 is provided at least at the corresponding position of the lamp plate 5. During phototherapy, the area of ​​the patient's skin irradiated by the lamp plate 5 is more prone to heat accumulation due to the high intensity of the light. By providing the vent 7 at least at the position of the lamp plate 5 on the inner shell 3, excessive heat accumulation caused by the lamp plate 5 irradiating the patient's skin can be prevented.

[0072] In some embodiments, the density of the vent holes 7 at the corresponding position of the lamp panel 5 is greater than the density of the vent holes 7 at the non-corresponding position of the lamp panel 5, thereby further balancing the temperature at the corresponding position of the lamp panel 5 and other positions, enhancing the permeability of the containment space, and increasing the air heat exchange rate in the containment space.

[0073] As an example, the loose-fitting headgear 100 shown in Figure 1(b) is particularly suitable for implementing multi-zone balanced stimulation programs. Of course, by flexibly controlling the lamp panel 5, this loose-fitting headgear 100 can also implement localized concentrated stimulation programs as needed.

[0074] Figure 2(a) shows a schematic diagram of a phototherapy device according to a second embodiment of the present application. As shown in Figure 2(a), the phototherapy device includes a head-mounted device 100 with communication connection and a portable control terminal 104.

[0075] The support mechanism 101 adopts a hollow frame that is pressed against the head 103 of the object. The array 102 of the near-infrared irradiation unit forms a discrete irradiation module that is fixedly installed on the hollow frame. Under the action of the hollow frame, the irradiation module is closely attached to the forehead, top of the skull, and above the ears of the object's head, so as to emit near-infrared light to these parts.

[0076] As an example, the control terminal 104 may be equipped with operation buttons, such as, but not limited to, a start button, a pause button, and a stop button, so that the operator can control the phototherapy process by pressing the buttons. The control terminal 104 may also be equipped with a display to present the operator with operation information of the phototherapy process, such as, but not limited to, light intensity adjustment and the remaining time of the current treatment.

[0077] Specifically, for example, the phototherapy device with the structure shown in Figure 2(a) is particularly suitable for implementing localized concentrated stimulation protocols and / or for the treatment of early stages of Alzheimer's disease (e.g., MCI, mild dementia) and for preventative medical interventions for Alzheimer's disease. Furthermore, the phototherapy device with the structure shown in Figure 2(a) is highly portable, allowing users to conveniently use it at home or while traveling, thereby ensuring the frequency and continuity of phototherapy.

[0078] Figure 2(b) shows a schematic diagram of a phototherapy device according to a third embodiment of this application. The control and processing terminals can be referenced in the preceding embodiments and are not shown here for simplicity. Unlike the headgear 100 shown in Figures 1(b) and 2(a), the support mechanism 101 forms a significantly wider, arched or umbrella-shaped receiving space, and is further away from the subject's head 103. Furthermore, the support mechanism 101 is rigidly mounted to a support or wall, and the array 102 of near-infrared irradiation units forms discrete irradiation modules mounted on the inner wall of the support mechanism 101.

[0079] In some embodiments, the synergistic irradiation conditions of irradiated surface area ratio and irradiation power level can characterize the correlation between irradiated surface area ratio and spatiotemporal average optical power density, such as the synergistic irradiation conditions used in localized concentrated stimulation schemes when the irradiated surface area ratio is between 30% and 40% or between 40% and 65%; or characterize the product of the average total power irradiated to the head of the object and the total irradiated surface area ratio, such as the synergistic irradiation conditions used in multi-zone balanced stimulation schemes when the irradiated surface area ratio is above 65%. In other embodiments, the synergistic irradiation conditions of irradiated surface area ratio and irradiation power level can be defined differently as needed, such as the integral of the power irradiated to each zone of the head of the object with respect to the irradiated surface area ratio of each zone, or the distribution of the product of the power irradiated to each zone of the head of the object and the irradiated surface area ratio of each zone, etc. By refining the synergistic irradiation conditions to the regional distribution, when there are large deviations in the irradiation dose in different brain regions, it is possible to more effectively identify the corresponding light power or light power density that is too low in a particular region, ensuring that there are no blind spots in the "modulation" and "excitation" of the cell population.

[0080] In some embodiments, the object head may include the head of the therapist or a reference head model of a group of therapists. The specific structural parameters of the object head mainly include head width, head length, head circumference, head sagittal arc, intertragus arc, morphological plane length, and head height, as shown in Figures 3(a)-3(f).

[0081] To facilitate the implementation of irradiation protocols, the reference scalp of the subject's head is divided into four sections: upper anterior skull (401a), top skull (401b), left lateral skull (401c), right lateral skull (401d), and posterior skull (401e). The specific division can be adjusted according to actual needs. For example, the division shown in Figures 4(a)-4(e) can be used. Specifically, this division is based on the 10-10 international standard lead system. The 10-10 international standard lead system is a standard for electrode placement in electroencephalography (EEG) recordings, providing a precise and consistent way to mark and locate electrodes on the head. In other words, the 10-10 system can be applied directly to the subject's head without transcranial application. This system is an extension of the earlier 10-20 system, proposed by the International Society for Electroencephalography (IEA) to standardize electrode placement in EEG recordings.

[0082] In the 10-10 system, electrode placement is based on anatomical landmarks of the head, including the nasal root, the inion, and the pre-auricular points. These landmarks are used to determine the anterior-posterior and lateral midlines of the head, allowing for electrode placement at a 10% ratio.

[0083] The 10-10 system's naming convention is based on the 10-20 system, but provides denser electrode placement, particularly in the base and anterior temporal lobe and the frontal lobe, locating areas often overlooked in the 10-20 system. Furthermore, the 10-10 system introduces new electrodes to allow for more precise localization of brain region boundaries, such as FC for electrodes between the frontocentral region, FT for electrodes between the frontotemporal region, CP for electrodes between the central-parietal region, and PO for electrodes between the parieto-occipital region. The 10-10 system's electrode placement effectively eliminates the influence of individual head shape and size differences, allowing the same electrode position to be accurately located at the same brain region node in different individuals. Its denser electrode positions, especially for the temporal and frontal lobes, enable more detailed division of the anterior superior cranial region 401a, cranial top 401b, left cranial region 401c, right cranial region 401d, and posterior cranial region 401e on the surface of the skull (outside the skull, scalp, and hair). Correspondingly, it also enables more detailed division of various brain regions (frontal lobe, parietal lobe, and temporal lobe) under the skull and dura mater.

[0084] In some embodiments, the anterior upper portion 401a, the top of the skull 401b, the left side of the skull 401c, the right side of the skull 401d, and the posterior portion of the skull 401e can be defined based on their boundary lines. Referring to Figures 4(a)-4(e), the anterior upper portion 401a is within a first region 402a enclosed by a first boundary line 400a and the total boundary line 400. According to the 10-10 standard lead system, the first boundary line 400a passes sequentially between the following electrode positions: between F7 and FT7, between F5 and FC5, between FC3 and C3, between FC1 and C1, between FCZ and CZ, between FC2 and C2, between FC4 and C4, between F6 and FC6, and between F8 and FT8. Note that the small protrusions at each electrode position in Figures 4(a)-4(e) are only for clearer illustration of the electrode positions in this application; such small protrusions may not actually be provided. For example, small protrusions may not be provided on the surface of the reference head mold, which will not be elaborated here.

[0085] Within the second region 402b enclosed by the second boundary line 400b, the top of the skull 401b passes sequentially between the following electrode positions according to the 10-10 standard lead system: between FC3 and C3, between FC1 and C1, between FCZ and CZ, between FC2 and C2, between FC4 and C4, between C6 and C4, between CP6 and CP4, between P6 and P4, between PO4 and P4, between PO4 and P2, between POZ and P2, between POZ and PZ, between POZ and P1, between PO3 and P1, between PO3 and P3, between P5 and P3, between CP5 and CP3, and between C5 and C3. The left cranial portion 401c is located within a third region 402c enclosed by a third boundary line 400c and a total boundary line 400. According to the 10-10 standard lead system, the third boundary line 400c passes sequentially between the following electrode positions: between FT7 and F7, between FC5 and F5, between FC5 and FC3, between C5 and C3, between CP5 and CP3, between P5 and P3, between P5 and PO5, and between P7 and PO7. The right cranial portion 401d is located within a fourth region 402d enclosed by a fourth boundary line 400d and a total boundary line 400. According to the 10-10 standard lead system, the fourth boundary line 400d passes sequentially between the following electrode positions: between FT8 and F8, between FC6 and F6, between FC6 and FC4, between C6 and C4, between CP6 and CP4, between P6 and P4, between P6 and PO6, and between P8 and PO8. Within the fifth region 402e enclosed by the fifth boundary line 400e and the total boundary line 400, the posterior cranial region 401e, according to the 10-10 standard lead system, passes sequentially between the following electrode positions: between P7 and PO7, between P5 and PO5, between P3 and PO3, between P1 and POZ, between PZ and POZ, between P2 and POZ, between P4 and PO4, between P6 and PO6, and between P8 and PO8. The term "passing between electrode positions A and B" in this application refers to an intermediate point on the line connecting electrode positions A and B. For example, this intermediate point could be the midpoint of the line or other points on the line, such as points at a 1:2 ratio from electrode positions A and B. In some embodiments, for the same boundary line, such as the fifth boundary line 400e, the points passing between paired electrode positions can be located at different ratios on the line to ensure a smooth sequential boundary line.

[0086] In some embodiments, the anterior upper part 401a, cranial top 401b, left cranial part 401c, right cranial part 401d, and posterior cranial part 401e can also be defined based on the electrode positions they contain. Referring to Figures 4(a)-4(e), the anterior upper part 401a forms a region including electrode positions FP2, FPZ, FP1, AF3, AF4, AF7, AF8, AFZ, FZ, F1, F2, F3, F4, F5, F6, F7, F8, FC1, FC2, FC3, FC4, and FCZ. The cranial top 401b forms a region including electrode positions CZ, C1, C2, C3, C4, CPZ, CP1, CP2, CP3, CP4, PZ, P1, P2, P3, and P4. The left cranial portion 401c forms a region including electrode positions FT7, FC5, T7, C5, TP7, CP5, P7, and P5. The right cranial portion 401d forms a region including electrode positions FT8, FC6, T8, C6, TP8, CP6, P8, and P6. The posterior cranial portion 401e forms a region including electrode positions PO7, PO5, PO3, PO2, PO4, PO6, PO8, O1, O2, and O2.

[0087] As an example, in Figures 4(a)-4(e), the upper anterior cranial portion 401a, the top cranial portion 401b, the left cranial portion 401c, the right cranial portion 401d, and the posterior cranial portion 401e are connected to each other without any openings and occupy the entire surface area of ​​the reference skull portion 401 of the subject's head; however, this is merely an example. In some embodiments, the upper anterior cranial portion 401a, the top cranial portion 401b, the left cranial portion 401c, the right cranial portion 401d, and the posterior cranial portion 401e occupy more than 70% of the surface area of ​​the first region 402a, the second region 402b, the third region 402c, the fourth region 402d, and the fifth region 402e, respectively, defined by their corresponding boundary lines; that is, the proportion can be as low as 70%. Sufficient irradiation of 70% of the surface area of ​​each region, through the optical diffusion effect of the subcranial brain tissue and the conduction between brain region nodes, achieves a comprehensive AD inhibition effect throughout the entire brain.

[0088] The above division method is merely an example. While the division of the upper anterior cranial region 401a, top cranial region 401b, left cranial region 401c, right cranial region 401d, and posterior cranial region 401e can be adjusted as needed, it is preferable that each part primarily corresponds to the frontal lobe, parietal lobe, left temporal lobe, right temporal lobe, and occipital lobe, respectively. For example, each part of the upper anterior cranial region 401a, top cranial region 401b, left cranial region 401c, right cranial region 401d, and posterior cranial region 401e can be divided into multiple island-shaped sub-regions around each group of electrode sites, as shown in Figure 5(a). Alternatively, each part can be divided into a continuous, interconnected island-shaped region, as shown in Figure 5(b), with small holes provided, some of which can be created around the electrode sites.

[0089] More preferably, the anterior superior cranial region 401a is distributed across the prefrontal lobe, the frontal lobe, and the frontal-central region, as shown in Figure 5(c). Further, the top cranial region 401b is distributed across the central region, the central-parietal lobe, and the parietal lobe; the left cranial region 401c and the right cranial region 401d are distributed across the frontal-temporal lobe, the temporal lobe, and the temporal-parietal lobe; and the posterior cranial region 401e is distributed across the parietal-occipital lobe and the occipital lobe. More preferably, the left cranial region 401c and the right cranial region 401d are distributed across the lower part of the frontal-central region, the frontal-temporal lobe, the temporal lobe, the lower part of the central region, the inferior parietal lobe, the temporal-parietal lobe, and the lower part of the central-parietal lobe. This distribution ensures that each region contains connection sites between different brain regions, and irradiation of each region ensures sufficient irradiation of these connection sites, thereby improving the transmission pathways for the "modulation" and "excitation" responses of the cell population.

[0090] In some embodiments, during the manufacturing of phototherapy devices, a reference head model of the patient population can be used to simulate, model, or test the attenuation and transmission of near-infrared light. Specifically, a reference head model with a representative size can be selected based on the patient population. For example, since the majority of AD patients are over 60 years old, the parameters of the reference head model for this age group could be: head width 140-166 mm, head length 170-196 mm, head circumference 525-583 mm, morphological surface length 104-130 mm, sagittal arc 304-372 mm, intertragic arc 320-375 mm, and head height 206-253 mm.

[0091] Specifically, the parameter range of this reference head model falls at the intersection of the parameter values ​​of P1, P5, P10, P50, P90, P95, and P99 for women in this age group and the parameter values ​​of P1, P10, P50, P90, P95, and P99 for men in this age group. Therefore, it is highly representative of both men and women in this age group.

[0092] In some embodiments, the parameters of the reference head model can be refined as follows: head width 152 mm, head length 184 mm, head circumference 536.7 mm, morphological surface length 109.3 mm, sagittal arc 355.6 mm, intertragic arc 324.1 mm, and head height 206 mm. These refined parameters are at least partially determined based on the P50 parameter values ​​for women and men of this age group. For example, the head width and head length here are the average of two corresponding P50 parameter values. The P50 parameter values ​​for women of this age group are as follows: head width 149 mm, head length 180 mm, head circumference 548 mm, morphological surface length 111 mm, sagittal arc 335 mm, intertragic arc 342 mm, and head height 228 mm. The P50 parameters for men in this age group are as follows: head width 155mm, head length 188mm, head circumference 565mm, morphological face length 121mm, sagittal arc 343mm, intertragic arc 351mm, and head height 231mm. It can be seen that the parameters of this baseline head model have a good match with the P50 parameters of women and men in this age group, thus making it more representative. Furthermore, the cephalofacial index of this parameter is 82%, which is also consistent with the range of cephalofacial indices of the dominant head shape—Brachycephaly—in Chinese (and even East Asian populations). Therefore, the parameters of this baseline head model are particularly representative of Chinese (and even East Asian populations). In some embodiments, for populations with other cephalofacial indices, such as, but not limited to, major human populations in Europe, South Asia, and Africa, the parameters can be adaptively adjusted to achieve good representativeness.

[0093] The electrode positions of the 10-10 international standard lead system can be measured and marked on the reference head mold. In some embodiments, by adopting the above division of the upper anterior skull 401a, top skull 401b, left side skull 401c, right side skull 401d, and posterior skull 401e, simulations, modeling, or tests can be performed according to the details of the intended localized concentrated stimulation scheme or multi-zone balanced stimulation scheme. In some embodiments, the simulation or modeling results can be used to verify whether the designed phototherapy device can meet the required synergistic irradiation conditions under the intended implementation scheme. The structure of the phototherapy device, especially the three-dimensional spatial arrangement of the lamp panels, can be adjusted accordingly. After verification, a prototype of the designed phototherapy device can be manufactured, and the prototype can be used to irradiate the reference head mold for testing and verification. It is understood that if the actual test results on the reference head mold are good, given that the size of the reference head mold is well representative of the individual head sizes of the patient population, the results of subsequent phototherapy tests on the patient population will have a high degree of consistency. This manufacturing process can balance manufacturing costs and treatment effects.

[0094] Specifically, in some embodiments, the synergistic irradiation conditions of the irradiated surface area ratio and the irradiation power level can be defined as follows: when the irradiated surface area ratio of the emitted near-infrared light to the head of the object is 30% to 40%, the spatiotemporal average optical power density irradiated to the head of the object is 117 mW / cm². 2 Above and 230mW / cm 2 Below. For example, the spatiotemporal average optical power density (in mW / cm²) irradiated onto the head of the object at this irradiated surface area ratio. 2 () can be any point in the range of values ​​from 117 to 230, starting from 117 and distributed at intervals of 0.5-1.

[0095] When the irradiated surface area is between 40% and 65%, the spatiotemporal average optical power density irradiated onto the object's head is 110 mW / cm². 2 Above and 230mW / cm 2 Below. For example, the spatiotemporal average optical power density (in mW / cm²) irradiated onto the head of the object at this irradiated surface area ratio. 2 () can be any point in the range of values ​​from 110 to 230, starting from 110 and distributed at intervals of 0.5-1.

[0096] When the irradiated surface area ratio is above 65%, the average synergistic dose irradiated to the target head is between 2750 W*% and 14100 W*%, where the average synergistic dose is the product of the irradiated surface area ratio and the average total power, and the spatiotemporal average optical power density irradiated to the target head is 230 mW / cm². 2 For example, at this irradiated surface area ratio, the average synergistic dose (in W*%) irradiated to the head of the target can be any point in the range of 2750 to 14100, starting from 2750 and distributed at intervals of 10.

[0097] However, in the actual manufacturing and verification process, it is not necessary to exhaustively list every ratio of the above irradiated surface area proportions. By selecting a portion of them, it is also possible to simulate, model, or test whether the phototherapy device meets the corresponding synergistic irradiation conditions.

[0098] By employing the flexible combination of the above-mentioned upper anterior cranial portion 401a, top cranial portion 401b, left cranial portion 401c, right cranial portion 401d, and posterior cranial portion 401e, multiple representative irradiation surface area ratios can be obtained, thereby facilitating the simulation and verification of localized concentrated stimulation schemes or multi-zone balanced stimulation schemes.

[0099] As an example, as shown in Figures 4(a)-4(e), the first region 402a, the second region 402b, the third region 402c, the fourth region 402d, and the fifth region 402e are respectively designated as the upper anterior part of the skull 401a, the top of the skull 401b, the left side of the skull 401c, the right side of the skull 401d, and the posterior part of the skull 401e. The ratio of the surface area of ​​each part to the surface area of ​​the reference skull is shown in Table 1. Table 1. Surface area ratios of the upper anterior part of the skull, the top of the skull, the left side of the skull, the right side of the skull, and the posterior part of the skull relative to the reference skull.

[0100] In other words, the emitted near-infrared light can irradiate any of the following regions of the subject's head: the upper front part of the skull; the upper front part and the top of the skull, as shown in Figure 6(a); the upper front part, the left side of the skull, and the right side of the skull, as shown in Figure 6(b); the upper front part, the left side of the skull, the right side of the skull, and the top of the skull, as shown in Figure 6(c); the upper front part, the left side of the skull, the right side of the skull, the top of the skull, and the posterior part of the skull, as shown in Figure 6(d). As an example, when only the upper front part of the subject's head is irradiated, the irradiated surface area ratio is 35.7% (satisfying 30% to 40%), and the spatiotemporal average optical power density irradiated on the subject's head is 117 mW / cm². 2 Above and 230mW / cm 2 The following conditions were met: when only the upper front part and top of the subject's head were irradiated, the irradiated surface area ratio was 59.21% (satisfying the range of 40% to 65%); or when only the upper front part, left side, and right side of the subject's head were irradiated, the irradiated surface area ratio was 64.03% (satisfying the range of 40% to 65%). The spatiotemporal average optical power density of the irradiated subject's head was 110 mW / cm². 2 Above and 230mW / cm 2The following applies: When irradiating the upper front, left side, right side, and top of the skull, the irradiated surface area ratio is 87.54%, with an average synergistic dose ranging from 2750 W*% to 10800 W*% of the reference skull surface area. When irradiating the upper front, left side, right side, top, and back of the skull, the irradiated surface area ratio is 100%, with an average synergistic dose ranging from 2750 W*% to 14100 W*% of the reference skull surface area. In other words, after the reference head model of the subject's head is manufactured, if each part is divided as described above, targeted irradiation according to the corresponding combination of the parts can easily accommodate multiple irradiated surface area ratios from 30% to 100%, such as 35.7%, 59.21%, 64.03%, 87.54%, or 100%. In some embodiments, any irradiated surface area ratio in the range of 30% to 100% can be flexibly achieved by irradiating only a portion of each part or by irradiating a combination of several parts. For example, any percentage value starting from 30% and distributed at 5% intervals.

[0101] Accordingly, the phototherapy equipment can be adjusted, and the irradiation parameters under the corresponding combination mode can be tested to check whether the spatiotemporal average light power density or average synergistic dose meets the intended synergistic irradiation conditions. If so, the calibration of the irradiation parameters of the phototherapy equipment under this combination mode is complete. Furthermore, after leaving the factory, if the user adopts a custom combination mode of each component, the corresponding calibration can also be performed as above to ensure that the custom combination mode can meet the required synergistic irradiation conditions and ensure the treatment effect on AD.

[0102] In some embodiments, the spatiotemporal average optical power density corresponding to a first proportion of the surface area of ​​a reference scalp of the subject's head irradiated by the emitted near-infrared light is greater than the spatiotemporal average optical power density corresponding to a second proportion of the surface area of ​​the reference scalp of the subject's head irradiated by the emitted near-infrared light irradiated by the subject's head, wherein the first proportion is less than the second proportion. The first proportion and the second proportion can be selected from any of the following: For example, both the first proportion and the second proportion can be 30% to 40%. For example, the first proportion can be 30% to 40%, and the second proportion can be between 40% and 65%. For example, both the first proportion and the second proportion can be between 40% and 65%. For example, the first proportion can be between 40% and 65%, and the second proportion can be above 65%. Yet another example, both the first proportion and the second proportion can be above 65%. In some embodiments, the desired spatiotemporal average optical power density corresponding to various irradiated surface area proportions can be analyzed by simulating and modeling the light irradiation process of the phototherapy device relative to the subject's head. Specifically, the energy attenuation of near-infrared light of corresponding wavelengths in various parts of the scalp, skull, cerebrospinal fluid, dura mater, arachnoid mater, and pia mater can be taken into account. Simulations are then performed with the surface area ratio and spatiotemporal average optical power density of the target brain region, such as the prefrontal cortex, as the objective. This determines the irradiation area and spatiotemporal average optical power density of the reference scalp surface of the subject's head. During simulation, the irradiation surface area ratio can be adjusted by regulating the irradiation area of ​​the reference scalp surface. Based on the spatiotemporal average optical power density relationship between the first and second ratios mentioned above, the spatiotemporal average optical power density of the reference scalp surface can be adjusted accordingly. This yields a specific coordinated irradiation scheme for the reference scalp surface, which can then be used for subsequent calibration, testing, and actual operation of the phototherapy equipment.

[0103] As mentioned above, the inventors have creatively discovered that, for the efficacy of phototherapy in treating Alzheimer's disease (AD), the time-averaged irradiation power level and the ratio of irradiated surface area to brain tissue are crucial factors for synergistic effects. Correspondingly, the synergistic irradiation conditions required for near-infrared light to reach the subject's head can be characterized in various ways, particularly regarding the time-averaged irradiation power level. For example, the time-averaged irradiation power level can be characterized as the spatiotemporal average optical power density, total power, or a composite parameter calculated with the irradiated surface area (e.g., product, integral, etc.). In some embodiments, the average total irradiation power of the emitted near-infrared light reaching the subject's head is 23-140W, 29-120W, or 31-100W. In some embodiments, the corresponding average total irradiation power can also be adapted according to the course of AD.

[0104] For AD patients with unclear or dispersed target areas, a multi-zone balanced stimulation protocol is preferred. For example, irradiation can be applied to the anterior superior cranium, left lateral cranium, right lateral cranium, and top of the skull, or to the anterior superior cranium, left lateral cranium, right lateral cranium, top of the skull, and posterior cranium. The division of these areas can be found in other embodiments, but is not limited thereto. The spatiotemporal average optical power density applied to the anterior superior cranium is 50-120 mW / cm². 2 The spatiotemporal average optical power density irradiated onto the top of the skull is 60-120 mW / cm². 2 The spatiotemporal average optical power density irradiated the left and right sides of the skull was 32-85 mW / cm². 2 In some embodiments, the spatiotemporal average optical power density irradiated onto the upper anterior part of the skull, the top of the skull, the left side of the skull, or the right side of the skull can be 4-10 mW / cm², starting from the lower limit of the corresponding range mentioned above. 2 Any value obtained at intervals.

[0105] In some embodiments, if the anterior upper part 401a, the left side of the skull 401c, the right side of the skull 401d, the top of the skull 401b, and the posterior part of the skull 401e each contain corresponding electrode positions as shown in Figures 4(a)-4(e), the requirement for spatiotemporal average optical power density can be refined to the electrode site cluster, thereby accurately reflecting the fluctuation of the time-averaged optical power density of the electrode sites, especially at the boundaries of each part.

[0106] In some embodiments, when at least the upper anterior part of the skull, the left side of the skull, the right side of the skull, and the top of the skull are irradiated, the time-averaged optical power density at the electrode locations Fp1, Fpz, Fp2, AF3, AFz, AF4, F5, F3, F1, Fz, F2, F4, F6, FC1, FC2, FC3, FC4, FC5, FC6, C1, C2, C3, Cz, C4, C5, C6, CP1, CP2, CPz, CP3, CP4, P1, P2, and Pz is 50-90 mW / cm². 2 The time-averaged optical power density irradiated to electrode locations FCz, P3, P4, TP7, FT7, T7, FT8, T8, POz, P6, TP8, CP6, P5, CP5, F7, F8, AF7, and AF8 was 25-65 mW / cm². 2 .

[0107] In some embodiments, when irradiating the upper anterior part of the skull, the left side of the skull, the right side of the skull, the top of the skull, and the posterior part of the skull, the time-averaged optical power density irradiated to electrode positions P8, PO8, O1, O2, Oz, P7, and PO7 is 1 mW / cm². 2 Up to 30mW / cm 2 In other words, it can fluctuate within this range.

[0108] For a multi-zone balanced stimulation scheme, a headgear 100 with a loose-fitting headgear design as shown in Figure 1(b) can be used. In some embodiments, adjacent near-infrared irradiation units (such as LED beads) have a preset interval, and each near-infrared irradiation unit has a preset emission angle, such that when the object's head is positioned in the receiving space: near-infrared light is emitted from all points on the peripheral irradiation surface corresponding to the reference headgear portion of the object's head. The following is in conjunction with... Figures 7-9 Further description of the phototherapy device and its headgear 100, wherein the peripheral irradiation surface is implemented as the irradiation surface of the transparent inner shell 3, and the surface area of ​​the peripheral irradiation surface is 1200-1700 cm². 2 .

[0109] In some embodiments, a plurality of lamp panels 5 are mounted on the middle shell 2 via lamp panel fixing housings 9, the lamp panel fixing housings 9 being located on the side of the middle shell 2 closest to the outer shell 1. For example... Figure 8 As shown, in some embodiments, a lamp plate fixing shell 9 is provided inside the lamp plate receiving cavity 4. The lamp plate fixing shell 9 covers the middle shell 2 on the side near the outer shell 1. Multiple lamp plates 5 are arranged in layers from top to bottom along the lamp plate fixing shell 9, and the distance between two lamp plates 5 on the upper layer is greater than the distance between two adjacent lamp plates 5 on the lower layer, so as to ensure that different brain regions of the corresponding patients can achieve effective phototherapy. In some embodiments, the lamp plate density corresponding to the position of the patient's head is lower, while the lamp plates can be arranged more densely at other head positions other than the position of the patient's head, but this is only an example. Specifically, the inventors have creatively discovered that, especially in such Figures 7-9 In the head-mounted device 100 shown, a space of at least a few centimeters, or even close to 10 centimeters, is reserved on the top of the subject's head when the head is in place to reduce the pressure during phototherapy. However, the near-infrared light emitted by multiple LEDs can overlap on the surface of the subject's head after propagating through this gap, and the near-infrared beams emitted by each LED panel can also overlap on the surface of the subject's head after propagating through this gap, so that the light power density on the surface can be maintained at, for example, 80-120 mW / cm². 2The level of the near-infrared irradiation unit is as follows. Note that the multi-layered circumferential distribution of multiple lamp panels 5 is merely an example of an array of near-infrared irradiation units. The array of near-infrared irradiation units can also employ LEDs, laser diodes, or optical fibers transmitting near-infrared light from external sources, etc., which will not be elaborated upon here. In some embodiments, the array of near-infrared irradiation units can be specifically configured to emit near-infrared light with a duty cycle of 30%-70%, a wavelength of 650-1100 nm, and a frequency falling within the frequency range of alpha waves, the frequency range of gamma waves, or a neighborhood of both. A single near-infrared irradiation device constituting the near-infrared irradiation unit can be an LED with an average optical power of 90 mW or higher.

[0110] In other embodiments of this application, multiple light panels 5 can be directly disposed on the middle shell 2.

[0111] In some embodiments, such as Figure 8 As shown, the lamp panel fixing housing 9 is provided with six layers of lamp panels 5 at intervals, and the lamp panels 5 include at least one of the following configuration methods.

[0112] In one embodiment, in the first layer of light panels 10 closest to the top of the headgear, there is a first gap between two adjacent light panels. The length of the narrowest position a of the first gap ranges from 23mm to 26mm, and the length of the widest position b of the first gap ranges from 57mm to 60mm. Further, the length of the narrowest position a of the first gap ranges from 23.5mm to 25.5mm, and the length of the widest position b of the first gap ranges from 57.5mm to 59.5mm. Preferably, the length of the narrowest position a of the first gap is approximately 24mm, and the length of the widest position b of the first gap is approximately 59mm. Note that the reference to "approximately" or "approximately" in this application is intended to account for measurement errors.

[0113] In the second method, in the second layer light panel 11 adjacent to the first layer light panel 10, there is a second gap between adjacent light panels. The narrowest part of the second gap has a length ranging from 15mm to 18mm, and the widest part of the second gap has a length ranging from 41mm to 44mm. Further, the narrowest part of the second gap has a length ranging from 16mm to 17.5mm, and the widest part of the second gap has a length ranging from 41mm to 43mm. Preferably, the narrowest part of the second gap is approximately 16.7mm, and the widest part of the first gap is approximately 42.5mm.

[0114] In method three, in the third layer light panel 12 located below the second layer light panel 11, there is a third gap between adjacent light panels. The narrowest part of the third gap has a length ranging from 13mm to 16mm, and the widest part has a length ranging from 24mm to 27mm. Further, the narrowest part of the third gap has a length ranging from 13.5mm to 15.5mm, and the widest part has a length ranging from 24mm to 26mm. Preferably, the narrowest part of the third gap is approximately 14.2mm, and the widest part is approximately 25.3mm.

[0115] In method four, among the fourth, fifth, and sixth light panels 15 arranged sequentially from top to bottom below the third light panel 12, the fourth light panel 13 has a fourth gap between adjacent light panels. The narrowest part of the fourth gap ranges from 12mm to 15mm in length, and the widest part ranges from 19mm to 22mm in length. Further, the narrowest part of the fourth gap ranges from 13.5mm to 14.5mm in length, and the widest part ranges from 19.5mm to 21.5mm in length. Preferably, the narrowest part of the fourth gap is approximately 14mm in length, and the widest part is approximately 20.5mm in length.

[0116] In method five, a fifth gap exists between two adjacent light panels of the fifth layer light panel 14. The narrowest part of the fifth gap has a length ranging from 12mm to 15mm, and the widest part has a length ranging from 16mm to 19mm. Further, the narrowest part of the fifth gap has a length ranging from 13mm to 14.5mm, and the widest part has a length ranging from 16.5mm to 18.5mm. Preferably, the narrowest part of the fifth gap is approximately 13.8mm, and the widest part is approximately 18mm.

[0117] In method six, a sixth gap is formed between two adjacent light panels of the sixth layer light panel 15. The narrowest part of the sixth gap has a length ranging from 11mm to 14mm, and the widest part has a length ranging from 15mm to 18mm. Further, the narrowest part of the sixth gap has a length ranging from 12mm to 14mm, and the widest part has a length ranging from 15mm to 17mm. Preferably, the narrowest part of the sixth gap is approximately 13mm, and the widest part is approximately 16.2mm.

[0118] The above-mentioned structure can achieve dynamic and balanced overall temperature inside the headgear while illuminating the lamp panel 5 to achieve the phototherapy effect. The spacing of the lamp panels 5 and the setting between adjacent layers of the lamp panels 5 avoid concentrated heat dissipation of the lamp panels 5, prevent excessive local temperature inside the headgear, and save energy.

[0119] In optional embodiments, such as Figure 8 As shown, the gaps between adjacent lamp panels 5 in each layer have their narrowest and widest positions, respectively, with the width of the gap between adjacent lamp panels 5 on the upper layer being greater than the width of the gap between adjacent lamp panels 5 on the lower layer. This significantly reduces the possibility of excessively high local temperatures inside the phototherapy headgear caused by the dense arrangement of lamp panels 5, while ensuring the lamp panels 5 provide illumination for phototherapy. Furthermore, due to the structural design of the phototherapy headgear, the inner diameter of the accommodating space gradually increases from top to bottom. Therefore, the spacing between the first layer of lamp panels 10 and the second layer of lamp panels 11 is increased, ensuring uniform light power density while preventing heat dissipation from the lamp panels 5 from accumulating in the headgear, thus facilitating cooling. To achieve uniform light power density throughout the accommodating space, the optimal average light power of the first layer of lamp panels 10 and the second layer of lamp panels 11 can be between 75mW and 125mW, preferably 90-100mW.

[0120] like Figure 8 As shown, in some embodiments, the vertical spacing between the first lamp panel 10 and the second lamp panel 11 is 19mm to 25mm, preferably 19.5mm to 24.5mm. The vertical spacing between the second lamp panel 11 and the third lamp panel 12 is 14mm to 21mm, preferably 15mm to 20mm.

[0121] like Figure 8 As shown, in some embodiments, the vertical spacing between the remaining two adjacent light panels is 13mm to 19mm, preferably 14mm to 18mm. The vertical spacing between the two adjacent light panels is set so that the entire brain area can be irradiated, and the heat emitted by the light panel 5 can be prevented from accumulating in the accommodating space.

[0122] Therefore, the arrangement of the lamp panel 5 can illuminate the entire area of ​​the patient's head without affecting the normal progress of light therapy, and can also improve the comfort of the treatment process. The area of ​​the patient's head includes the temporal lobe, occipital lobe, frontal lobe and parietal lobe.

[0123] In addition, such as Figure 9 As shown, the lamp panel 5 is connected to the lamp panel fixing frame 17, and the lamp panel 5 is fixed to the lamp panel fixing shell 9 through the lamp panel fixing frame 17. In some embodiments, the spacing between adjacent lamp panel fixing frames 17 in each layer is similar to or the same as the spacing between the corresponding adjacent lamp panels 5.

[0124] Back Figure 7Referring to Figure 1(b), in some embodiments, the headgear has an annular connecting portion 18, with the bottoms of the outer shell 1 and the middle shell 2 respectively connected to the connecting portion 18. The connecting portion 18 has multiple ventilation openings 16 communicating with the lamp panel receiving cavity 4, and the area of ​​each ventilation opening 16 located at the rear end of the headgear is larger than the area of ​​each ventilation opening 16 located at the front end of the headgear. Further, the ventilation openings 16 can be elongated. This can increase the airflow entering from the rear end of the headgear, thereby improving the cooling effect of the lamp panel receiving cavity 4 and balancing the cooling effect at the back of the head and forehead. It can also reduce the heat transfer from the lamp panel receiving cavity 4 to the cold air cavity 6, thereby improving the cooling effect on the receiving space.

[0125] In some embodiments, the top of the headgear is provided with an exhaust vent, which communicates with the lamp panel receiving cavity 4 and is used to extract the hot air inside the lamp panel receiving cavity 4.

[0126] In some embodiments, a total of 80 lamp panels 5 are distributed inside the headgear. The size of the near-infrared light emission port of each lamp panel 5 is 28mm×28mm with a tolerance of ±0.2mm, and the lamp beads are arranged in a 3×3 array.

[0127] We conducted a series of clinical trials using a phototherapy device with this structure. As an example, the near-infrared irradiation unit array emits near-infrared light with a center wavelength of 810 nm, a duty cycle of 50%, and a frequency of 10 Hz; however, this is merely an example.

[0128] In some embodiments, near-infrared light may be emitted with a duty cycle of 30%-70%, a wavelength of 650-1100nm, and a frequency falling within the frequency range of alpha waves, the frequency range of gamma waves, or a neighborhood of both, which will not be elaborated here.

[0129] In some embodiments, the array of near-infrared irradiation units is specifically configured to irradiate the subject's head with at least 8260-42250 joules of energy over a continuous irradiation period of 5 minutes, as a unit dose. 8260 joules of energy irradiation over 5 minutes is equivalent to continuous irradiation of the head cover at a time-averaged power of 27.5 W, with a head cover surface area of ​​612.35 cm². 2 Based on calculations, the spatiotemporal average optical power density is 45 mW / cm². 2 A 5-minute irradiation of 42,250 joules of energy is equivalent to continuous irradiation of the scalp at an average time power of 140W, with a scalp surface area of ​​612.35 cm². 2 Based on calculations, the spatiotemporal average optical power density is 230 mW / cm². 2The inventors discovered in clinical trials that it is difficult for some patients with moderate to severe Alzheimer's disease (AD) to irradiate continuously for 10 to 30 minutes without interruption. Some AD patients have severe cognitive impairment and are uncooperative, while others frequently experience abnormalities in limb movement, such as muscle stiffness and flexion, muscle atrophy and weakness, and apraxia. Using 5-minute intervals as the unit dose means that every 5 minutes of irradiation has a certain degree of inhibitory effect on AD.

[0130] For example, the required energy dose to the subject's head within a one-hour timeframe, such as three unit doses (at least 24,800-126,800 joules), can be delivered in separate or continuous effective unit doses. The cumulative dose delivered in this way, compared to a continuous 15-minute cumulative dose, can achieve a comparable AD suppression effect. In actual treatment, even if the AD patient's condition or operational malfunction causes an interruption, the operator only needs to ensure the required cumulative irradiation time within the single timeframe is met. There is no need to restart the phototherapy equipment, reset the current irradiation dose, or forcibly interrupt the irradiation. Specifically, if the subject is cooperative and the treatment is progressing smoothly, continuous irradiation for 15 minutes can be performed. If the subject is uncooperative or the treatment is not progressing smoothly, for example, if the subject needs to use the restroom after 6 minutes, the treatment can be temporarily interrupted and resumed upon their return. The interruption time can be flexibly adjusted according to the subject's needs, as long as the required irradiation duration is achieved within one hour. This significantly reduces the difficulty of phototherapy for AD patients with severe cognitive impairment or motor abnormalities who are uncooperative, as well as for groups with varying degrees of AD severity (such as nursing home residents of different age groups), and even for caregivers with insufficient experience in caring for AD patients.

[0131] In some embodiments, the array of near-infrared irradiation units is specifically configured to irradiate the subject's head with at least 24,800 to 1,014,050 joules of energy per day as the daily cumulative dose. It can be seen that the daily cumulative dose can have a range of nearly 40 times, with a lower limit of 15 minutes of cumulative irradiation at a time-averaged irradiation power of 27.5 W and an upper limit of 2 hours of irradiation at a time-averaged irradiation power of 140 W. The inventors have discovered that, using the phototherapy device of this application, the daily cumulative dose can be adjusted over a wide range according to the subject's adaptability. Specifically, if the subject has high compliance with phototherapy and a good individual response, the array of near-infrared irradiation units is specifically configured to provide an accelerated daily cumulative dose by continuously irradiating for more than 30 minutes within a single hour, and this can be done up to four times per day. This accelerated daily cumulative dose is equivalent to several days' worth of the lower limit of the daily cumulative dose. If the subject needs to interrupt treatment for several days due to specific circumstances, the accelerated daily cumulative dose can be implemented first, thus increasing the flexibility and convenience of phototherapy. Furthermore, although the mechanism of action is not yet clear, the improvement in cognitive performance after administering an accelerated daily cumulative dose to individual volunteers was even better than the effect of administering the same cumulative dose over several days. In some embodiments, the weekly cumulative dose irradiated to the subject's head can be as low as 24,800 joules, and the irradiation time can be as short as 15 minutes.

[0132] In some embodiments, the array of near-infrared irradiation units is specifically configured to deliver at least 124,000 joules (27.5W - 15 minutes - 5 times) - 7,100,000 joules (230mw / cm²) at separate single-time cumulative doses over a week. 2 - 2 hours per day - 7 days) of energy irradiation is applied to the subject's head as a weekly cumulative dose. Specifically, the cumulative dose for a single period can be administered 1, 2, 3, 4, 5, 6, 7 or 8 times per week.

[0133] Specifically, the array of near-infrared irradiation units is configured such that the cumulative weekly dose is more than 8 times over 8 weeks, preferably more than 16 times over 16 weeks, as the cumulative dose for the treatment course.

[0134] In some embodiments, the interruption time between two treatment sessions shall not exceed half the duration of the treatment session in order to minimize the risk of a relapse in AD lesions caused by treatment interruption.

[0135] The applicant used the phototherapy device shown in Figure 1(a) and Figure 1(b) to conduct a clinical trial on the experimental group (i.e. the treatment group). The spatiotemporal average light power density of the phototherapy device at various parts of the reference head model of the subject's head and the time average light power density of the irradiation surface of the inner shell 3 corresponding to the center position of the lamp plate are shown in Table 2.

[0136] Table 2 Spatiotemporal average optical power density of the phototherapy device at various parts of the reference head model

[0137] The applicant conducted a clinical trial on the experimental group (i.e. the treatment group) using the operating parameters in Table 3 with the phototherapy equipment.

[0138] Table 3 Operating parameters of phototherapy equipment

[0139] In this clinical trial, the phototherapy device, with the subject's head positioned within the space created by the support structure, emitted near-infrared light that covered the upper anterior, top, left, right, and posterior parts of the skull, with an irradiated surface area ratio greater than 65%. This met the synergistic irradiation conditions of irradiated surface area ratio and irradiation power level, as shown in Tables 2 and 3. The average synergistic dose irradiated to the subject's head was approximately 3200 W*% to 4800 W*%, and the spatiotemporal average optical power density irradiated to the subject's head was 230 mW / cm². 2 the following.

[0140] The inclusion criteria for this clinical trial are as follows: (1) meeting the core criteria for probable Alzheimer's disease (AD) as defined by the National Institute on Aging-Alzheimer's Association (NIA-AA); (2) cranial MRI results (within 6 months) supporting a possible diagnosis of AD; (3) age between 50 and 85 years, regardless of gender; (4) MMSE score < 26 points, able to cooperate in completing the scale assessment; (5) patients are not currently taking medication. If they are taking psychotropic or cognitive-improving medications, the dosage must be stable for at least 12 weeks before the trial and remain unchanged during treatment.

[0141] Exclusion criteria: (1) Contraindications to MRI, such as metal implants or claustrophobia; (2) Other types of dementia or other mental or neurological disorders, such as depression or Parkinson's disease; (3) History of stroke or epilepsy; (4) Photosensitivity to sunlight or visible light, or increased skin sensitivity in the treatment area; (5) Severe visual or hearing impairment; (6) History of alcohol or drug addiction; (7) Any other condition that would make a person unsuitable to participate in this study.

[0142] Based on inclusion and exclusion criteria, a total of 27 patients were enrolled, with 13 in the experimental group and 14 in the control group. The treatment group received whole-head near-infrared light stimulation: wavelength 810 nm, frequency 10 Hz, with each participant receiving 30 minutes of treatment once daily, 6 days a week, for 4 months. The sham treatment group (control group) followed the same protocol as the near-infrared light therapy group, but used a sham treatment headgear. The light emitted by the sham treatment device was visually identical to that of the near-infrared treatment device, and it produced similar sounds and a warm sensation on the scalp during treatment. However, the light power was extremely weak and was largely absorbed by the tissue, failing to stimulate brain tissue. See [link to relevant documentation]. Figure 10 As shown.

[0143] The scale assessments were conducted at months 2 and 4 during treatment, and at months 6 and 8 after treatment ended. Figure 10 As shown. The assessors, participants, and their caregivers were unaware of the treatment allocation throughout the study, until its conclusion. Furthermore, the treatment allocation was not discussed by any personnel involved throughout the study. All participants believed they received genuine near-infrared therapy.

[0144] Ultimately, a total of 18 patients (9 in the treatment group and 9 in the control group) completed 4 months of treatment and 4 months of assessment. One patient only completed the MMSE scale assessment, failing to complete the ADAS-Cog scale. The ADAS-Cog scale consists of 12 items covering memory, orientation, language, use of language, and attention. It can assess the severity of cognitive symptoms in Alzheimer's disease (AD) and changes in treatment, and is commonly used to assess the efficacy of treatment for mild to moderate AD (an improvement of 4 points is usually considered the clinical criterion for significant drug efficacy). The MMSE scale is the most widely used cognitive screening scale both domestically and internationally, covering orientation, memory, attention, calculation, language, and visuospatial abilities. Studies on the MMSE have found that in professional institutions such as memory clinics or in community hospitals, the MMSE has a sensitivity and specificity of over 80% in distinguishing between normal elderly individuals and those with dementia, demonstrating significant value in dementia screening.

[0145] To investigate the sustainability of the therapeutic effect of near-infrared light on AD patients, follow-up visits were conducted after treatment. A total of 14 subjects completed the 8-month follow-up (4 months after the end of treatment, 8 in the treatment group and 6 in the control group).

[0146] Referring to Figures 11(a) and 11(b), it can be seen that after 2 months of phototherapy, the ADAS-cog scale scores of the subjects in the treatment group decreased by an average of 1.11 points from baseline. After 4 months of treatment, the decrease continued at a greater rate, with an average reduction of 6.04 points from baseline. The statistical significance within the group was p=0.034<0.05, both significantly better than the scores in the control group. In the 2 months following the end of treatment, the ADAS-cog scale scores of the treatment group fluctuated less, remaining at an average reduction of 5.59 points from baseline by the end of 2 months. The statistical significance within the group was p=0.009<0.05. At the follow-up visit 2 months after the end of treatment, the ADAS-cog scale scores of the treatment group even began to decline further, reaching an average reduction of 8.25 points from baseline by 4 months after the end of treatment. The statistical difference within the group was p=0.008<0.05. Based on the ADAS-cog scale score, the phototherapy device of this application achieved beneficial effects that have never been seen in other existing phototherapy devices in papers and related literature: within 4 months of phototherapy, the ADAS-cog scale score showed a greater slope of decline after the second month compared to the first two months; after the end of phototherapy, follow-up visits every 2 months revealed that the biochemical reaction caused by the irradiation energy of the near-infrared light delivered to the subject's head continued to trigger the inhibitory effect after the end of phototherapy, not only maintaining the inhibitory effect on AD to a certain extent, but also continuing to promote the inhibitory effect on AD, and no deterioration or regression of the ADAS-cog scale score occurred.

[0147] Referring to Figures 12(a) and 12(b), it can be seen that after 2 months of phototherapy, the subjects in the treatment group showed an average increase of 0.67 points in their MMSE scores from baseline. During the subsequent 2 months of phototherapy, the MMSE scores continued to increase with a greater slope, reaching an average increase of 2.78 points from baseline by 4 months of phototherapy, both significantly better than the control group (p=0.025<0.05). Both the ADAS-cog and MMSE scores showed similar improvement effects during the first and last 2 months of phototherapy: a greater slope of increase during the last 2 months. Furthermore, similar to the continued improvement in ADAS-cog scores after phototherapy, even after phototherapy was discontinued, the MMSE scores continued to rise for 2 months after the end of phototherapy, maintaining a similar upward slope as during phototherapy, reaching an average increase of 3.89 points from baseline by 2 months after the end of phototherapy (p=0.004<0.05). Four months after the phototherapy ended, the MMSE score in the treatment group remained comparable to the MMSE score obtained four months after phototherapy, without any regression. In other words, based on the MMSE score, the biochemical response caused by the near-infrared light irradiation energy delivered to the subject's head continued to trigger an inhibitory effect even after the phototherapy ended. This not only maintained the inhibitory effect on AD to a certain extent but also further enhanced the inhibitory effect on AD, without any regression in the ADAS-cog score.

[0148] The results of follow-up visits during and after phototherapy, combined with ADAS-Cog and MMSE scores, also confirmed the optimized "photocharging" and sustained benefit process of the phototherapy device mentioned above: the subject's brain had a larger "photocharging capacity," a deeper "photocharging depth," and a faster "photocharging speed." The scale scores improved significantly in the first two months and the last two months of phototherapy, and the improvement occurred at a stable slope without stagnation. The subsequent "endurance" and sustained benefits were better. The effect of phototherapy for two months was maintained for at least two months after the end of phototherapy, and even for more than four months after the end of phototherapy. Moreover, the biochemical reaction caused by "photocharging" continued to trigger inhibitory effects after the end of phototherapy and continued to promote the inhibitory effect on AD without deterioration or regression.

[0149] Furthermore, four months after receiving near-infrared light therapy, resting-state functional magnetic resonance imaging (fMRI) of the treatment group showed enhanced ALFF in multiple brain regions of the frontal, occipital, and temporal lobes (P<0.05), indicating increased neuronal excitability and spontaneous activity, providing neuroimaging evidence for the corresponding improvement in cognitive function. Meanwhile, no adverse events related to the experimental device were observed in this trial.

[0150] Although phototherapy lasted for 4 months in this clinical trial, it demonstrated deep regulation and sustained, even cumulative, benefits. With continued use for longer periods, such as 6 months, 8 months, 10 months, ... more than 1 year, or even year-round use, the benefits are expected to continue to increase, showing a more significant disease-modifying effect.

[0151] Furthermore, although exemplary embodiments have been described herein, their scope includes any and all embodiments based on this disclosure that have equivalent elements, modifications, omissions, combinations (e.g., schemes involving intersections of various embodiments), adaptations, or alterations. Elements in the claims will be interpreted broadly based on the language used in the claims and are not limited to the examples described in this specification or during the implementation of this application, and such examples will be interpreted as non-exclusive. Therefore, this specification and examples are intended to be considered illustrative only, and the true scope and spirit are indicated by the following claims and the full scope of their equivalents.

[0152] The above description is intended to be illustrative and not restrictive. For example, the above examples (or one or more of them) can be used in combination with each other. Other embodiments can be used by those skilled in the art when reading the above description. Furthermore, in the above detailed description, various features may be grouped together to simplify the disclosure. This should not be construed as an intention that a feature of the disclosure that is not claimed is necessary for any claim. Rather, the subject matter of this disclosure may be less than all the features of a particular disclosed embodiment. Thus, the following claims are incorporated herein by reference as examples or embodiments, wherein each claim is an independent, separate embodiment, and these embodiments are contemplated to be combined with each other in various combinations or arrangements. The scope of this disclosure should be determined by reference to the appended claims and the full scope of their equivalents.

[0153] The above embodiments are merely exemplary embodiments of this disclosure and are not intended to limit this disclosure. The scope of protection of this disclosure is defined by the claims. Those skilled in the art can make various modifications or equivalent substitutions to this disclosure within its substance and scope, and such modifications or equivalent substitutions should also be considered to fall within the scope of protection of this disclosure.

Claims

1. A method for validating a phototherapy device for treating Alzheimer's disease and related conditions, characterized in that, Using the aforementioned phototherapy device, the intended implementation scheme is executed on a reference head model of the treatment population, testing the attenuation and transmission of the emitted near-infrared light relative to the reference head model, and verifying whether the phototherapy device meets the required synergistic irradiation conditions.

2. The verification method according to claim 1, characterized in that, It also includes designing phototherapy equipment and using a reference head model of the patient population to simulate the attenuation and transmission of near-infrared light in the design of the phototherapy equipment, in order to verify whether the designed phototherapy equipment can meet the required synergistic irradiation conditions under the intended implementation scheme.

3. The verification method according to claim 2, characterized in that, Also includes: If the designed phototherapy device does not meet the required synergistic irradiation conditions under the intended implementation scheme, the design of the phototherapy device structure shall be adjusted accordingly.

4. The verification method according to claim 3, characterized in that, The adjusted structure of the phototherapy equipment includes the three-dimensional spatial arrangement of the near-infrared light irradiation units of the phototherapy equipment.

5. The verification method according to claim 1, characterized in that, The reference head mold for the treatment population is marked with the electrode positions of the 10-10 international standard lead system.

6. The verification method according to claim 1, characterized in that, The baseline head model of the treatment population is divided into the upper anterior part of the skull, the top of the skull, the left side of the skull, the right side of the skull, and the posterior part of the skull.

7. The verification method according to claim 6, characterized in that, Also includes: By employing flexible combinations of the anterior upper part of the skull, the top of the skull, the left side of the skull, the right side of the skull, and the posterior part of the skull, multiple representative irradiation surface area ratios are obtained, thereby enabling the simulation and verification of localized concentrated stimulation schemes or multi-zone balanced stimulation schemes.

8. The verification method according to claim 1, characterized in that, The reference head mold for the patient population has specific structural parameters of the patient population's head.

9. The verification method according to claim 8, characterized in that, The specific structural parameters of the head include head width, head length, head circumference, sagittal arc of the head, intertragus arc, morphological surface length, and head height. Optionally, it also includes the head and face index.

10. The verification method according to claim 8, characterized in that, The specific structural parameters of the baseline head model of the therapeutic population are associated with the age group, sex, and ethnicity of the therapeutic population.

11. The verification method according to claim 8, characterized in that, The parameters of the baseline head model for East Asian populations over 60 years of age are: head width 140-166 mm, head length 170-196 mm, head circumference 525-583 mm, morphological face length 104-130 mm, sagittal arc 304-372 mm, intertragus arc 320-375 mm, and head height 206-253 mm.

12. The verification method according to claim 8, characterized in that, The test of the attenuation and transmission of the emitted near-infrared light relative to the reference head model specifically includes: measuring the spatiotemporal average optical power density of the emitted near-infrared light at various parts of the reference head model.

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