JP7689375B2 - Forgetfulness treatment device - Google Patents

Description

The present invention aims to provide an instrument for treating MCI non-invasively and safely in the technical field of 40 Hz therapy for the prevention, alleviation, and treatment of dementia.

Strategies for developing therapeutic drugs for Alzheimer's disease (AD) can be broadly divided into three categories: disease modification therapy, which inhibits the progression of pathological changes; symptomatic therapy, which improves symptoms; and neuro-regeneration therapy, which repairs damaged nerve cells and promotes their regeneration (Non-Patent Document 1). However, even now, traditional medicines using biochemical substances have not yet achieved a treatment that is safe, effective, and sufficiently low-cost for patients.

Until now, it has been said that there is "no fundamental cure" for dementia in the elderly, but recently, by adding the perspectives of electrical, information, and systems engineering, progress has been made in elucidating the mechanisms of the disorder, and there have been an increasing number of successful clinical trials in which digital medicine has been applied clinically. In particular, it is known that if appropriate treatment measures can be administered at the MCI stage, before the onset of dementia and when it is not interfering with daily life, the effectiveness of treatment can be greatly improved.

Below, we will list the background technologies of digital medicine from a systems engineering perspective, with the aim of applying digital medicine treatments for AD that have been confirmed to be effective to the treatment of mild cognitive impairment (MCI), a precursor to dementia.

(1) System and control perspective The human body can function normally only as long as the brain, nerves throughout the body, and the complex control system distributed throughout the body like a chemical plant are functioning properly. In particular, since the human body is not a product developed or manufactured based on blueprints designed by humans, the only way to perfect repair methods is through trial and error experiments and analysis of the object that already exists (the human body). This is nothing other than the perspective of reverse engineering based on the academic field of cybernetics.

(2) System theory for identifying fault locations in neurological disorders in the cerebrum Non-patent literature 2 is a paper that proposes the integrated triple network model as a powerful paradigm that links large-scale brain networks with psychopathology. Advances in methodology in this field are promoting new ways of thinking about brain connectivity disorders such as autism, schizophrenia, and dementia. This theory integrates the brain into three large-scale networks and shows functional disorders such as cognition that occur like connectivity disorders in communication systems. The three large-scale networks are the default mode network (DMN), which controls past memories and circular thoughts related to the future and self and others, the central executive network (CEN), which attempts to solve problems in a straight line while referring to perceptions (including emotions) in the here and now, and the salience network (SN), which notices changes in the situation and switches to operate only one of the DMN and CEN.

(3) Connectivity of different brain regions and cognitive function Non-Patent Document 3 is an important study that showed that when stimulating different brain regions, cognitive impairment can be improved or, conversely, induced by adjusting the phase angle (same relative to opposite phase) of the stimulation. There is a cross-frequency coupling called "phase amplitude coupling (PAC) between theta wave frequency (4-8 Hz) and gamma wave frequency (25 Hz or more)" between the prefrontal cortex and the temporal region, and in elderly people with working memory defects, theta-gamma PAC in the temporal region and theta phase synchronization between the prefrontal cortex and the temporal region are impaired. In addition, the results of an experiment in which working memory impairment was rapidly induced in young adult subjects using alternating current electrical stimulation (tACS, transcranial alternate current stimulation) designed to desynchronize cortical interactions between the frontotemporal regions are presented.
This phenomenon suggests that when multiple phase-synchronized stimuli are applied to multiple locations in the brain, the therapeutic effect (and side effects) may differ depending on the phase difference setting, and so requires caution.

(4) "Perception Therapy Device 20" as a type of 40Hz therapy
In Non-Patent Document 4 published in 2016, it was revealed that when 40 Hz brainwaves are augmented by 40 Hz stimulation of the brain nerves, the immune cell microglia phagocytose and reduce amyloid beta and tau protein, which are causative substances of Alzheimer's disease (AD). As a result of this research, the basis of "40 Hz therapy" (Patent Document 1) as a digital medicine that functions as a disease modification therapy to suppress the progression of pathological changes in Alzheimer's disease has become public knowledge.
This revolutionary "40 Hz therapy" is not only being studied in the form of a sensory therapy device 20 that uses the phenomena of SSVEP and ASSR to induce brain waves of approximately 40 Hz through visual and auditory stimulation of light and sound, but also in the form of a PBM therapy device 10 that uses photobiomodulation (PBM) to irradiate near-infrared light of approximately 40 Hz from the nasal cavity, and clinical research is being actively conducted to apply it to magnetic stimulation therapy (TMS, rTMS) that applies stimulation of approximately 40 Hz to the head.

(5) Sensory therapy device 20 using light source 170
According to a report of a 2021 Phase II clinical trial (Non-Patent Document 5, Non-Patent Document 6) of a sensory therapy device 20 using a light source 170, brain waves were induced using a 2-foot square LED light-emitting panel installed 5 feet away from the subject as the light source 170 to have the subject focus on 40 Hz light and sound and not observe the surroundings, and as a result, a statistically significant therapeutic effect was obtained for "associative memory of faces and names" related to the default mode network (DMN). However, no therapeutic effect was reported related to the central executive network (CEN) and the salience network (SN).

The article also states that, because subjects tended to become sleepy during the clinical trial, a monitor screen was installed in the center of a two-foot square LED panel to entertain the subjects and prevent them from falling asleep. It also states that the quality of the subjects' sleep improved during the clinical trial, which had a favorable effect on dementia treatment.

(6) Sensory therapy device 20 using LCD elements
Between 2019 and 2020, applications were filed in Japan and the United States at roughly the same time for a 40 Hz therapy treatment device (U.S. Patent Publication 2, Japanese Patent Publication 3) that uses liquid crystal (LCD) elements to flicker ambient light at approximately 40 Hz to provide visual stimulation through light.
In a conventional treatment device (Patent Document 1) that requires the patient to gaze at a light-emitting body 170, problems arose such as the inability to use non-pharmacological therapies such as exercise therapy and cognitive therapy in combination with 40 Hz therapy because the patient could not freely observe the surrounding environment. To solve these problems, an improvement was made so that the subject can freely observe the surrounding environment through sunglasses (hereinafter abbreviated as LCD sunglasses 180) with LCD elements that blink at approximately 40 Hz built into the lens part.

To stimulate the sense of hearing with a sound of about 40 Hz that is phase-synchronized with the LCD sunglasses 180, audio equipment such as earphones, headphones, or speakers is used as a treatment tool. This is similar to Patent Document 1 and the like.
In addition, the sensory therapy device 20 using the LCD sunglasses 180 also has the effect of the mechanism of action of 40 Hz therapy as a disease modifying therapy that suppresses the progression of pathological changes in Alzheimer's disease, since 40 Hz brain waves are enhanced by 40 Hz stimulation of the cranial nerves.

In the following, whether the light-emitting body 170 is used as a therapeutic device for visual stimulation by light or the LCD sunglasses 180 are used, these will be collectively referred to as the "sensory therapy device 20."

<Note 1: Expressed as 40 Hz or approximately 40 Hz>
Even when the notation "40 Hz" is used for the frequency to which 40 Hz therapy is applied, the numerical value of the repetition frequency of the stimulation used in the treatment does not necessarily have to be exactly 40.0 Hz, and a frequency value of about 40 Hz may be applied within the range in which the mechanism of action of the disease modifying therapy that suppresses the progression of pathological changes in Alzheimer's disease in Patent Document 1 and Non-Patent Document 4 functions. When it is desired to express this meaning explicitly, the notation "approximately 40 Hz" may be used instead of "40 Hz," but this essentially has the same meaning.

<Note 2: The expressions "blinking" or "flickering">
In the text of this invention, the expressions "blinking" and "flickering" are used, but "blinking" is mainly used in the context of operating a light source in two stages, on/off, with a square wave as in Patent Document 1, and "flickering" tends to be mainly used in the context of making the light beam brighter/dimmer in multiple stages with a waveform other than a square wave (e.g., a sine wave) as in Patent Document 3. However, from the viewpoint of exerting the mechanism of action of 40 Hz therapy, both have substantially the same meaning in the present invention.

(7) SSVEP and ASSR
Regardless of whether the source of the 40 Hz light is the light emitter 170 or the LCD sunglasses 180, the technique of inducing brain waves with light and sound stimuli is called SSVEP (Steady State Visual Evoked Potential) and ASSR (Auditory Steady State Response), with SSVEP detected by electrodes of an electroencephalograph (EEG) placed on the occipital region and ASSR detected by electrodes of an electroencephalograph (EEG) placed on the forehead and parietal region (Non-Patent Document 7).
In other words, since the sensory therapy device 20 forcibly generates 40 Hz brain waves in two different parts of the brain that correspond to light and sound, respectively, the appropriateness of the setting of the phase difference between the two types of stimuli, light and sound, may affect the therapeutic effect (or side effects) of the 40 Hz therapy. This point must be taken into consideration.

(8) Photobiomodulation (PBM) Therapy Photobiomodulation is a technology that utilizes the phenomenon in which light aids in energy production processes such as cellular mitochondria and positively influences cellular metabolism, resulting in clinical benefits such as cell regeneration, faster wound healing, pain relief, and improved function.

Photobiomodulation has the following characteristics: if the energy density of the irradiated light is too high, cells are damaged; if the energy density is moderate, cell activity is suppressed; and if the energy density is weak but sufficient, cells regenerate. In other words, the three levels of light energy density produce significantly different effects, and the light energy density that is appropriate for the effect varies greatly depending on the type of cell.

Patent Document 4 describes an existing PBM therapy device 10 that irradiates light from above the scalp through the skull to the cerebral cortex, and further irradiates light from inside the nasal cavity through the skull under the cerebrum to the back of the forehead. This utilizes photobiomodulation technology to exert the effects of neuro-regeneration therapy, which repairs and promotes regeneration of nerve cells damaged by dementia, while also being able to use 40 Hz therapy, which flashes light stimuli at approximately 40 Hz when irradiating near-infrared light, and is therefore expected to serve as a treatment that also doubles as disease-modifying therapy.

Non-Patent Document 8, published in 2015, proposes irradiating the substantia nigra, located deeper than the hippocampus, with near-infrared (wavelength 808 nm) laser light from the oral cavity or ventricles, with the aim of treating Parkinson's disease with photobiomodulation.
In this paper, the light transmittance of each human tissue, which is the basis for the amount of energy to be irradiated, was calculated by anatomical methods of dead human tissue samples and computer simulation of the light path that would absorb the least amount of energy. In addition to the method of invasively implanting a light source in the ventricle of a monkey, the paper also proposes a method of placing a laser light source in the oral cavity, in which a light source with a high optical output is water-cooled and the light is irradiated to the target area using an endoscope.

It has been stated that experiments with mice have shown that an energy density of 1 to 15 mW/cm2 is required to reach the substantia nigra compacta, and that, by calculating backwards from the light transmittance of the simulation results, the light energy to be irradiated from the oral cavity towards the substantia nigra compacta is required to be 1 watt per square centimeter (i.e., 1000 mW/cm2).

Although this paper provides the idea of "directly irradiating the hippocampus through the mouth," it should be noted that it is not practical as an idea for treating live human subjects, since it is dangerous to shine such a powerful laser light through the mouth of a living human patient toward the brain.
In other words, this document does not indicate that "the idea of directly irradiating the hippocampus from the mouth is practical," but rather that "directly irradiating the hippocampus from the mouth requires a dangerous level of light energy of 1 watt per square centimeter, and therefore the method of irradiating the hippocampus from the mouth is dangerous and should be avoided."
By the way, Patent Document 4 from 2020 uses light irradiation from the nasal cavity, and does not use direct irradiation from the oral cavity to the hippocampus.

On the other hand, the inventor of the 2021 PBM therapy device 10 (Patent Document 5) actually used a highly directional LED element to irradiate near-infrared light with a strong light energy density similar to that of PBM, which irradiates the cerebral cortex from above the scalp through the skull, through the oral cavity, passing through the sphenoid bone (the skull bone located under the cerebrum), and toward the hippocampus deep in the brain.
In this experiment, the light was irradiated into the oral cavity of a patient (the inventor himself was the subject) for approximately 20 minutes. As a result, symptoms of amnesic MCI (memory loss) were seen to improve rapidly and significantly after light irradiation.
However, a subsequent MRI scan revealed a very slight white shadow in the cells around the target point of irradiation. Although the causal relationship was unclear, the inventors pointed out that a key issue going forward would be to find a level of energy density that could be irradiated while ensuring safety, and have since discontinued the experiment.

(9) Brain areas where MCI lesions are observed According to Non-Patent Document 9, MCI is classified into "amnestic MCI (aMCI)" accompanied by memory disorders such as forgetfulness, and "non-amnestic MCI" without forgetfulness, and 848 out of 917 MCI patients had amnestic MCI. Furthermore, the affected areas of MCI are mainly in the left and right amygdala and hippocampus, and also spread to the left temporal pole and thalamus, and the left and right precuneus. Among them, amnesic MCI revealed a decrease in gray matter and a decline in cognitive function in the amygdala, hippocampus, and thalamus. In addition, it is said that the limbic thalamus is strongly involved in AD.
In summary, the main lesions of MCI are located in the left and right temporal regions and deep in the brain, and can also spread to other areas.

(10) Appropriate light energy density in PBM According to Non-Patent Document 10, it is known that the energy density of light to be irradiated in PBM can produce contradictory results depending on the wavelength of light, pulse mode, treatment period, etc., and some researchers recommend less than 100 mW/cm2 or five times that. In particular, it shows different trends depending on whether the target cells have a large or small number of mitochondria. It also states that "research cases in which the effect is poor in cells with high mitochondrial activity seem to be due to overdosing rather than underdosing."
In summary, this document lists cases in which the appropriate light energy density for each target tissue cell varies by orders of magnitude, from 1800 mW/cm2 down to less than 1 mW/cm2.
In other words, "the appropriate light energy density required to achieve the desired effect cannot be determined without actually conducting experiments in which light energy is irradiated to each targeted cell."
<Notes>
In the present invention, the name of the physical quantity described in the unit "power (mW) per unit area (cm2)" of the light beam 40 irradiated from the treatment device, i.e., "mW/cm2", is expressed as "energy density".
In terms of using the original physical terminology correctly, it should be expressed as "luminous flux power density." However, in order to prevent the description in the specification from becoming even more difficult to understand, the terminology has been unified by using a simpler term (light energy density 140) that is intuitively easy to understand.

Special table 2019-502429 publication US-A1-2020/0108270 publication JP 2022-002674 A Special Publication No. 2020-534042 JP 2021-100727 A

Nemoto, "Future anti-dementia drugs and fundamental dementia treatments awaiting future development", MEDICINAL, 2012/5 Vol. 2, No. 5, pp. 120- Vinod Menon. , “Large-scale brain networks and psychopathology: a unifying triple network model”, Trends Cogn Sci. 2011 Oct;15(10):483-506 Robert M. G. Reinhart et al., “Working memory revived in older adults by synchronizing rhythmic brain circuits”, Nature Neuroscience volume 22, pages820-827 (2019) Hannah F. Iaccarino, Li-Huei Tsai et al., “Gamma frequency entrainment attenuates amyloid load and modifications microglia” , Nature. 2016 Dec 7;540(7632):230-235. Diane Chan et al., “40Hz sensory stimulation induces gamma entrainment and effects brain structure, sleep and cognition.” in patients with Alzheimer’s disease”, MedRxiv, Posted March 03, 2021. Diane Chan et al., “4Gamma Frequency Sensory Stimulation in Probable Mild Alzheimer’s Dementia Patients: Results of a Preliminary Clinical Trial”, MedRxiv, Posted May 17, 2021. Rafal Kus et al., “Integrated trimodal SSEP experimental setup for visual, auditory and tactile stimulation”, J Neural Eng. 2017 Dec; 14(6) A. Pitzschke et al., “Red and NIR light dosimetry in the human deep brain”, Phys Med Biol. 2015 Apr 7;60(7):2921-37. Thomas Nickl-Jockschat et al., “Neuroanatomic changes and their association with cognitive decline in mild cognition.” “impairment: a meta-analysis”, Brain Struct Funct. 2012 Jan; 217(1): 115-25 Randa Zein et al., “Review of light parameters and photobiomodulation efficiency: dive into complexity”, J Biomed Opt. 2018 Dec;23(12):1-17

There are two problems that this invention aims to solve.

(1) First problem (insufficient therapeutic effect of conventional methods)
The main lesions of MCI are mainly located in the left and right temporal lobes and deep brain regions, so it is important to have a therapeutic effect on these two regions. In addition, the quality of the coordination of cognitive functions in each region of the brain (i.e., functional connectivity) can be estimated by using electroencephalography coherence (phase synchronization) as a guide.

According to a clinical trial report of the conventional "perceptual therapy device 20 using the light source 170," it was reported that the coherence of 40 Hz brainwaves increased in many of the brainwave electrodes placed on the scalp, but detailed information was not made public. In addition, the presence or absence of an increase in coherence in the deep brain was also not disclosed.
Furthermore, in tests conducted after the clinical trial to evaluate the improvement of the subjects' cognitive abilities, many evaluation items showed that the treatment had less effect than initially expected.
This suggests that there may be some areas of the brain where the therapeutic effect of the conventional sensory therapy device 20 is insufficient.

The inventor also conducted a follow-up test using the conventional "sensory therapy device 20 using LCD sunglasses 180", but in the case of MCI patients, the EEG electrodes where an increase in coherence was observed were only about 50% to about 70% of the entire scalp, mainly including the frontal, parietal and occipital regions, and there was particularly noticeable instability in the increase in coherence in the left and right temporal regions. The coherence in the deeper brain is unknown as the inventor does not have the means to verify it.

In short, although coherence increases relatively stably in the frontal, parietal, and occipital regions, where stimulation of approximately 40 Hz can be applied using the conventional sensory therapy device 20, there is no certainty that coherence increases stably in the temporal and deep brain regions, where stimulation of approximately 40 Hz cannot be applied.
In other words, since stimulation of approximately 40 Hz is not applied to the left and right temporal regions and deep brain, "the conventional sensory therapy device 20 alone may not be effective enough in treating MCI."

(2) The second issue (ensuring safety when using stimulation methods together)
If the stimulation of approximately 40 Hz is insufficient with the conventional sensory therapy device 20, it may seem that the problem can be easily solved by simply using the PBM therapy device 10, which utilizes photobiomodulation technology, in combination with the device to irradiate light energy of approximately 40 Hz to reinforce the stimulation.

However, when different stimuli are applied to multiple brain sites, it is known that cognitive impairment can be improved if the phase difference between the stimuli is set appropriately, whereas cognitive impairment can be induced if the phase difference value is inappropriate (Non-Patent Document 3). Therefore, care must be taken to properly manage the phase difference between multiple stimuli.

In the inventor's own experience, when experimenting with the sensory therapy device 20, the inventor was overcome by an extremely intense feeling of sleepiness and a slight headache, to the point of feeling in danger, when the phase difference between two phase-synchronized stimuli, light and sound, was set to +90 degrees. It is true that the setting of the phase difference between the phase synchronization of multiple stimuli can have a significant effect on the therapeutic effect (or side effects).

In other words, when the sensory therapy device 20 and the PBM therapy device 10 are used in combination (i.e., simultaneously) to provide multiple types of stimulation and forcibly generate brain waves in different parts of the brain, phenomena such as brain waves interference, cancellation, or synchronization problems may occur in many parts of the brain, which may affect the functional connectivity and cognitive functions in the brain.
Therefore, when using multiple types of stimulation in combination, it is dangerous if sufficient care is not taken in managing the phase difference in the waveforms of stimulations that are generated repeatedly at about 40 Hz by the sensory therapy device 20 or the PBM therapy device 10.

Furthermore, if multiple therapeutic devices, such as the sensory therapy device 20 and the PBM therapy device 10, are used simultaneously as stimulation means without phase synchronization, a dangerous situation will occur in which the phase difference between the multiple stimuli will continue to fluctuate uncontrollably between 0 degrees and ±180 degrees over time due to slight frequency errors between the multiple stimuli, which are repeated at a frequency of around 40 Hz.

(1) Solution to the first problem (insufficient therapeutic effect of conventional methods)
In order to solve the problem that "the conventional sensory therapy device 20 alone may not be effective enough in treating MCI," it is sufficient to additionally provide a PBM therapy device 10 that provides new stimulation to the deep brain and the left and right temporal regions, and to combine and phase-synchronize these multiple stimulation means at a common frequency of approximately 40 Hz to reinforce the stimulation to the brain.

For deep brain regions, light may be irradiated from the oral cavity to the hippocampus over the shortest possible distance, as described in Patent Document 5. For this purpose, the first priority is to find an appropriate upper limit for the light energy density.
In addition, a PBM therapy device 10 can be realized that can stimulate the hippocampus, left and right amygdala, thalamus, and the like, as well as the back side of the temporal region (i.e., the deep brain side) at approximately 40 Hz.

In addition, for the left and right temporal regions, the conventional BM therapy device 10, which stimulates the scalp from above with light energy, can be improved so that it can be used in combination with a sensory therapy device 20 and a PBM therapy device 10, which stimulates the deep brain, thereby reinforcing the approximately 40 Hz stimulation that is lacking in the left and right temporal regions.

In the present invention, in order to grasp the light energy density appropriate for the BM therapy device 10, the inventor himself conducted an experiment as a subject to find a value that would provide therapeutic effects. Furthermore, a therapeutic device with a simple structure that can be used by MCI patients without any hindrance to daily life has been realized. The specific contents will be described in detail in Example 1 below.
In addition, a treatment device with a simple structure for illuminating the left and right temporal regions and the deep brain was also realized. The "back side of the temporal region (deep brain side) and the deep brain region" will be described in detail in Example 2, and the "front side of the temporal region (scalp side)" will be described in detail in Example 3.

(2) Solution to the second problem (ensuring safety when using stimulation methods together)
As already mentioned, the brain regions to which stimulation is applied are different between the conventional sensory therapy device 20 and the PBM therapy device 10 of the present invention. In addition, when using a combination of stimulation means in multiple therapeutic devices, a safety measure is required to set the phase difference between multiple stimuli to an appropriate value.

Therefore, in order to safely manage the phase difference of the stimulation between each brain region, a phase control device 150 is provided that comprehensively controls the phase difference of each stimulation.
Furthermore, the conventional sensory therapy device 20 and the PBM therapy device 10 of the present invention are provided with a function of a separate excitation operation 100 capable of controlling the phase difference between a plurality of types of stimuli with an external synchronization signal 130. The details of this phase control device 150 will be described in detail in the fourth embodiment.

The combination of LCD sunglasses 180 and headphones 164 as a conventional sensory therapy device 20 was able to alleviate mild symptoms of "brain fog" within an hour. However, it was not very effective in treating symptoms of "memory loss" caused by MCI deep in the brain.

When the PBM therapy device 10 disclosed in Examples 1, 2, and 3 of the present invention is used, it is possible to alleviate mild symptoms of "forgetfulness" within one hour, which could not be improved by conventional techniques.

In Example 4, by using the sensory therapy device 20 and the PBM therapy device 10 in combination, it became possible to reduce the symptoms of mild forgetfulness and brain fog that occurred simultaneously within one hour.

However, in severe cases where MCI has progressed to the point where patients are experiencing both severe forgetfulness and severe brain fog, the above-mentioned treatment within one hour may not be able to alleviate symptoms.

In such cases, it is advisable to apply the treatment device of the present invention as a continuous treatment method, for example, one hour of treatment every day for three months, with the dosage and administration method based on clinical trials conducted by a medical institution. Alternatively, it is advisable to use the device in combination with exercise therapy or cognitive therapy, or to use the device in combination with appropriate medicines if available, and to carry out treatment based on the guidance of a doctor.

In other words, the present invention makes it possible to treat MCI from mild to severe, or by using appropriate treatment devices alone or in combination depending on symptoms such as forgetfulness and brain fog.

The area where brainwaves are generated by the sensory therapy device 20 and the area affected by MCI An example of a sensory therapy device 20 that uses light and sound stimulation at approximately 40 Hz (Example 1) LED lance with 40 Hz light source for unidirectional irradiation in the oral cavity (Example 2) LED mouthpiece with 40 Hz light source that irradiates in multiple directions inside the mouth (Example 3) LED pad for optical stimulation of the temporal region from the scalp side (Example 4) General explanation regarding phase synchronization (Example 4) Phase control device for controlling multiple stimulus sources Supplementary explanation for Example 2 and Example 4 (Embodiment 4) Modification of Phase Control Device (Example 4) Self-excited operation and externally excited operation

(1) Effect of the Sensory Therapy Device 20 on the Area Affected by MCI FIG. 1 shows the area where electroencephalograms are generated by the sensory therapy device 20 and the area affected by MCI.
In the figure, (L) indicates the area at the back of the head where stimulation with 40 Hz light generates 40 Hz brain waves, and (S) indicates the wide area from the forehead to the parietal region where stimulation with 40 Hz sound generates 40 Hz brain waves.
Furthermore, among the main affected areas of MCI, the areas deep in the brain, including the hippocampus, amygdala, and thalamus, are shown in (A), and the areas including the temporal pole of the temporal region are shown in black in (B).

Note that MCI can occur in areas other than (A) and (B) where functional connectivity is reduced due to aftereffects of cerebral infarction, and some patients experience only brain fog without forgetfulness caused by damage or atrophy of the hippocampus. In such cases, stimulating a wide area from the front to the back of the head with the sensory therapy device 20 can improve mild brain fog symptoms.

According to the report of the second phase clinical trial of the treatment device for AD (Non-Patent Document 5, Non-Patent Document 6), the "increase in amplitude" of 40Hz EEG was confirmed not only in the frontal and parietal regions (S) and the occipital region (L) but also in the temporal scalp EEG electrodes and the EEG electrodes embedded deep in the brain by the light and sound stimulation of 40Hz. As a result, it is described that the mechanism of action of immune cell microglia phagocytosing the causative substances of Alzheimer's disease (amyloid beta and tau protein) by the 40Hz EEG extends to the entire brain.
In a follow-up test conducted by the inventor using LCD sunglasses 180 and earphones, etc., an "increase in amplitude" of 40 Hz EEG was confirmed in all of the EEG electrodes placed across the scalp, indicating that the therapy functions as a "disease-modifying therapy" that prevents AD through a similar mechanism of action.

On the other hand, from the perspective of improving cognitive impairment caused by reduced functional connectivity in large-scale brain networks, it is important that the 40-Hz EEG not only has an "increase in amplitude" but also an "increase in coherence" in response to phase-synchronized 40-Hz light and sound stimuli.
Therapies that increase coherence and eliminate the symptoms of cognitive impairment due to large-scale network connectivity disorders could serve as “symptomatic therapies” to improve the symptoms of MCI.

However, according to the reports of the phase 2 clinical trial (Non-Patent Document 5, Non-Patent Document 6), detailed data on the inter-electrode coherence of EEG signals measured at the scalp was not made public, and it was only stated that coherence had increased. Furthermore, no data on coherence deep in the brain was made public.

The inventor of the present invention conducted a follow-up test using himself as a subject, a multi-channel digital electroencephalograph OpenBCI (registered trademark) for research, and phase-synchronized 40 Hz light and sound stimulation. As a result, increased coherence was observed in approximately 50% to 70% of all electrode combinations.

Specifically, for EEG electrodes placed on the frontal, parietal, and occipital regions, which are surrounded by the (S) and (L) points where brain waves induced by light and sound stimuli are generated, an increase in coherence was observed between almost all electrodes. However, for the left and right temporal regions, the increase was about 50%, and the observed regions were constantly fluctuating and unstable.
Although the inventors do not have the means to measure electroencephalograms in the deep brain, the deep brain is similar to the left and right temporal lobes in the sense that it is not surrounded by brain regions such as (S) and (L) where electroencephalograms are induced and generated, and it is highly likely that the increased coherence in the deep brain is also unstable.

To briefly summarize the above explanation, an analysis of the EEG data from the sensory therapy device 20 reveals the problem that the increase in coherence of 40 Hz EEG for treating MCI may be insufficient in the deep brain and temporal lobe.

(2) MCI symptoms that can be eliminated with 40 Hz light and sound stimulation and MCI symptoms that cannot be eliminated The inventor developed LCD sunglasses 180 (Patent Document 3) for the purpose of eliminating brain fog caused by aftereffects of a cerebral infarction in the cerebral cortex that the inventor suffered in 2018, and succeeded in non-invasively eliminating mild brain fog symptoms known as “non-amnesic MCI” within 30 minutes using this sensory therapy device 20.
However, after he began to show mild symptoms of forgetfulness, a condition known as amnesic MCI, which is related to the hippocampus, he was unable to eliminate the forgetfulness symptoms and was troubled.

Therefore, by 2021, they had developed a PBM therapy device 10 that irradiates the hippocampus with near-infrared light that flickers at about 40 Hz, and succeeded in eliminating mild symptoms of "forgetfulness" within 30 minutes (Patent Document 5). However, there was a concern that a light beam 40 that was too strong could damage brain cells, and there were issues such as the need to determine a safe irradiation amount (light energy density 140) and the need to improve the completeness of the treatment device.
In the following, "near-infrared light in the wavelength range (650-1000 nm) that is called the biological window 3 and transmits through biological tissue" is abbreviated to "near-infrared" or "near-infrared light." Please note that this does not refer to the general technical term "near-infrared light (wavelength 800 nm-1200 nm, or 700 nm-2500 nm)."

In this invention, (1) an embodiment in which the safety of the PBM therapy device 10 that irradiates near-infrared light that flickers at approximately 40 Hz has been improved is introduced, (2) a PBM therapy device 10 that has been improved in ease of use when irradiating near-infrared light that flickers at approximately 40 Hz not only to the hippocampus but also to the amygdala, thalamus, temporal pole, and other areas affected by MCI, and (3) a treatment device for combining the PBM therapy device 10 with a sensory therapy device 20 to perform combined treatment is also introduced.

In the following, we will first briefly explain the prior art and application examples of a sensory therapy device 20 that can eliminate mild symptoms of brain fog, and then provide a detailed explanation using examples related to the present invention.

(3) Sensory Therapy Instruments 20
FIG. 2 shows an example of a sensory therapy device 20 that is a phase-synchronized light and sound therapy device at approximately 40 Hz that is effective in relieving mild symptoms of brain fog.

Figure 2(a) is a schematic diagram of the clinical trial device described in the Phase II clinical trial reports (Non-Patent Document 5, Non-Patent Document 6), which shows the prior art. The clinical trial device is a square LED panel 172 with sides measuring 2 feet (approximately 61 cm) and a speaker 166 placed 5 feet (approximately 152 cm) from the subject, and provides the subject with a 40 Hz flashing light and clicking sound.

Figure 2(b) shows an example of an application in which a bright white LED light bulb 174 is blinked at approximately 40 Hz, and an audio stimulus is applied in which a clicking sound that is phase-synchronized with the optical stimulus is heard through headphones 164 while the subject continues to watch the light that passes through light diffusion glasses 176 in which a white, translucent optical scattering plate is fitted in place of a lens.
In the past, one treatment method was to simply place a small, dim LED light bulb 174 in a corner of a room and flash it at about 40 Hz. However, due to the lack of light stimulation, there was a problem that the increase in amplitude of the induced brain waves at about 40 Hz was insufficient and the increase in coherence was only slight.
As a countermeasure, in the example of FIG. 2(b), in order to induce strong brain waves by having as many cone cells in the retina as possible participate in the brain wave induction by SSVEP, the white light stimulus entering the eye is made to cover the entire visual field so that the cone cells that perceive bright light of the three primary colors can function sufficiently, and it is desirable that the brightness of the light entering the eye is 600 Lux or more.
For patients who are bedridden, it is recommended to place an extremely bright LED light bulb 174 that flashes at about 40 Hz as close to the patient's face as possible. In order to efficiently generate 40 Hz brain waves, it is desirable to use white light to evenly stimulate the three types of cone cells in the retina that correspond to the three primary colors of light. For this reason, a white light source is used so that the entire field of vision is covered in white light, and white light diffusion glasses 176 are worn during treatment.
It is important to keep your eyes open while looking at the flashing white light in order to ensure a stable therapeutic effect. Closing your eyes and looking at the red light that penetrates the blood vessels of your eyelids, or falling asleep during treatment, will decrease the therapeutic effect.

Figure 2(c) is also an application example. This is a treatment method in which LCD sunglasses 180 are flickered at about 40 Hz outdoors on a bright sunny day, and the patient sits with his or her back to the sun in front of a large south-facing white tile or plaster wall to receive the light stimulus. When the illuminance is measured in this state just before it enters the LCD sunglasses 180, it is between 4,000 Lux and tens of thousands of Lux in the Tokyo area of Japan. The sound stimulus is a clicking sound of about 40 Hz that is phase-synchronized with the LCD sunglasses 180 and heard through earphones 168.

Figure 2(d) is also a conventional technique (Patent Document 3), and shows an example of using LCD sunglasses 180 in combination with outdoor exercise therapy. When looking directly at sunlight, the pupils close, and the light stimulus flickering at about 40 Hz becomes weaker and is less likely to be transmitted to the brain, so it is a good idea to try not to look directly at the sun, such as by turning your back to the sun or wearing a hat with a brim. Since the light stimulus is weaker when looking at a dark object, it is better to look at a bright object as much as possible and move your viewpoint so that you can clearly sense the flickering of light, which will increase the effect of eliminating brain fog.
In addition, for sound stimulation, for traffic safety when walking outdoors, it is recommended to use bone conduction earphones 162 so that surrounding sounds can be heard.

As described above with reference to FIG. 2, in the prior art or application example, the sensory therapy device 20 is composed of a visual stimulation device 800 and an auditory stimulation device 810.
The visual stimulation device 800 is an illuminant 170 such as an LED panel 172 or an LED bulb 74 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of a lens portion at about 40 Hz.
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of approximately 40 Hz, a headphone 164, and a speaker 166.
In other words, on the premise that the sound is heard with both ears, the sound generator 160 may be stereo or monaural, and the speaker 166 may be one or more.

In this Example 1, we will introduce a digital medical treatment device used in symptom improvement therapy for MCI, which flashes near-infrared light in a wavelength range (650 to 1000 nm) called the biological window 3 that transmits through biological tissue with a repeating waveform of approximately 40 Hz, and irradiates the affected area of MCI, such as the hippocampus, from the oral cavity to stimulate it at approximately 40 Hz.
The name of the treatment instrument described in Example 1 is "LED lance 200," and an image of the invention is shown in FIG.

(1) Matter of the Invention In this embodiment 1, the following two matters of the invention will be mainly described so as to clarify the technical ideas and design contents of the matters of the invention.
Although Example 1 includes many inventive matters that define more detailed matters, in order to avoid complicating the explanation, only the following two inventive matters will be extracted and explained in detail.

<Invention A of Example 1>
The main inventive features of the LED lance 200 are as follows:
"In digital medical treatment devices used in symptom improvement therapy for MCI,
The PBM therapy instrument 10 includes an LED lance 200 that blinks a light source in a wavelength range called a biological window 3 that transmits biological tissue with a repetitive waveform of about 40 Hz and irradiates the MCI affected area from inside the oral cavity with a light energy density 140 of a predetermined value 5 or less,

The LED lance 200 includes an LED light source 30, a gripping portion 80, and an LED driving device 50.
The LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the wavelength range of 650 to 1000 nm of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40;
The gripping portion 80 is a rod-shaped member for inserting the LED light source 30 disposed at the tip of the LED lance 200 into the oral cavity while holding the LED lance 200 by hand, and then manipulating the position and irradiation direction of the LED light source 30.
The LED driving device 50 is a device that supplies a driving current to the LED element 60 to irradiate the luminous flux 40 from the LED light source 30 at the light energy density 140 of 10 mW/cm or less as the predetermined value 5,

The LED driving device 50 also includes a 40 Hz signal source 210, an LED driving circuit 220, an output adjusting means 230, and an output monitoring means 240.
The 40 Hz signal source 210 outputs a command value 250 of a time series waveform of about 40 Hz of the luminous flux 40 emitted by the LED light source 30 of the LED lance 200;
The LED driving circuit 220 receives the command value 250 output from the 40 Hz signal source 210 and supplies a driving current to the LED light source 30;
The output adjustment means 230 continuously and/or discontinuously adjusts the light energy density 140 of the light flux 40 emitted from the LED light source 30;
The output monitoring means 240 indirectly or directly measures and displays the light energy density 140 irradiated by the LED lance 200.

<Invention B of Example 1>
Furthermore, the functions of the 40 Hz signal source, including separate excitation, self-excitation, and switching, can be summarized as follows:
The command value 250 issued by the 40 Hz signal source 210 is
The LED driver 50 is provided with a self-excited/separately excited switching means 260 for generating the LED by a separate excited operation 100 or a self-excited operation 105.
When generating the command value 250 by the separately excited operation 100, the signal source built into the 40 Hz signal source 210 is synchronized in phase with the synchronization signal 130 input from the outside to generate the command value 250.
In the case of generating the command value 250 by the self-excitation operation 105, a signal source incorporated inside the 40 Hz signal source 210 generates the command value 250 independently.
Characterized in that
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 1.

(2) Issues of Example 1 In Patent Document 5, the inventor irradiated near-infrared light to the hippocampus as a subject. As a result, the symptom of "forgetfulness" of MCI was resolved, and it was confirmed that this treatment method was effective. However, a subsequent MRI examination revealed tiny white shadows in the brain cells around the hippocampus, and although the causal relationship was unclear, the experiment was discontinued. In Example 1, the issue is to realize a treatment device that ensures safety by setting the amount of irradiation to be irradiated to the affected area of MCI, that is, the light energy density of 140, within an appropriate range.
Another challenge is to provide a phase-synchronized stimulation of approximately 40 Hz to the area affected by MCI in combination with the sensory therapy device 20 in order to compensate for the increase in coherence caused by the sensory therapy device 20.

(3) Solution The solution becomes clear by considering this treatment device as a PBM therapy device 10 that applies photobiomodulation (PBM) technology. In other words, the PBM technology utilizes the following characteristics: if the light energy density 140 irradiated is too high, cells are damaged, if it is moderate, cell activity is suppressed, and if it is weak but sufficient, cells regenerate.
In the present invention, a weak light energy density 140 is used, but even in this case, the brain cells are still forcibly stimulated by the blinking of light at about 40 Hz, so it can be used as a supplementary stimulus to supplement the coherence increase caused by the sensory therapy device 20. To do this, a synchronization signal 130 for use in conjunction with the sensory therapy device 20 is input to the LED lance 200 to operate it with the separate excitation operation 100.

Therefore, we decided to reduce the light energy density 140 by an order of magnitude compared to the experiment in Patent Document 5, and to apply as weak a light energy density 140 as possible within the range that is sufficient to relieve the symptom of "forgetfulness."
However, it is necessary to take into consideration that the value of the light energy density 140 to be irradiated in PBM differs depending on the type of cells in the target tissue, and further that the effective value of the light energy density 140 varies from person to person.

Therefore, the design policy for this PBM therapy device 10 was arrived at as a technical concept that "ensures safety from various perspectives while allowing each individual patient to explore the optimum value for themselves (or to improve their symptoms at that time)."

(4) Criteria for selecting light energy density The upper limit of the light energy density 140 must be set within a safe range that does not cause damage to the human body.
According to Non-Patent Document 10, some researchers recommend high-density power of less than 100 mW/cm2 or five times that level as the experimental conditions for PBM. However, other researchers believe that low-density power of less than 1 mW/cm2 is sufficiently useful in terms of pharmacological effects.
Even if a literature contains values that seem useful, the effective values that are actually useful will vary depending on the type of cells or tissue to be irradiated, the desired effect, or the irradiation conditions, so simply imitating the light energy density values listed in the literature will be of no use.

For this reason, I gave up relying on literature information and instead acted as a test subject myself, testing at various light energy densities 140, with the results below.

<Result 1>
When a light beam 40 flickering at approximately 40 Hz with a high light energy density of 140, which had an instantaneous maximum value of over 100 mW/cm2 when measured 1 cm away from the tip of the highly directional LED element, was irradiated into the oral cavity for approximately 20 minutes, the events that had just occurred to me flashed back in my mind like a slideshow.
Subsequently, a white shadow was discovered in the MRI images, and the experiment was halted due to concerns about the danger.

<Result 2>
An optical lens that greatly expands directivity is attached to an LED element, and a light beam 40 that flickers at about 40 Hz with a light energy density of 140 and an instantaneous maximum value of 10 mW/cm2 measured at a position 1 cm away from the tip is irradiated in the oral cavity for about 20 minutes. After that, by chance, when the patient went to a parking lot, he was able to memorize the number plate of a parked car as an image just by glancing at it. The image disappeared from his memory after three days, but he ruminated on it many times during that time and remembered it, so after three days he was able to remember the contents of the number plate as text information. Since then, no particular health problems have occurred.

The inventor himself believes that the experimental results in these two cases are at a level that can be called "abnormally strong memory," and that they are "more than necessary excessive doses" of stimulation of the hippocampus for the purpose of treating MCI.
Therefore, going forward, we have decided to apply an instantaneous maximum value of 10 mW/cm2 (10 milliwatts per square centimeter) as the upper limit of the light energy density 140 that can be safely used without causing any health hazards in "a treatment instrument that irradiates a light beam 40 while flickering at approximately 40 Hz from inside the oral cavity toward the hippocampus." The light beam 40 is measured at a position 1 cm away from the tip of the optical system 70 attached to the LED element.

Therefore, the light energy density 140 was further lowered and the experiment was continued on the premise that the device would be used as a symptom-improving therapy that can temporarily improve the symptoms of forgetfulness.
<Result 3>
The inventor himself conducted trial and error to find a light energy density 140 that would restore the state of "forgetfulness" to "one's original memory" in about 30 minutes of treatment, but the value varied from a few mW/cm2 to less than 1 mW/cm2 at a position 1 cm away from the tip of the LED's optical lens, depending on the physical condition of the day and the degree of "forgetfulness". There does not appear to be a fixed optimal value. Therefore, as a treatment device, it is necessary to design it so that weak light of less than 1 mW/cm2 can be used for treatment with an upper limit of 10 mW/cm2, while adjusting the output through trial and error.

Therefore, the light energy density 140 of all the PBM therapy devices 10 of the present invention is set to an upper limit of 10 mW/cm2 as a predetermined value 5, and is used in a range smaller than this. On top of that, in order to be able to further lower the light energy density 140, it was decided to provide an output adjustment means 230 for adjusting the drive current of the LED light source 30 by the LED drive device 50.
The predetermined value of 5 was commonly applied to all the embodiments of the present invention, and a necessary and sufficient effect was obtained.

(5) Design Guidelines for the First Embodiment The design guidelines for the treatment device of the first embodiment are as follows:
1) This treatment device will be designed to be held by the MCI patient and used through trial and error.
2) The density of light energy that can be irradiated is variable, with only an upper limit set so as not to damage brain cells.
3) The density of the emitted light energy will be as weak as possible within the range that is effective in relieving forgetfulness associated with MCI, making it a PBM treatment device that also aims to regenerate damaged brain cells.
4) To ensure safety, the treatment device must be equipped with a fail-safe function that immediately disables irradiation if the means for limiting the upper limit of the light energy density of the treatment device fails.
5) To prevent errors in setting the light energy density of the treatment equipment, a function will be provided that allows patients to monitor the output themselves.

(6) Description of the diagrams of Example 1 Figure 3 is a diagram for explaining the LED lance 200 of Example 1, which is a 40 Hz light source that is irradiated intraoral. The treatment instrument "LED lance 200" described in Example 1 is an instrument that can be used by trial and error by the MCI patient himself/herself by holding the rod-shaped gripping part 80 in his/her hand. Therefore, it is possible to irradiate weak near-infrared light toward an effective site, such as the amygdala, thalamus, or temporal pole adjacent to the hippocampus as the affected area of MCI, while feeling the situation in which the patient's own subjective symptoms are improved.

Figures 3(a) and 3(b) show the location of the hippocampus. The light beam 40 emitted by the LED light source 30 penetrates the biological tissues in the brain, including the skull (sphenoid bone, etc.) below the brain, and irradiates the hippocampus, etc.

3C is a diagram showing how the LED lance 200 is inserted into the oral cavity to irradiate the hippocampus. The LED lance 200 is held by hand, and the LED light source 30 at the tip of the LED lance 200 is inserted into the oral cavity, and the gripping part 80 is a rod-shaped member that controls the position and irradiation direction of the LED light source 30.
Since MCI patients themselves do not know the exact location of the hippocampus, it is a good idea to follow the instructions of the doctor who is treating them to get a rough idea of where it is. Since the light beam 40 emitted by the LED lance 200 is wide, it is sufficient to include the hippocampus within the wide light beam 40 even if the central optical axis of the LED lance 200 does not hit the hippocampus precisely.

3D is a diagram showing the configuration of the LED lance 200. The rear end of the LED lance 200 is connected to the LED driving device 50 via an electric wire. The LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the wavelength range of 650 to 1000 nm of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40.
By arranging a plurality of LED light sources 30 on the tip of the gripping portion 80 or on the side near the tip and emitting a plurality of light beams 40, it is possible to widen the directivity of the overall light beam 40 composed of the plurality of light beams 40 emitted by the LED lance 200. In addition, by bending the LED lance 200 near the tip and providing LED light sources 30 on the side, it is also possible to emit light in a plurality of directions at the same time.

In addition, since the directivity of light radiation from the semiconductor chip 65 and the directivity of light radiation from the LED element 60 sealed in the transparent resin case are diverse, the optical system 70 that adjusts the half-value angle of the directivity of the light beam 40 is designed to adjust the half-value angle so that the hippocampus is included in the expanded light beam 40, taking into consideration the predetermined value 5 as the upper limit of the light energy density 140 and a practical driving current that does not overheat the LED light source 30. Of course, if the lens shape at the tip of the transparent resin case of the LED element 60 alone meets the design conditions, this optical system 70 can be used as is.

The LED driver 50 is equipped with an output adjustment knob as an output adjustment means 230 for the patient to adjust the output, and an ammeter as an output monitoring means 240 for the patient to monitor the output. The maximum drive current of the LED light source 30 that irradiates near-infrared light is set by a control circuit built into the LED driver 50.

FIG. 3E is a diagram for explaining the configuration of a control system of the LED driving device 50.
The LED driving device 50 also includes a 40 Hz signal source 210, an LED driving circuit 220, an output adjustment means 230, an output monitoring means 240, and a power source such as a battery.
The 40 Hz signal source 210 uses a control microcomputer to output a command voltage of an arbitrary waveform with a repetition period of 40 Hz (for example, a sine wave, a rectangular wave with a selectable duty ratio, a triangular wave, a stepped waveform, or a waveform specified by storing an output every millisecond in memory, etc.) as a command value 250 for a time series waveform of approximately 40 Hz for the light beam 40 emitted by the LED light source 30 of the LED lance 200.

The LED drive circuit 220 receives the command value 250 output by the 40 Hz signal source 210 and supplies a drive current to the LED light source 30 .
The output adjustment means 230 continuously and/or discontinuously adjusts the light energy density 140 of the luminous flux 40 emitted from the LED light source 30, and may set the drive current supplied to the LED elements 60 of the LED light source 30 by changing the amplification factor of the LED drive circuit 220 with a variable resistor or switch. Alternatively, although not shown, waveform parameters such as the amplitude and average value of the command value can be specified using a volume or the like on the 40 Hz signal source 210 side. Of course, parameters of the program of the control microcomputer may also be adjusted.
The output monitor 240 indirectly or directly measures and displays the light energy density 140 irradiated by the LED lance 200. In Fig. 4(e), an ammeter is used to indirectly measure the relative increase or decrease in the light energy density 140. Alternatively, although not shown, the light flux 40 of the LED light source 30 may be divided and detected by an optical sensor to directly measure and display the light energy density 140.

If an inappropriately large current flows through the LED element 60 of the LED light source 30 due to a failure in the electronic circuit, such as a short circuit in the feedback resistor circuit, and a luminous flux 40 with an excessively high light energy density 140 is emitted, there is a risk of damaging brain cells. Therefore, for the purpose of a fail-safe, a highly sensitive fuse of, for example, 20 mA or 30 mA is provided in series with the main circuit through which the LED drive current flows, as shown in Figure 3(e).
Although not shown in the figure, it is also possible to connect multiple high-sensitivity fuses in series to reduce the probability of a non-melting accident caused by a defective fuse, or to provide a drive circuit such as a buzzer that emits a warning sound to inform the patient that treatment must be interrupted if the fuse blows.

Incidentally, Patent Document 5 discloses a method of construction in which an LED element or laser light source is stored in a separate housing and light energy is transmitted to the LED lance 200 via optical fiber, as well as various shapes and structures of the LED lance 200, so a person skilled in the art would be able to easily modify the design based on this invention.

The command value 250 issued by the 40 Hz signal source 210 is
The LED driver 50 is provided with a self-excited/separately excited switching means 260 for generating the separately excited signal 100 or the self-excited signal 105.
When generating the signal by the separate excitation operation 100, the signal source built into the 40 Hz signal source 210 is synchronized in phase with the synchronization signal 130 input from the outside to generate the command value 250.
When the command value 250 is generated by the self-excitation operation 105, a signal source incorporated inside the 40 Hz signal source 210 generates the command value 250 independently.

That is, the LED driving device 50 can be provided with a switch for switching between the separately excited operation 100 and the self-excited operation 105. When the LED lance 200 is used alone, the 40 Hz signal source 210 is switched to the self-excited operation 105, and a signal as the command value 250 with a repetition period of about 40 Hz is automatically output using the built-in signal source.
Alternatively, when the LED lance 200 is used in combination with another treatment instrument, the operation is switched to the separate excitation operation 100, a synchronization signal 130 of about 40 Hz is input, and a signal is output by resetting the phase of the signal as the command value 250 for each repetition period so that the phase matches the synchronization signal 130 of about 40 Hz from the outside.

Incidentally, the self-excited/separately excited switching means 260 may be a manual switch, or an automatic switch may be used so that the device operates in the separate excited mode 100 when it detects that a synchronization signal 130 has been input from the outside, and operates in the self-excited mode 105 when the synchronization signal 130 has not been input from the outside.
Of course, when the design is changed to a dedicated machine for the self-excited operation 105 or the separate excited operation 100, the design can be changed to function only for the self-excited operation 105 or the separate excited operation 100, and the self-excited/separate excited switching means 260 is not required.

FIG. 3(f) is a simple circuit example of the LED driver 50 of FIG. 3(e).
The 40 Hz signal source 210 uses a control microcomputer to output the above-mentioned arbitrary waveform command voltage from the analog output AO. In this figure, in order to prevent harmonic components of 80 Hz and 120 Hz from being mixed into the waveform of the light beam 40 that flickers at a fundamental frequency of 40 Hz generated by the LED light source 30, the waveform of the command voltage is a sine wave with a lower limit of 0 V, an upper limit of 3 V, and an average value of 1.5 V.

The LED driving device 50 drives the LED driving transistor TR1 using a full-swing operational amplifier OP1 in response to a power supply voltage of +5 V. A feedback resistor circuit consisting of R5, R6, R7, SW1 and VR1 is provided on the emitter side of TR1, and a voltage drop caused by the current passing through the LED element 60 of the LED light source 30 is used as a voltage feedback signal to operate a differential amplifier circuit using the operational amplifier OP1.
For example, when the total value of the feedback resistance circuit is 300Ω, the waveform of the current value output from the LED drive circuit is a sine wave with a lower limit of 0 mA, an upper limit of 10 mA, and an average value of 5 mA.
The ammeter displays approximately the average value of the current flowing through the LED light source 30, and therefore displays approximately 5 mA.

The output adjusting means 230 continuously and/or discontinuously adjusts the light energy density 140 of the light flux 40 emitted from the LED light source 30 .
This feedback resistor circuit is also used as the output adjustment means 230, and for example, a specialist at a pharmacy or the like who sells medical equipment according to a doctor's prescription turns on and off a switch SW1 built into the LED driving device 50 to discontinuously switch the upper limit of the current flowing through the LED element 60 of the LED light source 30 to switch the current range. Also, if the patient receiving treatment adjusts the variable resistor VR1 linked to the output adjustment knob, the drive current flowing through the LED element 60 of the LED light source 30 can be continuously adjusted.

The output monitor 240 indirectly or directly measures and displays the light energy density 140 emitted by the LED lance 200 .
The ammeter display is an output monitoring means 240 that indirectly monitors the light energy density 140 irradiated during treatment for the purpose of comparison with the patient's own experience of symptom improvement in the past. Therefore, it is sufficient that the reproducibility of the display is relatively maintained, and the accuracy of the absolute value of the display is not a major issue. The ammeter display is used by the MCI patient to make a decision to increase or decrease the light energy density 140 according to his or her symptoms, and by the patient or a caregiver to check whether or not a light energy density 140 significantly different from normal is being used by mistake during treatment. If sufficient reliability can be ensured, a digital display ammeter or an ammeter with a data recording function may be applied.
Alternatively, it goes without saying that a semiconductor illuminometer (i.e., a photodiode) may be provided that splits the luminous flux 40 output by the LED lance 200 and directly measures its intensity, thereby measuring and monitoring the light energy density 140.

Non-patent document 8 proposes combining an endoscope with a laser light source inserted into the oral cavity. Applying this idea, for example, when a near-infrared LED (wavelength 850 nm) for communication is used in the LED lance 200 to irradiate light at about 40 Hz, the image can be observed with an inexpensive imaging semiconductor for an infrared camera that is sensitive to a wavelength of 850 nm. Therefore, if a small infrared camera is also installed at the tip of the LED lance 200 and images are taken intermittently during light irradiation, and the patient himself/herself observes the image of the area being irradiated with light using a monitor image during treatment, the light can be reproducibly directed in the direction of irradiation as instructed by the doctor, which has the effect of improving the treatment effect.

As a method for switching the 40 Hz signal source 210 to the self-excited operation 105 and outputting a signal with a repetition frequency of about 40 Hz using a built-in signal source, an arbitrary waveform stored in memory can be generated by a control microcomputer in accordance with the elapsed time, for example, by referring to Patent Document 3. Alternatively, the command voltage to be output may be defined using a time function such as a sine wave function in accordance with the elapsed time counted in microseconds by the OS of the control microcomputer.
The method of separately excited operation 100 can be achieved by, for example, resetting a stored signal waveform or a function-defined signal waveform in accordance with the pulse of a synchronization signal input from the outside, as in the design example of 3D active glasses for watching stereoscopic television, which alternately blink the lenses of the left and right LCD elements in synchronization with a phase synchronization signal transmitted from the television. In any case, the circuit design of the self-excited operation 105 and separately excited operation 100 of the 40 Hz signal source 210 and the self-excited/separately excited switching means 260 can be easily realized by a person skilled in the art by modifying the design of existing technology.

(7) Precautions for Example 1 There are three important precautions to take when an MCI patient uses the LED lance 200 treatment device.

[Note 1]
Therapeutic devices using photobiomodulation (PBM) technology have the characteristic that they can regenerate and repair cells even if the light energy density 140 is weak as long as it is sufficient. On the other hand, when the LED lance 200 is irradiated with a high light energy density 140, memory is temporarily and rapidly improved, which may cause a certain kind of "strong pleasure."
Therefore, if one forgets the original purpose of improving the symptom of "forgetfulness" in MCI patients and greedily administers an excessive amount of light energy density 140 in an attempt to "strengthen memory," not only will the function of cell regeneration decrease, but it may even cause cell damage, although this will vary from person to person.
Therefore, one should not be greedy and increase the light energy density 140 too much in an attempt to strengthen one's memory.

[Note 2]
Machines can break down. If a malfunction occurs, such as the optical system 70 that spreads the light at the tip of the LED lance 200 becoming detached, and the directivity of the LED element 60 becomes sharp, the light energy density 140 in the optical axis direction will suddenly increase, and there is a risk of damaging brain cells.
In order to avoid this risk, it is desirable to use an LED light source 30 that has a wavelength range of the biological window, but whose optical spectral characteristics make it appear slightly red to the human eye (for example, red light with a wavelength of 850 nm or less within the range of the biological window). In this way, just before performing a treatment, the LED lance 200 can be tilted by 30 degrees or more in a dark place and the semiconductor chip 65 of the LED element 60 can be checked for a malfunction of the optical system 70 by checking that it is shining slightly red. If the light emitted by the LED light source 30 can be seen normally no matter which direction it is tilted to, there is a high possibility that there is no significant defect in the optical characteristics.

[Note 3]
Even if the optical system is normal, saliva or other liquids may adhere to the optical system and inadvertently change the optical characteristics. As a precaution, if water droplets or other liquids are noticeably adhering to the surface of the optical system during treatment after it is inserted in the mouth, we recommend wiping off the water droplets from time to time.

(8) Effect of Example 1 By using the LED lance 200, an MCI treatment device of the present invention, an amnesic MCI patient suffering from forgetfulness can operate the treatment device according to his/her subjective symptoms, and temporarily improve and treat the forgetfulness symptoms as a symptom improvement therapy.

In addition, the light beam 40 emitted by the LED lance 200 treatment device flickers (or flashes, which is a synonym) at approximately 40 Hz, and the mechanism of action described in Patent Document 1 and Non-Patent Document 4 has the effect of preventing or delaying the risk of MCI progressing to Alzheimer's disease.

Furthermore, because the light beam 40 emitted by the treatment device LED lance 200 is weak, it also has the effect of regenerating already damaged cells in the affected area of MCI through the mechanism of action of photobiomodulation.

Furthermore, photobiomodulation stimulates brain cells in the affected area of MCI at approximately 40 Hz, so by properly managing the phase difference when used in conjunction with the sensory therapy device 20, it is possible to simultaneously treat the brain fog and forgetfulness symptoms of MCI. (See Example 4 for details)

In this Example 2, a digital medical treatment device used in symptom improvement therapy for MCI is introduced, which flashes near-infrared light in a wavelength range (650 to 1000 nm) called the biological window 3 that transmits through biological tissue with a repeating waveform of about 40 Hz, and irradiates the affected area of MCI, such as the hippocampus, from the oral cavity to stimulate it at about 40 Hz.
The name of the treatment device described in Example 2 is LED mouthpiece 400, and an image of the invention is shown in FIG.

(1) Matter of the Invention In this Example 2, the following four matters of the invention will be mainly described so as to clarify the technical ideas and design contents of the matters of the invention.
Although the second embodiment also includes many inventive matters that define more detailed matters, in order to avoid complicating the explanation, only the following inventive matters will be extracted and explained in detail.

<Invention A of the Second Embodiment>
The main inventive features of the LED mouthpiece 400 are as follows:
"In digital medical treatment devices used in symptom improvement therapy for MCI,
The PBM therapy device 10 is an LED mouthpiece 400 that blinks a light source in a wavelength range called a biological window 3 that transmits biological tissue with a repetitive waveform of about 40 Hz and irradiates the MCI affected area from inside the oral cavity with a light energy density 140 of a predetermined value 5 or less,

The LED mouthpiece 400 includes an LED light source 30, a mouthpiece unit 410, and an LED driving device 50.
The LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the wavelength range of 650 to 1000 nm of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40;
The mouthpiece unit 410 includes a mouthpiece 460 that is fitted to the upper or lower jaw dentition and fixed inside the oral cavity while maintaining the reproducibility of the position and direction in a mouthpiece coordinate system 420, three or more contrast member insertion points 450 that define a coordinate transformation matrix 440 of two orthogonal coordinate systems, the mouthpiece coordinate system 420 and a skull coordinate system 430, and a connecting member 470 that arranges the LED light source 30 in the mouthpiece 460 while maintaining the reproducibility of the installation position and irradiation direction,
The LED driving device 50 is a device that supplies a driving current to the LED element 60 to irradiate the luminous flux 40 from the LED light source 30 at the light energy density 140 of 10 mW/cm or less as the predetermined value 5,

The LED driving device 50 also includes a 40 Hz signal source 210, an LED driving circuit 220, an output adjusting means 230, and an output monitoring means 240.
The 40 Hz signal source 210 outputs a command value 250 of a time series waveform of about 40 Hz of the light flux 40 emitted by the LED light source 30 of the LED mouthpiece 400;
The LED driving circuit 220 receives the command value 250 output from the 40 Hz signal source 210 and supplies a driving current to the LED light source 30;
The output adjusting means 230 continuously and/or discontinuously adjusts the light energy density 140 of the light flux 40 emitted from the LED light source 30;
The output monitoring means 240 indirectly or directly measures and displays the light energy density 140 emitted by the LED mouthpiece 400.

<Invention B of the Second Embodiment>
Mouthpiece section 410 , which is structured to be fixed to the upper jaw, is characterized by an LED board section 480 .
The mouthpiece portion 410, which is structured to be fixed to the upper jaw, further includes an LED board portion 480.
The LED substrate unit 480 is connected to the connecting member 470, and the LED light source 30 is arranged on the LED substrate unit 480. The LED light source 30 is arranged at a position and in a direction of irradiation so that the irradiation target point 490 is included in the light beam 40.
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 2.

<Invention C of the Second Embodiment>
The mouthpiece portion 410 that is structured to be fixed to the lower jaw is characterized in that the LED light source 30 is directly attached to a connecting member 470 .
The LED light source 30 is connected to the connecting member 470 and arranged, and the position and irradiation direction of the LED light source 30 are maintained so that the irradiation target point 490 is included in the light beam 40.
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 2.

<Invention Item D of Example 2>
Furthermore, the functions of the 40 Hz signal source, including separate excitation, self-excitation, and switching, can be summarized as follows:
The command value 250 issued by the 40 Hz signal source 210 is
The LED driver 50 is provided with a self-excited/separately excited switching means 260 for generating the LED by a separate excited operation 100 or a self-excited operation 105.
When generating the command value 250 by the separately excited operation 100, the signal source built into the 40 Hz signal source 210 is synchronized in phase with the synchronization signal 130 input from the outside to generate the command value 250.
In the case of generating the command value 250 by the self-excitation operation 105, a signal source incorporated inside the 40 Hz signal source 210 generates the command value 250 independently.
Characterized in that
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 2.

(2) Problems of Example 2 In the above-described Example 1, the LED lance 200 treatment device was introduced, which is intended to be used by an amnesic MCI patient whose condition is mild enough that he or she can operate the treatment device by himself or herself.
However, as the symptoms of MCI progress, it becomes difficult for the patient to determine the appropriate light energy density 140 and operate the treatment instrument to target the affected area, and the MCI lesion to be treated spreads from deep within the brain to the temporal region, making treatment difficult with the LED lance 200, which can only irradiate a light beam spread in a single direction.

(3) Solution: In order to treat patients with advanced symptoms of amnesic MCI, the problem is solved by simultaneously irradiating multiple affected areas with multiple light beams 40. Specifically, the problem is solved by using a treatment device, an LED mouthpiece 400, in which multiple LED light sources 30 are incorporated in a mouthpiece fixed to the patient's upper or lower jaw dentition.

Also, taking into consideration that the device will be used by patients whose judgment has been impaired by MCI, the technical concept is based on the idea that a prescription will be provided to the patient after examination and consultation at a medical institution, and that the patient or caregiver will purchase a custom-made product (or a standard product with adjusted control parameters, etc.) from a specialist digital pharmaceutical company based on specifications such as device dimensions and control parameters.
Therefore, since the adjustment means for the light energy density 140 is necessary for a specialist to set parameters in accordance with a prescription, an output adjustment means 230 for adjusting the light energy density 140 is also provided as in the first embodiment.

As with Example 1, there is a fail-safe design that uses a highly sensitive fuse to cut off excessive output in the event of a breakdown in the treatment device, and there is also a means for indirectly monitoring the output by measuring the drive current to check whether there are any abnormalities in the irradiation conditions, or a means for directly monitoring the output by measuring a portion of the irradiated light, thereby preventing accidents.

(4) Detailed Description of Example 2 FIG. 4 is a diagram illustrating an LED mouthpiece 400 equipped with multiple LED light sources 30 that irradiate light beams 40 that flicker at approximately 40 Hz in multiple directions within the oral cavity.
FIG. 4(a) is a diagram explaining the definition of coordinates for calculating a coordinate transformation matrix 440 between the three-dimensional coordinate system of the mouthpiece and the three-dimensional coordinate system of the skull used in the present invention for the purpose of irradiating multiple MCI affected areas with a light beam 40 from inside the oral cavity as irradiation target points 490, and a method of measuring parameters for the coordinate transformation.

A contrast agent (lead for X-rays, iodine solution for CT, gadolinium preparation or iron preparation for MRI, etc.) can be enclosed at the right end point Pr, the front center point Pc, and the left end point Pl of the mouthpiece part 410 used for the patient examination, and it is also possible to use it without enclosing the contrast agent after imaging of the skeleton and various parts of the brain.
Alternatively, mouthpiece portion 410 containing a contrast agent may be used during measurement, and mouthpiece portion 410 made to the same dimensions but containing no contrast agent may be used during treatment after measurement.
The above-mentioned three points, the right end point Pr, the front center point Pc, and the left end point Pl, are called contrast medium insertable points 450.

This contrast member insertion point 450 is a representative point for measuring coordinates by X-ray, CT or MRI in order to calculate a coordinate transformation matrix 440 for transforming the three-dimensional coordinate system of the mouthpiece and the three-dimensional coordinate system of the skull.
There is a concern that the leakage of contrast medium during a long treatment period after the measurement is completed may cause health damage. Therefore, in order to improve safety, it is desirable to fix the mouthpiece 410 to the patient's dentition and perform an examination of the patient, complete the coordinate measurements of the skull and various parts of the brain, and determine the coordinate transformation matrix 440 for the coordinate transformation to be applied to the patient. Then, for the treatment of the patient thereafter, use the mouthpiece 410 of the same dimensions without the contrast medium sealed therein.

The mouthpiece coordinate system 420 defines an x-axis from the left end point pl to the right end point pr, and a perpendicular line is drawn from the front center point pc to the x-axis, with the intersection point being the origin p0 of the mouthpiece coordinate system 420. The y-axis is defined from the origin p0 to the front center point pc. Finally, the z-axis is defined to pass through the origin p0 and point upward at right angles to the x-axis and y-axis. Therefore, the mouthpiece coordinate system 420 is a right-handed three-dimensional Cartesian coordinate system.
By defining mouthpiece coordinate system 420 in this manner, the origin p0 and xy plane of mouthpiece coordinate system 420 are uniquely defined by the three contrast member insertable points 450, as well as the direction of the upward z-axis perpendicular to the xy plane.

Therefore, if the length from the origin p0 to the right end point pr is a and the length from the origin p0 to the front center point pc is b, the coordinates of each point in the mouthpiece coordinate system 420 are: origin p0 = [0, 0, 0], right end point pr = [a, 0, 0], and front center point pc = [0, b, 0].
Incidentally, if the length from the origin p0 to the left end point pl is c, then the left end point pl = [-c, 0, 0].

Next, the skull coordinate system 430 defines an X-axis from the left ear canal of the subject's skull to the right ear canal, a perpendicular line is drawn from the anterior fontanelle of the subject's skull to the X-axis, and the intersection point is set as the origin of the skull coordinate system 430. A Z-axis is defined from this origin to the anterior fontanelle of the skull. Finally, a Y-axis is defined forward, passing through the origin of the skull coordinate system 430 and perpendicular to the X-axis and Z-axis. Therefore, the skull coordinate system 430 is also a right-handed three-dimensional Cartesian coordinate system.
By using the skull coordinate system 430 defined in this manner to measure the three coordinates of the contrast member insertion point 450 through imaging from multiple directions using an X-ray device, CT, or MRI, the parallel movement from the origin p0 of the mouthpiece coordinate system 420 to the origin of the skull coordinate system 430 and the rotational movement amounts about the x, y, and z axes are uniquely defined.

The coordinate value P0 in the skull coordinate system 430 of the origin p0=[0,0,0] in the mouthpiece coordinate system 420 can be obtained from the above-mentioned definition of the origin p0 of the mouthpiece coordinate system 420 using the coordinate points of the left end point PL, the right end point PR, and the front center point PC measured by an X-ray device or the like. If the coordinate value P0 corresponding to the origin p0 of the mouthpiece coordinate system 420 in the skull coordinate system 430 measured by an X-ray device or the like is set to P0=[Vx, Vy, Vz], the translation matrix of the mouthpiece coordinate system 420 and the skull coordinate system 430 can be calculated from this value.
Furthermore, by performing a similar parallel translation on the coordinate values of the right end point PR and the front center point PC measured in the skull coordinate system 430 for the two points in the mouthpiece coordinate system 420, the rotational translation matrices about the origins of each of the mouthpiece coordinate system 420 and the skull coordinate system 430 can be uniquely calculated.

Therefore, the mouthpiece portion 410 containing contrast agent at the three contrast member insertable points 450 is fitted onto the dentition in the oral cavity, and the coordinate values of the three contrast member insertable points 450 (i.e., the left end point pl, the right end point pr and the front center point pc) in the skull coordinate system 430 are measured using an X-ray device or the like, whereby the translation matrix and rotational translation matrix between the two coordinate systems are uniquely defined.
In addition, since both the mouthpiece coordinate system 420 and the skull coordinate system 430 are right-handed systems and both units of length are SI units of physical quantities, the length scale ratio is 1: 1. Furthermore, there is no geometric shear relationship in the linear transformation between the mouthpiece coordinate system 420 and the skull coordinate system 430.

Therefore, by utilizing known affine transformations in two three-dimensional orthogonal coordinate systems, it is possible to define a coordinate transformation matrix 440 between the mouthpiece coordinate system 420 and the skull coordinate system 430 and its inverse matrix. By superimposing the coordinate position and irradiation direction of the LED light source 30 measured on the mouthpiece coordinate system 420 and the coordinates of the affected area of MCI measured on the skull coordinate system 430 using CT, MRI, or the like, it is possible to display the LED light source 30 and the affected area of MCI on the same three-dimensional orthogonal coordinate system.
In other words, while drawing a diagram using a design tool such as 3D CAD, the position and irradiation direction of the LED light source 30 on the mouthpiece coordinate system 420 can be designed so that the LED light source 30 is irradiated toward the coordinates of the affected area of MCI, such as the hippocampus.
To calculate and define coordinate transformation matrix 440, a minimum of three contrast member insertable points 450 are required: the left end point pl, the right end point pr, and the front center point pc, which are described in the definition of mouthpiece coordinate system 420. However, the number of contrast member insertable points 450 may be increased to three or more in order to improve measurement accuracy.

<A mouthpiece worn on the upper jaw>
FIG. 4(b) is a schematic diagram of a prototype LED board unit 480, and is an example of designing the position and irradiation direction of the LED light source 30 on the mouthpiece coordinate system 420 in order to irradiate the LED light source 30 toward the coordinates of the affected area of MCI.
The LED board section 480, which is a part of the mouthpiece section 410 that is structured to be fixed to the upper jaw, is connected to the connecting member 470 of the mouthpiece 460 and has the LED light source 30 disposed thereon. The position and irradiation direction of the optical axis are oriented in an appropriate direction so that the irradiation target point 490, such as the hippocampus, is included in the light beam 40, and the LED board section 480 is fixed to maintain that position and direction.
In Fig. 4B, eight surface-mounted LED elements are arranged as the LED light source 30 so that eight optical axes are generated in different directions. The number of irradiated light beams 40, i.e., the number of mounted LED elements, may be other than the eight illustrated in the figure. However, the light energy density 140 of the irradiated light beams 40 is used in a range smaller than 10 mW/cm2 as the predetermined value 5.

Figure 4(c) is a schematic diagram of a prototype mouthpiece section 410. In this figure, the mouthpiece section 410 is attached to the upper jaw dentition, and the LED board section 480 is attached between two connecting members 470 provided on the left and right sides of the inside of the mouthpiece 460 so that the eight optical axes of the LED light source 30 extend diagonally upward from the upper jaw mouthpiece section 410. The driving current for the LED light source 30 is supplied from an LED driving device 50 (not shown) via an electric wire.

The shape of the LED substrate 480 and the mounting positions and optical axis directions of the surface-mounted LED elements serving as the LED light source 30 were determined so that the directions of the eight optical axes and the spread of the light beam 40 would include the location of the MCI-affected area, such as the hippocampus, described in the mouthpiece coordinate system 420.
Since the light beam 40 is designed to spread widely, even if the center of the optical axis does not pinpoint the center of the affected area of MCI, the affected area of MCI can be properly included in the spread light beam 40. At the stage of industrial use, if the LED board unit 480 is created in a precise shape using a 3D printer or the like to match the shape of the upper part of the patient's mouth, the discomfort felt in the patient's mouth can be reduced.

In addition, at the prototype stage, the wiring of the LED board section 480 and the surface-mounted LED elements serving as the LED light source 30 were wrapped in food wrap in order to prevent electrical leakage due to saliva in the mouth. At the industrial use stage, it is essential to cover them with a nearly transparent waterproof cover that efficiently transmits near-infrared light.

While the mouthpiece portion 410 used by fitting it to the upper jaw dentition has been introduced above, it is also possible to realize a mouthpiece portion 410 used by fitting it to the lower jaw dentition.
That is, the LED mouthpiece 400 includes an LED light source 30, a mouthpiece unit 410, and an LED driving device 50.
The LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the wavelength range of 650 to 1000 nm of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40.
The mouthpiece unit 410 includes a mouthpiece 460 that is fitted around the upper or lower jaw dentition and fixed inside the oral cavity while maintaining the reproducibility of the position and direction in a mouthpiece coordinate system 420, three or more contrast member insertion points 450 that define a coordinate transformation matrix 440 between two orthogonal coordinate systems, the mouthpiece coordinate system 420 and a skull coordinate system 430, and a connecting member 470 that arranges the LED light source 30 in the mouthpiece 460 while maintaining the reproducibility of the installation position and irradiation direction,
The LED driving device 50 is a device that supplies a driving current to the LED element 60 to cause the LED light source 30 to irradiate the light flux 40 with a light energy density 140 of 10 mW/cm 2 or less as a predetermined value 5 .

Figure 4 (d) shows the external dimensions of a surface-mounted LED element (model number OSI3120641E, wavelength 850 nm, standard test current 20 mA) used as the LED element 60 in the prototype of the LED light source 30, which includes a semiconductor chip 65 that emits light with an output wavelength (or peak wavelength) that corresponds to the near-infrared wavelength region called the biological window 3 in this invention. The half-value angle of this LED element 60 is wide at 35 degrees. In the prototype LED light source 30, in order to further weaken the light energy density 140, a (handmade) optical lens was attached to the light-emitting end of the LED element 60 to further widen the half-value angle to more than about 40 degrees. For industrial use, a dedicated lens or an LED with a dedicated lens should be used.

For reference, the method for making a handmade lens is described below. A uniform thickness protective film is applied to a flat surface such as a hand mirror, and a jig is made to temporarily fix a surface-mounted LED element facing downwards. Next, UV-curing transparent adhesive BONDIC (registered trademark) is poured between the protective film and the LED element and cured with UV light. Due to the influence of surface tension, a transparent prototype lens optical system 70 with a base shape as shown in the figure is created.
When peeling the prototype LED light source 30 from the mirror surface, the optical system 70 made of the handmade lens is likely to come off from the LED element 60. Therefore, if a groove is cut horizontally with a diamond cutter along the contour of the hemispherical head of the LED element 60 before pouring the adhesive, the strength of the adhesive is improved and the optical system 70 is less likely to come off from the LED element 60.

FIG. 4( e ) shows the configuration of the LED driving device 50 .
The LED driving device 50 also includes a 40 Hz signal source 210 , an LED driving circuit 220 , an output adjusting means 230 , and an output monitoring means 240 .
The 40 Hz signal source 210 outputs a command value 250 for a time-series waveform of approximately 40 Hz for the luminous flux 40 emitted by the LED light source 30 of the LED mouthpiece 400, the LED drive circuit 220 inputs the command value 250 output by the 40 Hz signal source 210 and supplies a drive current to the LED light source 30, the output adjustment means 230 continuously and/or discontinuously adjusts the light energy density 140 of the luminous flux 40 irradiated from the LED light source 30, and the output monitoring means 240 indirectly or directly measures and displays the light energy density 140 irradiated by the LED mouthpiece 400.

In other words, the design concept of the basic configuration of the LED driver 50 is the same as in Example 1, with the 40 Hz signal source 210 and LED driver circuit 220 connected to an ammeter, a highly sensitive fuse, and the LED light source 30, and drive power being supplied from a power source. In this example, eight LED light sources 30 are connected in series and driven with the same drive current value. The power supply voltage is set to 15 V to accommodate the voltage drop of the LEDs.

The ammeter functions as an output monitoring means 240 similar to that of the first embodiment, and is an indirect monitoring means for the light energy density 140 to check whether the same driving current is being normally supplied during treatment compared to the past. Of course, a photodiode or the like may be provided to directly monitor the light energy density 140 by dividing the light flux emitted by the LED, and display and monitor the light output.

In FIG. 4, all of the LED light sources 30 incorporated in the LED mouthpiece 400 are controlled by a single LED driver 50. However, if the design is modified to provide one LED driver 50 for each of several LED light sources 30 or for each individual LED light source 30, it is possible to modify the design so that each of the multiple light beams 40 irradiates a light beam 40 with a light energy density of 140 that matches the characteristics of the cells in the affected area of MCI.

<Switching between self-excitation and external excitation>
The command voltage as command value 250 issued by 40 Hz signal source 210 is generated by a switching means 260 between self-excitation and separate excitation arranged in LED driving device 50 through separate excitation operation 100 or self-excitation operation 105. When generated through separate excitation operation 100, the command value 250 is generated by synchronizing the phase of the signal source incorporated inside 40 Hz signal source 210 with a synchronization signal 130 input from the outside, and when generated through self-excitation operation 105, the command value 250 is generated independently by the signal source incorporated inside 40 Hz signal source 210.

In other words, as in the first embodiment, the 40 Hz signal source 210 can be provided with a manual changeover switch for switching between separate excitation operation 100, which generates a command voltage in phase synchronization with an external synchronization signal 130, and self-excited operation 105, which generates a command voltage autonomously or independently using an internal signal source, in the LED driving device 50. Alternatively, the separate excitation operation 100 and self-excited operation 105 may be automatically switched depending on the presence or absence of an external synchronization signal 130, or switching may not be necessary if a dedicated product for separate excitation operation 100 or self-excited operation 105 is designed.

4(f) shows an example circuit of LED driver 50. The design concept is the same as in Example 1, and a 40 Hz signal source 210 capable of switching between self-excitation and separate excitation outputs a sine wave waveform with an amplitude of 0 to 3 V as a command voltage, and an LED drive circuit 220 feeds back the LED drive current as a voltage through a feedback resistor circuit.
As in the first embodiment, a feedback resistor circuit consisting of R5, R6, R7, SW1, and VR1 is provided in the LED drive circuit 220, and the resistance value is changed continuously by VR1 and discontinuously by SW1 to adjust the current flowing to the LED light source 30.

In the second embodiment, in order to allow a specialist to set the drive current based on a doctor's prescription, the specialist opens the housing of the LED drive device to adjust the SW1 for adjusting the feedback resistance and the variable resistor VR1.
However, if the doctor decides to give the patient the freedom to make adjustments, the prescription can specify a product designed in such a way that the variable resistor VR1 can be adjusted with an output adjustment knob attached to the housing, as in the first embodiment.
For a detailed explanation of other operations, please also refer to the explanation of FIG. 3(e) and FIG. 3(f) in the first embodiment.

<Mouthpiece worn on the lower jaw>
In the present invention, based on the design concept of the present invention, a mouthpiece that is fitted to the lower dentition is also used with an LED light source 30 incorporating an optical system 70 (or incorporating the LED element 60 as a resin lens) for the purpose of irradiating a small light beam 40 with a light energy density of 140 for photobiomodulation, and the half-value angle is increased to widen the light beam 40, and the current flow is further limited so that the energy density 140 is set to a predetermined value 5 of 10 mW/cm2 or less.
The mouthpiece portion 410 fixed to the lower jaw has an extremely simple structure so as to inhibit tongue movement inside the mouth as little as possible, and the LED light source 30 that irradiates a light beam 40 with a wide spread inside the oral cavity is directly attached to the connecting member 470, and the position and irradiation direction of the LED light source 30 are held by the mouthpiece fixed to the lower jaw so that the irradiation target point 490 such as the hippocampus is included within the spread of the light beam 40.

Figure 8 (a) shows how to use the mouthpiece part 410, which is fitted around the lower jaw dentition. The wires that supply the driving current for the LED light source 30 are taken out from the left side of the lip to prevent them from being bitten off by the teeth. The way the wires are taken out can be modified as needed to make it easier to use.

In the mandibular-type mouthpiece 460 of FIG. 8( b ), an optical system 70 is incorporated into the LED light source 30 (or is integrated as a lens at the tip of the transparent resin case of the LED element 60), and the LED light source 30 is attached and fixed directly to the connecting member 470 of the mouthpiece 460 (i.e., without an LED board portion 480).
The teeth groove of the lower jaw type mouthpiece 460 faces downward, so the mouthpiece 460 is fixed by fitting the lower jaw teeth into the teeth groove.
In addition, since the dental groove of the maxillary type mouthpiece 460 faces upward, the maxillary teeth are fitted into the dental groove to fix the mouthpiece 460; however, as with the mandibular type mouthpiece 460, the LED light source 30 may be directly attached to the connecting member 470 of the maxillary type mouthpiece 460 and the light beam 40 may be directed to irradiate the area affected by MCI.

The conventional mandibular mouthpiece of Patent Document 5 used a narrow, highly directional light beam 40 to irradiate light with a high light energy density 140, with the technical idea of pinpointing the hippocampus alone.
On the other hand, the present invention adopts a design concept of "based on photobiomodulation technology, limiting the LED drive current to a low value, and further irradiating the weak light beam 40, which is widely expanded by a lens system, including the cells surrounding the hippocampus, and indiscriminately regenerating all cells in the irradiated area if they are damaged." Therefore, the weak light is irradiated without avoiding it from hitting unintended cells around the hippocampus.
For this purpose, the position and direction for fixing the LED light source 30 to the connecting member 470 of the mouthpiece 460 are designed using a three-dimensional CAD or the like based on the coordinate system of FIG.

8B shows an example in which the lower right LED light source 30 irradiates the upper left hippocampus as well, and the lower left LED light source 30 irradiates the upper right hippocampus as well. By "crossing the light beams 40 inside the oral cavity" in this way, a relatively long distance can be secured from the LED light source 30 to the irradiation target point 490, and the light beams 40 of the LED light source 30 with a large half-value angle can be easily spread, so that a wide area deep in the brain can be irradiated with a small number of LED elements.
Incidentally, while FIG. 8(b) illustrates an example in which two LED light sources 30 are provided, the design may be modified so that two or more LED light sources 30 are attached to the mouthpiece 460 to irradiate an even wider area deep in the brain.

In the prototype, the LED light source 30 was protected with transparent food wrap to prevent saliva from entering and shorting out the electronic circuit, but when producing the mouthpiece 460 as an actual product at the industrial application stage, it is desirable to design it so that the LED light source 30 and the electrical wire outlet are waterproofed and encapsulated in a transparent resin material that transmits near-infrared light.

(5) Effect of Example 2 By using the MCI treatment device LED mouthpiece 400 of the present invention, it is possible to irradiate multiple optical axes and treat multiple affected areas simultaneously, so that the treatment effect can be achieved without delay even for patients with advanced MCI, and the forgetfulness symptom can be treated as a symptom improvement therapy.

In addition, the light beam 40 emitted by the LED mouthpiece 400 flickers at approximately 40 Hz, and the mechanism of action described in Patent Document 1 has the effect of preventing or delaying the risk of the condition progressing to Alzheimer's disease.

In addition, because the light beam 40 emitted by the treatment device LED mouthpiece 400 is weak, it also has the effect of regenerating already damaged cells in the affected area of MCI through the mechanism of action of photobiomodulation.

Furthermore, photobiomodulation stimulates brain cells in the affected area of MCI at approximately 40 Hz, so by properly managing the phase difference when used in conjunction with the sensory therapy device 20, it is possible to simultaneously treat the brain fog and forgetfulness symptoms of MCI. (See Example 4 for details)

In this Example 3, we will introduce a digital medical treatment device used in symptom improvement therapy for MCI, which flashes near-infrared light in a wavelength range (650 to 1000 nm) called the biological window 3 that transmits through biological tissue with a repeating waveform of approximately 40 Hz, irradiates the affected area of MCI on the side of the head from above the scalp, and transmits through the skull to stimulate at approximately 40 Hz.
The name of the treatment device explained in the third embodiment is called an LED pad 600, and an image of the invention is shown in FIG.

(1) Matter of the Invention In this embodiment 3, the following four matters of the invention will be mainly described so as to clarify the technical ideas and design contents of the matters of the invention.
Although the third embodiment also includes many inventive matters that define more detailed matters, in order to avoid complicating the explanation, only the following inventive matters will be extracted and explained in detail.

<Invention A of the Third Embodiment>
The main inventive features of the LED pad 600 are as follows:
"In digital medical treatment devices used in symptom improvement therapy for MCI,
The LED pad 600 is a PBM therapy device 10 that blinks a light source in a wavelength range called a biological window 3 that transmits biological tissue with a repetitive waveform of about 40 Hz and irradiates the MCI affected area from above the scalp with a light energy density 140 of a predetermined value 5 or less,

The LED pad 600 includes an LED light source 30, an LED pad body 610, and an LED driving device 50.
The LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the wavelength range of 650 to 1000 nm of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40;
The LED pad body 610 includes a connecting member 625 that is connected to a head fixing member 620 that fixes the LED pad body 610 to the head and determines the emission position and emission direction of the light beam 40 emitted from the LED light source 30, and a transparent plate 630 that emits the light beam 40 from the LED pad body 610. The LED pad body 610 is further configured with an internal structure of a matrix system 640 in which the LED light sources 30 are arranged vertically and horizontally, or a backlight system 650 in which the LED light source 30 is incorporated as a light source of a backlight 660.
The LED driving device 50 is a device that supplies a driving current to the LED element 60 to irradiate the luminous flux 40 from the LED light source 30 at the light energy density 140 of 10 mW/cm or less as the predetermined value 5,

The LED driving device 50 also includes a 40 Hz signal source 210, an LED driving circuit 220, an output adjusting means 230, and an output monitoring means 240.
The 40 Hz signal source 210 outputs a command value 250 of a time series waveform of about 40 Hz of the luminous flux 40 emitted by the LED light source 30 of the LED pad 600;
The LED driving circuit 220 receives the command value 250 output from the 40 Hz signal source 210 and supplies a driving current to the LED light source 30;
The output adjusting means 230 continuously and/or discontinuously adjusts the light energy density 140 of the light flux 40 emitted from the LED light source 30;
The output monitoring means 240 indirectly or directly measures and displays the light energy density 140 emitted by the LED pad 600.

<Invention B of Example 3>
The invention relates to the internal structure of the matrix type 640 of the LED pad body 610:
The internal structure of the matrix type 640 is such that the transmission plate 630 that transmits the light beam 40 is disposed on the ceiling surface of the LED pad body 610, and the LED light sources 30 that irradiate the light beam 40 toward the transmission plate 630 are disposed vertically and horizontally on the bottom surface of the LED pad body 610.
Characterized in that
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 3.

<Invention C of the Third Embodiment>
The invention relates to the internal structure of the backlight system 650 of the LED pad body 610:
The internal structure of the backlight system 650 is characterized in that the transparent plate 630 that transmits the light beam 40 is disposed on the ceiling surface of the LED pad body 610, and the bottom surface of the LED pad body 610 is provided with a backlight 660 that is composed of the LED light source 30, a reflector plate 662, and a light guide plate 664 and/or a diffusion plate 666 that irradiates the light beam 40 toward the transparent plate 630.
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 3.

<Invention Item D of Example 3>
Furthermore, the functions of the 40 Hz signal source, including separate excitation, self-excitation, and switching, can be summarized as follows:
The command value 250 issued by the 40 Hz signal source 210 is
The LED driver 50 is provided with a self-excited/separately excited switching means 260 for generating the LED by a separate excited operation 100 or a self-excited operation 105.
When generating the command value 250 by the separately excited operation 100, the signal source built into the 40 Hz signal source 210 is synchronized in phase with the synchronization signal 130 input from the outside to generate the command value 250.
In the case of generating the command value 250 by the self-excitation operation 105, a signal source incorporated inside the 40 Hz signal source 210 generates the command value 250 independently.
Characterized in that
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 3.

(2) Problems of the Third Embodiment The third embodiment has two problems.
<Deep brain irradiation alone is insufficient to improve "severe forgetfulness">
As described in Examples 1 and 2, the symptom of "mild forgetfulness" caused by MCI lesions located only in the deep brain could be improved.
However, in cases of "severe forgetfulness" in which the lesion has spread to the side closer to the cortex of the temporal region (such as the temporal pole), simply irradiating the brain with weak near-infrared light based on photobiomodulation technology from deep inside the brain will result in the light being absorbed by biological tissue along the transmission path and will not penetrate from the deep brain to the lesion closer to the cortex.

<40Hz light and sound alone is insufficient to improve "severe brain fog">
In order to improve mild brain fog symptoms, conventional phase-synchronized 40 Hz light and sound stimulation can be used, and the "amplitude" of the 40 Hz component of the brainwaves increases not only in the frontal, parietal and occipital regions, but also in the temporal regions. This improves the symptoms of "mild" brain fog.
However, improving the severe brain fog symptoms caused by advanced MCI requires an increase in "coherence," which is phase-synchronized with 40 Hz light and sound stimuli. However, the increase in coherence is unstable in the left and right temporal regions, and 40 Hz light and sound cannot deliver 40 Hz stimulation to the temporal regions.

(3) Solution of Example 3 <Phase synchronization with irradiation from deep brain>
In order to alleviate symptoms of severe forgetfulness, if irradiation from the deep brain side in the above-mentioned Examples 1 and 2 does not reach the cortex, phase-synchronized light energy at 40 Hz can be irradiated from the cortical side of the temporal region.

<Phase synchronization with 40Hz light and sound>
To alleviate severe brain fog symptoms, it is sufficient to strengthen and stabilize the coherence of the temporal region by stimulating it with 40 Hz light and sound, as in the conventional technology. To achieve this, the cortical side of the temporal region is stimulated with phase-synchronized light energy at 40 Hz, and the temporal region is phase-synchronized.

<Irradiating the temporal region with light energy>
Ultimately, in order to improve symptoms of severe forgetfulness, it is sufficient to irradiate 40 Hz light energy from the temporal region in phase synchronization with the light energy irradiation from the deep brain side in Examples 1 and 2.
Additionally, severe brain fog symptoms can be alleviated by applying 40 Hz light energy to the temporal region in phase synchronization with conventional light and sound stimulation.
In either case, if the light energy emitted is too strong, it can damage brain cells and have the opposite effect, so it is sufficient to set an upper limit and limit the density of the light energy emitted.

(4) Design Guidelines for Example 3 The design guidelines for the treatment device for Example 3 were set to the following five points.
1) The treatment device is designed to be secured to the head using a headband (or head securing member 620 such as a hat, helmet, glasses, goggles or special device).
2) The density of light energy that can be irradiated is variable, with only an upper limit set so as not to damage brain cells.
3) The density of the emitted light energy will be kept as low as possible while still being effective in relieving the symptoms of MCI (forgetfulness and brain fog), making it a PBM treatment device that also aims to regenerate damaged brain cells.
4) Equipping the treatment device with a fail-safe function that immediately disables irradiation if the means for limiting the upper limit of the light energy density of the treatment device fails.
5) To prevent errors in setting the light energy density of the treatment equipment, a function will be provided that allows the patient to monitor the output themselves.

(5) Detailed Description of the Third Embodiment FIG. 5 is a diagram for explaining in detail the LED pad 600 for optically stimulating the temporal region from the scalp side according to the third embodiment.
The LED pad 600 is a digital medical treatment device used in symptom improvement therapy for MCI, and is a PBM therapy device 10 that blinks a light source in a wavelength range called the biological window 3 that transmits through biological tissue with a repeating waveform of approximately 40 Hz, and irradiates the MCI affected area from above the scalp with a light energy density 140 of a predetermined value 5 or less.

FIG. 5A is a diagram showing the positions of the cortex of the left and right temporal regions (P) as treatment target regions using the LED pad 600 of the third embodiment.
The right diagram in FIG. 5( a ) is a cross-sectional view of the brain as seen from the front, and (A) and (B) indicate affected areas deep in the brain where symptoms of forgetfulness are treated with the PBM therapy device 10 .
The left diagram in Figure 5(a) is a cross-sectional view of the brain seen from the side, showing the point (L) where brain waves are generated by 40 Hz light stimulation using the sensory therapy device 20, and the point (S) where brain waves are generated by sound stimulation.

5B is a diagram showing how to use the LED pad 600, and illustrates a method of fixing the LED pad body 610 to the left and right sides of the head using a headband as the head fixing member 620. The LED pad body 610 and the headband can be connected by various connecting methods such as a resin buckle or a Velcro (registered trademark) connecting member 625. For example, a hat, helmet, or a dedicated fixing tool can be used as the head fixing member 620, and a button, hook, snap, or the like for fixing a fixing band can be used as the connecting member 625 for connecting the LED pad body 610 to these and determining the emission position and emission direction of the light beam 40 emitted from the LED light source 30.
The LED pad 600 includes an LED pad body 610, an LED light source 30 disposed therein, and an LED driving device 50 that supplies an LED driving current to the LED pad body 610. The LED pad body 610 is connected to the LED driving device 50 by an electric wire such as a multi-core cable.

As in the first and second embodiments, each LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the range of 650 to 1000 nm of the wavelength of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40. If the necessary and sufficient directivity of the light beam 40 is obtained by the lens shape made of transparent resin formed in the emission part of the LED element 60, there is no need to add a new optical system.

It is also possible to design the LED element 60 (or laser light source) in the LED light source 30 to be incorporated into the LED driving device 50, in which case it goes without saying that some or all of the electrical wires can be replaced with optical fiber.

<Matrix method>
The upper diagram in Fig. 5(c) shows a front view of an example of a matrix system 640 in which 16 LED light sources 30 are arranged vertically and horizontally in 4 rows and 4 columns inside an LED pad body 610. The LED light sources 30 do not necessarily have to be arranged in a checkerboard pattern, and can be arranged two-dimensionally in the vertical and horizontal directions, such as in a staggered arrangement or a plane consisting of hexagons, as long as there are no problems such as excessive crowding that impairs the heat dissipation characteristics of the LED elements 60 of the LED light source 30.

5C is a side view of the LED pad body 610, showing the arrangement of the LED light sources 30 and the transparent plate 630. The internal structure of the matrix type 640 is such that the transparent plate 630 that transmits the light beam 40 is disposed on the ceiling surface of the LED pad body 610, and the LED light sources 30 that irradiate the light beam 40 toward the transparent plate 630 are arranged vertically and horizontally on the bottom surface of the LED pad body 610.
As shown in the figure, the light emitted from the LED light source 30 needs to travel a sufficient distance before it spreads and passes through the transmission plate 630, so the LED pad body 610 of this matrix type tends to be thick. Furthermore, since the light fluxes 40 overlap, the LED pad body 610 is characterized in that the light energy density 140 becomes higher toward the center. In other words, the peak of the light energy density 140 occurs in the center.
Although not shown, a light sensor for directly monitoring the brightness of the emitted light may be provided inside the LED pad body 610 .
The transmission plate 630 may be colorless and transparent, or may be white and semi-transparent to diffuse the light beam 40 .

<Backlight method>
The upper diagram in FIG. 5(d) is a front view of a backlight 660 structure constructed using near-infrared LEDs.
By adjusting the directivity of the light beam 40 emitted from the optical system 70 included in the LED light source 30 of the backlight system 650 to be thin horizontally, the design is such that most of the emitted light beam 40 passes through the light guide plate 664 from the side of the thin backlight 660, is reflected by the reflector plate 662, and then passes through the light guide plate 664 and/or the diffuser plate 666 toward the front.

In other words, the backlight 660 has a structure similar to that of an LED backlight built into an LCD monitor for a PC, with LED elements 60 arranged in a straight line as the LED light source 30 at the bottom of the backlight 660. This figure shows an example in which a light leakage section is provided on the side of the backlight 660, and by doing so, the light leaking from the side can be detected by an optical sensor, allowing the optical energy density 140 of the emitted light to be directly monitored by the optical sensor.

The lower diagram in Figure 5 (d) is a side view of the LED pad body 610 of the backlight type 650, in which near-infrared light irradiated from below by the LED light source 30 is reflected by a white or mirror-finished reflector 662 in a direction perpendicular to the screen of the backlight 660, and the entire screen is illuminated evenly with near-infrared wavelengths using a light guide plate or a diffusion plate.
In other words, the internal structure of the backlight system 650 includes a transparent plate 630 that transmits the light beam 40 on the ceiling surface of the LED pad body 610, and an LED light source 30 and a reflector 662 that irradiate the light beam 40 toward the transparent plate 630 on the bottom surface of the LED pad body 610, as well as a light guide plate 664 and/or a diffusion plate 666.
The backlight type 650 has a feature that light with a nearly uniform light energy density 140 can be emitted toward the right in the FIG. 5D direction. Also, the LED pad body 610 of the backlight type 650 tends to be thinner than that of the matrix type 640.
The transmission plate 630 may be colorless and transparent, or may be white and semi-transparent to diffuse the light beam 40 .

Incidentally, when replacing the white LEDs incorporated in the backlight of LCD monitor panels (hereinafter referred to as "commercial monitors") of commercially available small game machines, ultra-small notebook PCs, etc. with near-infrared LED light sources 30, it is desirable to modify the optical system 70 of the LED light source 30 to reduce its directivity. Then, the current passing through the LED light source 30 is controlled to blink at about 40 Hz. The liquid crystal display layer of FIG. 5(d) incorporated in the commercially available monitor may be removed.
Alternatively, as shown in FIG. 5(d), the liquid crystal display layer installed in a commercially available monitor may not be removed, and the entire liquid crystal display layer may be blinked at about 40 Hz to irradiate the light stimulus.

The design can also be modified so that the transparent plate 630 on the emission surface of the backlight 660 is covered with an "LCD element that controls the drive voltage to simultaneously blink the entire surface corresponding to the sunglasses lens" similar to the LCD sunglasses 180, a constant current is passed through the LED light source 30 to make the entire light-emitting surface of the backlight 660 shine with a uniform light energy density 140, and the LCD element is driven with a drive voltage with a time-series waveform that repeats at 40 Hz to blink the irradiated light beam 40 at 40 Hz.

Similarly, the translucent plate 630 on the exit surface of the matrix system 640 in FIG. 5C can be redesigned so that the LED light sources 30 emit light evenly and the translucent plate 630 is made of LCD elements similar to the LCD sunglasses 180 and blinks at 40 Hz.
In this way, various design modifications can be made based on the technical concept of the present invention.

Figure 5(e) is a diagram showing the configuration of the LED driving device 50. The LED driving device 50 is a device that supplies a driving current to the LED element 60 and causes the LED light source 30 to irradiate the light flux 40 with a light energy density 140 of 10 mW/cm2 or less as a predetermined value 5.

FIG. 5( e) shows an example in which eight surface-mounted LED elements 60 connected in series and a resistor R are combined into one set, and two sets of these are connected in parallel to balance the current with the resistor R to form an LED group.
5(e) corresponds to the LED light source 30, and each of the LED light sources 30 is provided with an optical system 70. The number of LED light sources 30 constituting the LED group can be changed in design depending on the device specifications such as the LED element characteristics and the dimensions and shape of the LED pad 600.
Based on the same design principles as in the first and second embodiments, a high sensitivity fuse (for example, 20 mA) and an ammeter are connected in series to the LED group, and current is supplied from the LED driving device 50 to the LED group.

The LED driving device 50 is also configured to include a 40 Hz signal source 210, an LED driving circuit 220, an output adjustment means 230, and an output monitoring means 240. The 40 Hz signal source 210 outputs a command voltage of an arbitrary waveform with a repetition frequency of about 40 Hz, such as a sine wave or a square wave, as a command value 250 of a time series waveform of about 40 Hz of the luminous flux 40 emitted by the LED light source 30 of the LED pad 600. The LED driving circuit 220 inputs the command value 250 output by the 40 Hz signal source 210 and supplies a driving current to the LED light source 30. The output adjustment means 230 continuously adjusts the LED driving current by using, for example, a variable resistor to adjust the light energy density 140 of the luminous flux 40 irradiated from the LED light source 30. It may also be discontinuously adjusted using a switch or the like. The output monitoring means 240 indirectly measures the light energy density 140 emitted by the LED pad 600 by displaying the LED drive current with an ammeter, or directly measures and displays the luminous flux 40 emitted by the LED light source 30 using an optical sensor such as that shown in FIG. 5(d).

Figure 5(f) is a specific circuit example of the LED driver 50, and as already explained in the first and second embodiments, the 40 Hz signal source 210 outputs a command voltage with an arbitrary waveform that repeats at 40 Hz as the command value 250, and the LED driver circuit 220 to which the command voltage is input supplies a drive current to the LED group. In the figure, a sine wave waveform with a maximum value of 3 V, a minimum value of 0 V, and an average value of 1.5 V is set as the command voltage for the LED driver circuit 220, and a drive current is supplied to the LED group using the current flowing through the feedback resistor circuit consisting of R5, R6, R7, SW1, and VR1.

In this case, if the total resistance value of the feedback resistor circuit is adjusted to, for example, 300 ohms, the current value flowing through the LED group is controlled to a maximum of 10 mA, a minimum of 0 mA, and an average of 5 mA.
Based on the arrangement of the LED light sources 30 of the LED pad 600 and the design of the optical system 70, the total resistance value of this feedback resistance circuit is set so that the upper limit value of the light energy density 140 irradiated by the LED pad 600 is equal to or less than the predetermined value 5 of 10 mW/cm2. In other words, by adjusting SW1, VR1 or R5, R4, and R3 constituting the feedback resistance circuit, the light energy density 140 can be adjusted to be equal to or less than the predetermined value 5. Of course, the design may be modified so that the amplitude and average value of the command voltage output by the 40 Hz signal source 210 are adjusted by a variable resistor or switch.

<About the 40 Hz phase-synchronized signal>
The LED pad 600 can be used alone to irradiate a specific brain region and treat only the cerebral cortex of that region. For example, as an example of using the LED pad 600 alone, it can be used to irradiate light for the purpose of preventing Alzheimer's disease by irradiating near-infrared light of about 40 Hz from any scalp part other than the temporal region (for example, the forehead, the parietal region, or the occipital region).

In Figures 5(e) and 5(f), in order to phase-synchronize the frequency of the LED drive current, which has a frequency of about 40 Hz and is supplied to the LED light source 30, with an external signal, a pulse-like synchronization signal 130 is input from the outside to a 40 Hz signal source 210.
This is for phase-synchronizing the stimulation caused by the near-infrared light irradiation of the LED pad 600 when used in combination with near-infrared light of approximately 40 Hz generated by a PBM therapy device 10 such as the LED lance 200 of Example 1 or the LED mouthpiece 400 of Example 2 for the purpose of improving symptoms of forgetfulness.
Alternatively, when used in conjunction with a conventional sensory therapy device 20 that uses light and sound stimulation at approximately 40 Hz to improve symptoms of brain fog, the LED pad 600 can also be used to phase-synchronize the stimulation caused by near-infrared light irradiation.

In other words, the command value 250 issued by the 40 Hz signal source 210 is generated by the separate excitation operation 100 or the self-excitation operation 105 by the self-excitation/separate excitation switching means 260 arranged in the LED driving device 50. When generated by the separate excitation operation 100, the command value 250 is generated by synchronizing the phase of the signal source incorporated inside the 40 Hz signal source 210 with the synchronization signal 130 input from the outside. When generated by the self-excitation operation 105, the command value 250 is generated independently by the signal source incorporated inside the 40 Hz signal source 210.
When the LED pad 600 is used alone, it can be used to irradiate the scalp of a specific brain region and treat only the cerebral cortex of that region alone. When designed exclusively for this single use, the externally input synchronization signal 130 and the self-excitation/separate excitation switching means 260 are not required, and the 40 Hz signal source 210 can output a 40 Hz command signal in self-excitation operation 105 without external synchronization with the 40 Hz synchronization signal, as in the first and second embodiments.

(6) Effects of the Third Embodiment <In the case of single use>
The LED pad 600 can apply a stimulation of about 40 Hz to the cerebral cortex from the scalp side using photobiomodulation technology. Therefore, not only can it be expected that the causative substances of Alzheimer's disease, such as amyloid β, can be reduced by the stimulation of about 40 Hz, but also that damaged brain cells can be healed by the weak light.
Therefore, the LED pad 600 can be used alone to irradiate light from any part of the scalp other than the temporal region for the purpose of preventing Alzheimer's disease.

<When used in combination with other treatment devices>
As in Example 4 described later, the LED pad 600 can also provide stimulation from the scalp side of the temporal region by being used in combination with the approximately 40 Hz stimulation to the deep brain in Examples 1 and 2 in phase synchronization. This makes it possible to improve forgetfulness symptoms of severe amnesic MCI that could not be cured by only the approximately 40 Hz stimulation to the deep brain in Examples 1 and 2.

In addition, as in Example 4 described below, if the light stimulation of the LED pad 600 with a weak light energy density of 140 is phase-synchronized with the conventional light and sound sensory therapy device 20 of approximately 40 Hz and applied to the temporal region, the coherence of the temporal region will increase stably, and severe brain fog symptoms that could not be cured by the conventional light and sound sensory therapy device 20 of approximately 40 Hz alone will be improved.

In this Example 4, in a digital medical treatment device used in symptom improvement therapy for MCI, a PBM therapy device 10 that flashes a light source in a wavelength range called a biological window 3 that transmits through biological tissue with a repeating waveform of about 40 Hz to irradiate a light beam 40 with a light energy density 140 of a predetermined value 5 or less toward the affected area of MCI, and a sensory therapy device 20 that uses the phenomena of SSVEP and ASSR to induce brain waves of about 40 Hz with visual stimulation by light and auditory stimulation by sound are introduced.
The name of the treatment device described in the fourth embodiment is called a phase control device 150. A general explanation of the phase of the treatment device is shown in Fig. 6, and an image of the contents of the invention is shown in Fig. 7, a part of Fig. 8, Fig. 9, and Fig. 10.

(1) Matter of the Invention In this embodiment 4, the following seven matters of the invention, including modifications, will be mainly described so as to clarify the technical ideas and design contents of the matters of the invention.
Although Example 4 includes many inventive matters that specify more detailed matters, in order to avoid complicating the explanation, only the following seven inventive matters will be extracted and explained in detail.

<Invention A of the Fourth Embodiment>
The main inventive features of the phase control device 150 are as follows.
"In digital medical treatment devices used in symptom improvement therapy for MCI,
A PBM therapy device 10 that irradiates a light beam 40 at an affected area of MCI with a light energy density 140 of a predetermined value 5 or less by blinking a light source in a wavelength range called a biological window 3 that transmits through biological tissue with a repetitive waveform of about 40 Hz, and a sensory therapy device 20 that uses the phenomena of SSVEP and ASSR to induce brain waves of about 40 Hz with visual stimulation by light and auditory stimulation by sound.
The present invention is characterized in that the PBM therapy device 10 and the sensory therapy device 20 are provided with a phase control device 150 that outputs the synchronization signal 130 for phase-synchronizing the phase angles 110 of two or more types of stimulations and setting and controlling the phase difference 120 of the phase angles 110 of the multiple types of stimulations.
"40Hz Therapeutic Device for MCI Treatment"

<Invention B of Example 4>
The PBM therapy device 10 in the fourth embodiment is characterized by performing a separate excitation operation 100 .
"The PBM therapy device 10 includes an LED light source 30 and an LED driving device 50, and the LED light source 30 includes a semiconductor chip 65 of an LED element 60 that irradiates a light beam 40 having an output wavelength (or peak wavelength) in the wavelength range of 650 to 1000 nm of the biological window 3, and an optical system 70 that adjusts the half-value angle of the directivity of the light beam 40,
The LED driving device 50 supplies a driving current to the LED element 60 to cause the LED light source 30 to irradiate the luminous flux 40 with the light energy density 140 of 10 mW/cm2 or less as the predetermined value 5.
At the same time, a separate excitation operation 100 is performed in which a drive current is supplied to the LED element 60 with a repetitive waveform of about 40 Hz in phase synchronization with a synchronization signal 130 input from the outside.
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 4.

<Invention C of the Fourth Embodiment>
The sensory therapy device 20 in the fourth embodiment is characterized in that it performs a separate excitation operation 100 in response to one synchronization signal 130 .
"The sensory therapy device 20 comprises a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820,
The visual stimulation device 800 is a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of a lens portion at about 40 Hz,
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of about 40 Hz, a headphone 164, and a speaker 166;
The audiovisual phase control device 820 performs the separate excitation operation 100 to control the phase of the stimulation by light and sound by setting the phase difference 120 between the visual stimulation device 800 and the auditory stimulation device 810 at a repetition frequency of about 40 Hz in phase synchronization with the "single" synchronization signal 130 input from the outside.
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 4.

<Invention Item D of Example 4>
The sensory therapy instrument 20 in the fourth embodiment is characterized in that it performs the separate excitation operation 100 in response to two synchronous signals 130 of light and sound.
"The sensory therapy device 20 comprises a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820,
The visual stimulation device 800 is a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of a lens portion at about 40 Hz,
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of about 40 Hz, a headphone 164, and a speaker 166;
The audiovisual phase control device 820 performs the separate excitation operation 100 to control the phase of the light and sound stimulation in the visual stimulation device 800 and the auditory stimulation device 810 at a repetition frequency of about 40 Hz in phase synchronization with the synchronization signal 130 "individual for visual and auditory input from the outside."
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 4.

<Invention Item E of Example 4>
The sensory therapy instrument 20 in the fourth embodiment is characterized in that it performs a self-excitation operation 105 and outputs a reference synchronization signal 830 .
"The sensory therapy device 20 comprises a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820,
The visual stimulation device 800 is a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of a lens portion at about 40 Hz,
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of about 40 Hz, a headphone 164, and a speaker 166;
The audiovisual phase control device 820 controls the phase of the stimulation by light and sound by setting the phase difference 120 between the visual stimulation device 800 and the auditory stimulation device 810 at a repetition frequency of about 40 Hz in phase synchronization with the "single reference synchronization signal 830 generated inside the sensory therapy device 20" and
A self-excitation operation 105 is performed to output the reference synchronization signal 830 to the outside.
A 40 Hz therapy device for treating MCI, as described in the invention item A of Example 4.

<Invention Item F of Example 4>
The phase control device 150 in the fourth embodiment is particularly characterized in that it outputs a synchronization signal 130 to both the PBM therapy device 10 and the sensory therapy device 20 .
The phase control device 150 phase-synchronizes the phase angles 110 of two or more types of stimulations among the PBM therapy device 10 and the sensory therapy device 20 that perform the separate excitation operation 100, and outputs the synchronization signal 130 that sets and controls the phase difference 120 of the phase angles 110 of the multiple types of stimulations.
A 40 Hz therapy device for treating MCI according to invention items A to D of Example 4.

<Invention Item G of Example 4>
The phase control device 150 in the fourth embodiment is particularly characterized in that it receives a reference synchronization signal 830 from the sensory therapy device 20 and outputs a synchronization signal 130 to the PBM therapy device 10 .
"The phase control device 150 inputs the reference synchronization signal 830 output by the sensory therapy device 20 performing the self-excitation operation 105, phase-synchronizes the PBM therapy device 10 performing the separate excitation operation 100, and outputs the synchronization signal 130 that sets and controls the phase difference 120 of the PBM therapy device 10.
"A 40 Hz therapy device for treating MCI, as described in the inventions A, B and E of Example 4"

(2) Problems of Example 4 Mild MCI has two main symptoms: forgetfulness and brain fog. Mild forgetfulness was improved by the PBM therapy device 10, which irradiates weak near-infrared light that flickers at about 40 Hz mainly toward the MCI-affected area deep in the brain, and mild brain fog was improved by the sensory therapy device 20, which activates SSVEP and ASSR through sensory stimulation with light and sound at about 40 Hz so as to strengthen the amplitude and coherence of electroencephalograms at about 40 Hz throughout the brain.

However, when MCI progresses and the condition worsens to the point where the affected area has spread to both the deep brain and the cortex, one of the above two treatment methods alone is no longer sufficient treatment, and there is a risk that the simultaneous stimulation of multiple parts of the brain can cause harmful confusion in the phase difference, leading to cognitive impairment and decline.

(3) Solution of Example 4 Since the problem is that "the occurrence of harmful phase differences" occurs due to "simultaneous stimulation of multiple parts of the brain," the solution to this problem is nothing other than "appropriately managing the phase differences in multiple simultaneous stimuli."
In other words, a therapeutic device is provided that intentionally and appropriately manages the phase difference between multiple types of stimuli by the PBM therapy device 10 and the sensory therapy device 20.

On the other hand, the phase synchronization described in the conventional methods of Non-Patent Documents 5 and 6 merely presents a mathematically self-evident fact that "the phase difference between the waveforms of a phase-synchronized 40 Hz rectangular light wave and a rectangular sound pulse (also called a click sound) is between 0 and ±180."
In other words, the conventional method does not disclose or suggest the technical idea of "actively and intentionally setting and maintaining a phase difference value" or "aiming for an effect specific to that value (or avoiding side effects)."

The technical concept that characterizes the present invention is to actively and intentionally set and maintain a phase difference value for the PBM therapy device 10 and the sensory therapy device 20, while aiming for effects such as safety specific to that value (or avoiding side effects).

(4) General Description of Phase Synchronization FIG. 6 is a diagram for explaining the definitions of phase angle and phase difference in the present invention using an example in the case where two waveforms with the same frequency are phase-synchronized.
Incidentally, as already explained, the notation 40 Hz in the present invention is merely abbreviated to include frequencies near 40 Hz within the range in which the mechanism of action of the 40 Hz therapy in Patent Document 1 and Non-Patent Document 4 is established, and therefore the expressions "approximately 40 Hz" and "40 Hz" express the same meaning in the present invention.

FIG. 6A is a diagram for explaining the definition of a phase difference of 0 degrees in the present invention with respect to the phase-synchronized waveforms of light and sound stimuli of approximately 40 Hz.
Here, as an example of the light stimulus waveform having a frequency of "about 40 Hz," to be precise, when a frequency of 41.67 Hz is applied, one period is 24.0 milliseconds. The illustrated light stimulus waveform depicts a square wave with a duty ratio of 50%.
The waveform of the sound stimulus also has a repetition frequency of approximately 40 Hz, which is phase-synchronized with the light; more precisely, it has the same frequency as the light, 41.67 Hz. In this figure, a clicking sound is depicted in the shape of a square wave with a pulse width of 1.0 millisecond and a duty ratio of 4.17%.
In this way, if the horizontal axis of a diagram explaining phase synchronization is written as elapsed time (milliseconds), the example of "approximately 40 Hz (or 40 Hz)" according to the notation used in this invention is not limited to 41.67 Hz and can also be other frequencies, so the values on the horizontal axis of the graph will change and the explanation and diagrams will become complicated.
Therefore, in the following explanations and figures regarding phase synchronization at a frequency of "approximately 40 Hz", the phase angle (degrees) or phase difference (degrees) will be expressed on the horizontal axis with values ranging from -180 degrees to +180 degrees.

In the present invention, as shown in FIG. 6(a), the phase angle is defined as 0 degrees at the moment when the rectangular wave of the optical stimulus rises from a "dark state with a logical value of 0" to a "bright state with a logical value of 1".
In addition, it is defined that "if, based on the phase of light, the moment when the two rectangular waves of light and sound rise from logical value 0 (dark light, no sound) to logical value 1 (bright light, sound) is the same, then the phase difference is 0 degrees."
Therefore, it is mathematically self-evident that the phase difference between the two rectangular waves of light and sound is between 0 degrees and ±180 degrees.

Figure 6 (b) shows the relationship between the phase difference of the square wave light and the click sound when the phase difference of the sound stimulus is set to -90 degrees with respect to the phase of the light. In other words, if the phase difference is -90 degrees, the sound stimulus occurs at a position earlier in time than the light stimulus.

FIG. 6C is a diagram defining the phase angle of a sine wave representing the fundamental frequency component of a square wave.
In the present invention, the moment when the rectangular wave of the optical stimulus rises from a logical value of 0 to a logical value of 1 is defined as a phase angle of 0 degrees. Therefore, for a sine wave, which is the fundamental frequency component of a rectangular wave with a duty ratio of 50%, if the moment when the sine wave crosses the average value and increases is defined as a phase angle of 0 degrees, then the timing for defining a phase angle of 0 degrees will match.

Figure 6 (d) shows the relationship between the phase difference of the sinusoidal light and the click sound when the phase difference of the sound stimulus is set to -90 degrees with respect to the phase angle of the light. In other words, if the phase difference is -90 degrees, the sound stimulus occurs at a position earlier in time than the light stimulus.

<Selection of phase difference (safety and side effects)>
Non-Patent Document 3, a conventional technique, describes that disrupting the phase difference between stimuli applied to different locations in the brain reduces the cognitive level of the subject.
Similarly, in a series of experiments conducted by the inventor, when the phase difference was set to +90 degrees (i.e., the sound was delayed by +90 degrees compared to the light), the subject (the inventor himself) experienced extreme drowsiness and a slight headache.
In other words, from the standpoint of ensuring safety, it is desirable to set the phase difference to 0, and in an experiment conducted by the inventor himself as a subject, whether the light waveform was a square wave or a sine wave, as long as the phase difference with the click sound was 0 degrees, the therapeutic effect in eliminating the brain fog symptoms of MCI was significant.
On the other hand, from the viewpoint of avoiding side effects, if the phase difference is increased to close to +90 degrees in the positive direction (i.e., the phase of the sound is delayed), there is a risk of temporary cognitive decline, such as drowsiness or headaches, although this may vary from person to person, so it is best to avoid making the phase difference too large.

For example, if a repeating stimulus sound at exactly 40.0 Hz is generated from a speaker, a huge, bright light source that flashes at exactly 40.0 Hz and a loud, high-quality speaker are placed about 2 m away from the subject, and a sound stimulus that is phase-synchronized with the light stimulus with a phase difference of 0 degrees is generated from the speaker, the speed of sound will be approximately 344 m at room temperature of 20°C.
Then, one wavelength of a 40.0 Hz sound is approximately 8.6 m, and if you listen to the sound from a distance of approximately 2 m, the phase delay of the sound will exceed 80 degrees, approaching 90 degrees. In this case, although there may be individual differences, there is a high possibility that effects such as drowsiness and headaches will occur, which is undesirable from the viewpoint of avoiding side effects.
If it is not possible to shorten the distance from the speaker to the subject due to circumstances at the treatment facility, etc., safety can be improved by setting a negative phase difference in the sound stimulus so that the phase difference at the moment the sound and light reach the subject is close to 0 degrees.

Similarly, we do not recommend a treatment method for treating MCI in which a large speaker 166 is placed in a corner of a large room and multiple patients each wear LCD sunglasses 180. The reason for this is that the phase difference between the light and sound for each patient will vary depending on the patient's position (more precisely, the distance from the speaker), resulting in uneven therapeutic effects. In fact, depending on the distance from the speaker, patients may feel extremely drowsy or experience a slight headache. Please exercise extreme caution when doing this.

When wired earphones 168 or headphones 164 are used as the auditory stimulation device 810, the phase delay of sound propagating through the air is so slight that it can be ignored.
Therefore, in the case of treatment using the sensory therapy device 20, when a large number of patients are treated together in a large room using a common large screen or individual LCD sunglasses 180 as the visual stimulation device 800, it is recommended to use wired earphones 168 or headphones 164 including bone conduction earphones 162 as the sound source 160 that emits sound at a repetition frequency of approximately 40 Hz as the auditory stimulation device 810.

Conversely, the specifications of the sound generator 160 as the wireless auditory stimulation device 810 vary from product to product. Please note that if the product has a large phase delay between the audio signal input and the sound output, the therapeutic effect may be uneven or unexpected, and the subject may feel extremely drowsy or have a slight headache.

As described above, even when applying two types of stimuli to different parts of the brain using light and sound of approximately 40 Hz as in conventional technology, the phase difference between each of the stimuli must be explicitly managed in order to control the quality of the therapeutic effect and eliminate risks. Furthermore, when applying multiple types of stimuli by using the PBM therapy device 10 and the sensory therapy device 20 in combination as in this Example 4, it is essential to have a means for explicitly setting and managing the phase difference between each of the stimuli, as explained below.

(5) Description of Example 4 FIG. 7(a) is a conceptual diagram of the treatment of severe MCI accompanied by forgetfulness and brain fog by simultaneously using LCD sunglasses 180 as a visual stimulation device 800 for light stimulation according to the prior art, earphones 168 as an auditory stimulation device 810 for sound stimulation, LED pads 600 for stimulating the left and right temporal regions with near-infrared light, and an LED lance 200 for stimulating the deep brain with near-infrared light.
In this diagram, the wires between the control device that supplies the drive current (or drive voltage) to each stimulation means are omitted, but during actual treatment, many wires will be surrounding the face, so in the case of MCI patients who are in poor health, care must be taken to prevent accidents by the wires becoming entangled around the neck or other parts of the body.

7(b) shows an example in which a helmet is used for treatment to prevent medical accidents caused by numerous electric wires around the face, and treatment tools such as electric wires and LED pads 600 are collectively assembled in the helmet. In the example shown in the figure, instead of the LED lance 200, an LED mouthpiece 400 is fixed to the helmet like a mask.
If the LCD sunglasses 180 and the headphones 164 are integrated as part of the helmet, it becomes easy to handle them as a treatment tool. At least one of the earphones 168 including the bone conduction earphones 162 as the sound generating body 160 that can hear the sound stimulation to both ears, the headphones 164, and the speakers 166 may be included.
When designing this helmet, it is possible to create a new design incorporating various designs and ideas, such as making the fixing position of the LED pad 600 variable, making the LCD sunglasses 180 fixed or flip-up type, and even improving the routing of the electrical wires inside the helmet.
The visual stimulation device 800 may use a light emitter 170 that emits light at a repetition rate of approximately 40 Hz instead of the LCD sunglasses 180 .

Figure 7 (c) shows an example of adjusting the phase angles of multiple treatment devices in a comprehensive manner. When the treatment device 10 of Example 1, Example 2, or Example 3 is used alone, the control device of the treatment device is used in self-excitation operation 105 to generate a frequency of 40 Hz. However, the example in this figure shows an example of use in separate excitation operation 100 in which a synchronization signal 130 is input from the outside to the LED driving device 50 and the sensory therapy device 20 of each PBM therapy device 10 to synchronize the phases.

7C, a phase control device 150 is provided to supply a synchronization signal 130 to each of the multiple treatment devices. In this figure, the phase control device 150 outputs the synchronization signal 130 to the perception therapy device 20 with the channel Ch-C as the reference phase.
In the present invention, the entire system is designed by "defining the light stimulus as the phase reference" in the sensory therapy device 20, and the phase of the light stimulus in the sensory therapy device 20 is externally synchronized by this reference phase signal Ch-C.
Specifically, an audiovisual phase control device 820 that performs a separate excitation operation 100 to control the phase of the light and sound stimulation by setting a phase difference 120 between a visual stimulation device 800 and an auditory stimulation device 810 at a repetition frequency of approximately 40 Hz in phase synchronization with a single synchronization signal 130 input from a phase control device 150 may be incorporated into the sensory therapy device 20.
In this case, the phase control device 150 operates in the self-excitation mode 105 .
In addition, when "sound stimulation is defined as the phase reference" and the design of the entire system is changed, the design of each device of Example 4 can be changed so that the phase of the sound is synchronized with the synchronization signal 130 from the phase control device 150, and a separate excitation operation 100 is performed by setting and controlling the phase difference 120 between the light and sound stimulations.

To summarize the above explanation, the sensory therapy device 20 is composed of a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820. The visual stimulation device 800 is a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of the lens portion at about 40 Hz.
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of about 40 Hz, a headphone 164, and a speaker 166.
The audiovisual phase control device 820 performs a separate excitation operation 100 in which the phase difference 120 between the visual stimulation device 800 and the auditory stimulation device 810 is set at a repetition frequency of approximately 40 Hz in phase synchronization with the single synchronization signal 130 input from outside, thereby controlling the phase of the light and sound stimuli.

In Fig. 7(c), the slider knob of the variable resistor provided on the operation panel of the phase control device 150 is operated to explicitly set a phase difference of, for example, ±40 degrees with respect to channel Ch-C as the phase reference for the synchronization signal 130 of about 40 Hz to be output to channel Ch-A (for the LED pad 600 provided on the scalp on the right side of the head), channel Ch-B (for the LED pad 600 provided on the scalp on the left side of the head), and channel Ch-D (for the LED lance 200 or the LED mouthpiece 400). The upper and lower limits of this phase difference can also be designed to be values other than ±40 degrees.
In clinical treatment, it is generally safe to set all sliders to a phase difference of 0 degrees. However, the doctor can explicitly set the phase difference for each channel based on the individual differences of patients or medical purposes such as improving sleep.

Figure 7(d) provides a simple explanation using an example in which a control microcomputer is used as the phase control device 150. To set the phase difference for each channel, the slider knob of the variable resistor is adjusted to generate an input voltage for each analog input channel, and the input voltage is converted into a target value for the set phase difference. Then, a synchronization signal 130 is output from the digital output (DO-1 to DO-4) of the control microcomputer with the phase difference for each channel.

Here, the synchronization signal 130 for each channel will be specifically described. In the present invention, the explanation is given on the premise of a repetition frequency of about 40 Hz, but for the purpose of making the explanation clear and concise, in this example, a pulse signal as the synchronization signal 130 is output at a phase angle of 0 degrees every 25 milliseconds, which corresponds to one period of 40.0 Hz, in the channel Ch-C serving as the phase reference.
In FIG. 7(d), the slider knob for channel Ch-A is set to a phase difference of 0 degrees, so that digital output DO-1 outputs a pulse signal as synchronization signal 130 at the same timing as channel Ch-C as the reference, that is, a phase difference of 0 degrees.
Since the slider knob for channel Ch-B is set to a phase difference of -20 degrees, the digital output DO-2 outputs the synchronization signal 130 at a timing with a phase difference of -20 degrees compared to the reference channel Ch-C. In other words, using a control microcomputer, while managing time at the 25 millisecond cycle exemplified above, a pulse signal as the synchronization signal 130 is output 25 milliseconds x 20 degrees/360 degrees = approximately 1.4 milliseconds earlier than the reference phase angle of 0 degrees.
Since the slider knob for channel Ch-D is set to a phase difference of +20 degrees, the digital output DO-4 outputs a pulse signal as the synchronization signal 130 at a timing with a phase difference of +20 degrees from the reference channel Ch-C. In other words, the pulse signal as the synchronization signal 130 is output 25 ms x 20 degrees/360 degrees = approximately 1.4 ms later than the reference.

<Excitation operation of the sensory therapy device 20 with a single input>
FIG. 8(c) illustrates the configuration of the sensory therapy device 20 described in FIG. 7(c) and FIG. 7(d).
The sensory therapy device 20 comprises a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820.
The audiovisual phase control device 820 has the function of performing a separate excitation operation 100 in which the phase difference 120 between the visual stimulation device 800 and the auditory stimulation device 810 is set at a repetition frequency of approximately 40 Hz "in phase synchronization with a single synchronization signal 130 input from the outside" to control the phase of the stimulation by light and sound.
In the present invention, the optical visual stimulus is used as the reference phase, so a synchronization signal for generating an optical stimulus is output to a visual stimulation device 800 (e.g., a 40 Hz light emitter 170 or LCD sunglasses 180) with a phase difference of 0 degrees from the synchronization signal 130 input to the audiovisual phase control device 820.
In addition, the audiovisual phase control device 820 has a function of setting the phase difference 120 using a variable resistor VR or the like, and applies the phase difference 120 to a synchronization signal 130 input from the outside, thereby outputting a synchronization signal for generating a sound stimulus to the auditory stimulation device 810.

<Modification 1: Separate excitation operation with multiple inputs of the sensory therapy device 20>
8(d) and 9(a) show modified examples in which the phases of the visual stimulus by light and the auditory stimulus by sound are designated by a phase control device 150. In the modified examples shown in FIG.
A synchronization signal 130 is output as a pulse from channel Ch-C based on the phase of the light stimulus, and the phase difference of the sound stimulus is set by slider knob C2 of the phase control device 150, and a synchronization signal 130 is output as a pulse from channel Ch-C2. These two synchronization signals 130 are supplied to the sensory therapy device 20.
FIG. 8(d) is a diagram for explaining the audiovisual phase control device 820 included in the sensory therapy device 20 of FIG. 9(a), and has the function of performing the separate excitation operation 100 of controlling the phase of the light and sound stimulation in the visual stimulation device 800 and the auditory stimulation device 810 at a repetition frequency of about 40 Hz “in phase synchronization with the individual synchronization signals 130 for vision and hearing input from the outside.”
8(d), if the visual stimulation device 800 and the auditory stimulation device 810 are provided with a function for performing the separately excited operation 100, the function of the audiovisual phase control device 820 in this modified example is simply to pass two synchronization signals 130. In other words, the audiovisual phase control device 820 inputs two synchronization signals 130, one for a visual stimulation by light input to the visual stimulation device 800 and the other for an auditory stimulation by sound input to the auditory stimulation device 810, and causes the visual stimulation device 800 and the visual stimulation device 800 to perform the separately excited operation 100 in phase synchronization with the respective synchronization signals 130 for vision and hearing.

Therefore, the detailed configuration of this modified example 1 is as follows:
The sensory therapy device 20 comprises a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820.
The visual stimulation device 800 is a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or LCD sunglasses 180 that control the transmittance of a lens portion at about 40 Hz,
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of about 40 Hz, a headphone 164, and a speaker 166.
The audiovisual phase control device 820 performs a separate excitation operation 100 that controls the phase of the light and sound stimulation in the visual stimulation device 800 and the auditory stimulation device 810 at a repetition frequency of about 40 Hz in phase synchronization with the respective synchronization signals 130 for vision and hearing input from the outside.
The detailed configuration of the phase control device 150 in this modified example 1 is as follows.
"The phase control device 150 phase-synchronizes the phase angles 110 of two or more types of stimuli among the PBM therapy device 10 and the sensory therapy device 20 performing the separate excitation operation 100, and outputs a synchronization signal 130 that sets and controls the phase difference 120 between the phase angles 110 of the multiple types of stimuli."
In this case, the phase control device 150 operates in the self-excitation mode 105 .

<Modification 2: Self-Excitation Operation of the Sensory Therapy Device 20>
FIG. 9B shows a modified example in which the phase control device 150 is controlled by the separate excitation operation 100 with the phase of the visual stimulation by light in the sensory therapy device 20 as a reference.
As shown in FIG. 10( a ), a reference synchronization signal 830 synchronized with the phase of the light stimulus is output as a pulse from the audiovisual phase control device 820 of the sensory therapy device 20 , and is input to the phase control device 150 as a phase reference.
Thereafter, a synchronization signal 130 is supplied to the PBM therapy device 10 based on the phase difference 120 set by the slider of the phase control device 150 .
That is, "the phase control device 150 inputs the reference synchronization signal 830 output by the perception therapy device 20 performing the self-excitation operation 105, phase-synchronizes the PBM therapy device 10 performing the separate excitation operation 100, and outputs a synchronization signal 130 that sets and controls the phase difference 120 of the PBM therapy device 10."

The phase difference 120 between the light and sound stimuli in the sensory therapy device 20 in Fig. 9(b) is set inside the sensory therapy device 20. That is, "the sensory therapy device 20 is composed of a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820, the visual stimulation device 800 being a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of the lens portion at about 40 Hz, the auditory stimulation device 810 being at least one of earphones 168 including a bone conduction earphone 162 as a sound generator 160 that emits sound at a repetition frequency of about 40 Hz, headphones 164, and speakers 166,
The audiovisual phase control device 820 controls the phase of the light and sound stimulation by setting the phase difference 120 between the visual stimulation device 800 and the auditory stimulation device 810 at a repetition frequency of about 40 Hz in phase synchronization with the "single reference synchronization signal 830 generated inside the sensory therapy device 20" and performing a self-excitation operation 105 that outputs the reference synchronization signal 830 to the outside.

In the present invention, a repetitive waveform of about 40 Hz is used, but as an example for simplifying the explanation, the phase control device 150 is designed to perform time management at an accurate 40.0 Hz, for example, as a mere example of a frequency in the vicinity of about 40 Hz. Then, the phase control device 150 is phase-synchronized with a quasi-synchronization signal 830 of accurate 40.0 Hz, which is regarded as a reference phase, and the synchronization signal 130 with a phase difference applied thereto is output to the PBM therapy device 10 toward Ch-A, Ch-B, and Ch-D in FIG. 9(b).
Incidentally, in the second modified example, when the sensory therapy device 20 is made to perform the self-excitation operation 105, a reference synchronization signal 830 synchronized with the phase of the light stimulus is output as a pulse based on the phase of the light stimulus to the visual sense and input to the phase control device 150 as a phase reference, but it is also possible to change the design so that the reference synchronization signal 830 is output as a pulse based on the “phase of the sound stimulus” as a reference.

As described above, in the fourth embodiment, the phase control device 150 was introduced as a treatment device that sets and controls the phase difference 120 between multiple stimuli when the PBM therapy device 10 and the sensory therapy device 20 are used in combination, but the design can be modified based on the technical concept of the present invention.
For example, the embodiment in which the phase difference 120 is set by the slider resistance using the phase control device 150 has been shown, but it is also possible to set it as a control parameter in a program or to specify it externally through communication.
Further, in the above example, the phase difference 120 is made variable, but all the phase differences 120 can be fixed to, for example, 0 degrees.
Furthermore, although a design example in which the PBM therapy device 10, the sensory therapy device 20, and the phase control device 150 are housed in separate housings has been described, a design change may be made in which these are integrated into a single housing.

In addition, in addition to the method of using the single PBM therapy device 10 and the sensory therapy device 20 in combination at the same time as shown in FIG. 7(a), or the method of using a helmet as shown in FIG. 7(b), it is also possible to combine them with known therapy devices based on the operating principle of a magnetic stimulation therapy device (TMS, tTMS, etc.) that applies electromagnetic stimulation to specific parts of the brain cortex by placing an electromagnetic coil on the scalp, or an electrical stimulation therapy device.
In this case, an electromagnetic therapy control device for controlling the phase of the stimulation emitted by the electromagnetic therapy device can be designed to be externally synchronized by a separate excitation operation 100, and the electromagnetic stimulation applied using the phase control device 150 of the present invention can be controlled by a synchronization signal 130 for each channel with a phase difference 120 so that it is phase synchronized with the phase angle 110 of multiple types of stimulation from other light or sound sensory therapy devices 20 or PBM therapy devices 10 using photobiomodulation technology, which can be easily added to the design based on the technical concept of the present invention.

Finally, a method of switching between the self-excited operation 105 and the separately excited operation 100 will be described using an example of a simple reset method.
In the upper diagram of Fig. 10(b), when there is no input of a synchronization signal, device A performs self-excitation operation 105 at, for example, 39.8 Hz. In other words, device A generates an output pulse with a period of about 25.13 milliseconds corresponding to a frequency of 39.8 Hz. In this example, a pulse is output, but any waveform with a repetition period of 39.8 Hz, such as a square wave or a sine wave, can be used.

In the lower diagram of FIG. 10( b ), a device B is added which generates a synchronization signal 130 of exactly 40.0 Hz and performs self-excitation operation 105 , and the synchronization signal 130 is input to device A.
Then, if device A is reset every 25.00 milliseconds with a synchronization signal 130 of exactly 40.0 Hz, device A, which has been performing self-excitation operation 105 with a period of 25.13 seconds, will begin to generate output pulses with a period of 25.00 seconds in synchronization with the synchronization signal 130 of exactly 40.0 Hz from device B, and will perform separately-excited operation 100.

The operation of this device A can be designed in a variety of ways for a variety of applications, such as synchronizing a bistable multivibrator with an external pulse in the case of a hardware circuit, or synchronizing and resetting the playback operation of a repeating waveform stored in internal memory with an external pulse in the case of a control microcomputer.

Incidentally, the phase control device 150 of the fourth embodiment performs self-excitation operation 105 in the cases of FIG. 7(c) and FIG. 9(a), and performs separate excitation operation 100 in synchronization with the reference synchronization signal 830 in the case of FIG. 9(b).

Summary of the invention as a whole
The present invention relates to a therapeutic device for MCI, and after explaining a conventional sensory therapy device 20 for treating "brain fog", the invention of a PBM therapy device 10 for treating "forgetfulness" was explained using a specific embodiment. Furthermore, a phase control device 150 for treating "severe MCI" by using the PBM therapy device 10 and the sensory therapy device 20 in combination was also explained.
In other words, each of the treatment devices and the phase control device 150 in the present invention constitutes a unified technical concept from the viewpoint of devices for treating the symptoms of MCI.

Below, 15 inventive items are listed in accordance with the technical concept of the present invention, and will be explained in accordance with the contents exemplified in each embodiment.
In the present invention, the name of the physical quantity described in the unit "power (mW) per unit area (cm2)" of the light beam 40 irradiated from the treatment device, i.e., "mW/cm2", is expressed as "energy density".
In terms of using the original physical term correctly, it should be expressed as "luminous flux power density." However, in order to prevent the description in the specification from becoming even more difficult to understand, the expression has been standardized by using a simpler term (light energy density 140) that is intuitively easy to understand.

<Invention 1>
Invention 1 relates to a new type of PBM therapy device 10 for treating "forgetfulness," and is a technology that combines the well-known 40 Hz therapy and photobiomodulation technology by irradiating weak light energy that flickers with a repetitive waveform of approximately 40 Hz from the oral cavity toward the affected area of MCI located deep in the brain, such as the hippocampus.
In the present invention, it was discovered that when "light is irradiated from the oral cavity toward the hippocampus or other areas deep in the brain for the purpose of treating forgetfulness," a light energy density of 10 mW/cm2 or less is sufficient to provide a sufficient effect.
Based on this discovery, the inventors have provided detailed explanations in paragraphs 0079 to 0085 on how the invention has been refined to be an extremely useful MCI treatment device for industrial use by incorporating output adjustment and monitoring means to ensure safety in the treatment of MCI patients.
Invention item 1 is as follows:

"A PBM therapy device 10 as a treatment device for MCI that applies photobiomodulation (PBM) in the oral cavity,

The PBM therapy device 10 includes an LED light source 30, an LED light source holder 35, and an LED driving device 50.
The LED light source 30 includes an LED element 60 having an output wavelength in the range of 650 to 1000 nm, which is called a biological window 3 and transmits light through biological tissue, and an optical system 70 for adjusting the directivity.
The LED light source holding unit 35 is a member that holds the LED light source 30 in the oral cavity and determines the position and irradiation direction.
The LED driving device 50 is a control device that supplies a driving current to the LED element 60 to irradiate the light beam 40 with a light energy density 140 of a predetermined value 5 or less while blinking with a repetitive waveform of about 40 Hz,

The LED driving device 50 also includes a 40 Hz signal source 210, an LED driving circuit 220, an output adjusting means 230, and an output monitoring means 240.
The 40 Hz signal source 210 outputs a command value 250 of a time series waveform of about 40 Hz,
The LED driving circuit 220 receives the command value 250 and supplies a driving current to the LED light source 30;
The output adjusting means 230 adjusts the light energy density 140 continuously and/or discontinuously;
The output monitor means 240 indirectly or directly measures and displays the optical energy density 140.

At the same time, the predetermined value 5 irradiated in the oral cavity is 10 mW/cm2.
A 40 Hz therapy device for treating MCI.

Invention item 1 is a PBM therapy device 10 as a treatment device for MCI that applies photobiomodulation (PBM) intraoral, which is a rewrite of the common parts of the LED lance 200 of Example 1 and the LED mouthpiece 400 of Example 2.
That is, in order to organize the common parts, a new concept of an LED light source holding portion 35 is created, and is replaced with the term grip portion 80 in the LED lance 200 and the term mouthpiece portion 410 in the LED mouthpiece 400, and is defined in detail in the invention 2 and subsequent sections. Other detailed expressions are based on the wording described in invention A of embodiment 1 and invention A of embodiment 2, and are rephrased in easy-to-read sentences by referring to the explanation regarding Fig. 3 of embodiment 1 and the explanation regarding Fig. 4 of embodiment 2.
If the wording is ambiguous, it is possible to revert to the precise invention statement for each embodiment.

It should be noted that the time series waveform of approximately 40 Hz at the command value of 250 refers to, as described in paragraph 0093, "an arbitrary waveform with a repetition period of 40 Hz (for example, a sine wave, a rectangular wave with a selectable duty ratio, a triangular wave, a stepped waveform, or a waveform specified by storing an output every millisecond in memory, etc.)."
In addition, the reason for using an output wavelength in the 650 to 1000 nm range, which is called the biological window 3 and which transmits through biological tissue, is that it is desirable for the light energy to be absorbed as little as possible by biological tissues such as bones, flesh, nerves, blood vessels, and blood, and for the light stimulus to reach the hippocampus and other parts of the brain from the oral cavity.
Furthermore, the output adjustment means 230 and the output monitoring means 240 are not "items that can be easily thought of and added." When counterfeits of the present invention appear on the market, they will probably try to avoid this patent by omitting the output adjustment means 230 and the output monitoring means 240. However, counterfeits that omit the output monitoring means 240 will be defective products that cause anxiety to MCI patients because they lack a means to avoid accidents that cause brain damage due to excessive light output during treatment. In addition, counterfeits that omit the output adjustment means 230 deprive patients of the freedom to independently select the strength of treatment. In other words, although these two functions seem easy to think of, they are actually essential elements of "trustworthy product specifications" that respect the safety and free will of patients as a treatment device for MCI.

<Invention 2>
Invention item 2 is an explanation of the LED lance 200 of invention item A in embodiment 1, which relates to the grip portion 80, expressed as the LED light source holding portion 35, which is a common term in invention item 1.
The grip portion 80 is described in detail in the description of Figure 3, but paragraph 0090 not only describes that the grip portion 80 is rod-shaped, but also states that "by arranging multiple LED light sources 30 on the tip of the grip portion 80 or on the side near the tip and emitting multiple luminous fluxes 40, it is possible to expand the directivity of the overall luminous flux 40 composed of the multiple luminous fluxes 40 emitted by the LED lance 200. In addition, by bending the LED lance 200 near the tip and providing LED light sources 30 on the side as well, it is possible to emit light in multiple directions simultaneously." This is incorporated in invention item 2 below.
In the LED lance 200, when multiple LED light sources 30 are used, there may be some overlapping portions of multiple light beams 40. Whether the number of LED light sources 30 is single or multiple, it is important for safety reasons to manage the upper limit of the light energy density 140 so that it is equal to or less than a predetermined value 5 at a distance of 1 cm from the tip of any optical system 70 of the LED light source 30.

In the first aspect of the invention, the PBM therapy device 10 is an LED lance 200,
The LED light source holding portion 35 is a gripping portion 80 having a rod-shaped member for controlling the position and irradiation direction of the LED light source 30 arranged at the tip or/and the side surface of the tip in the oral cavity.
A 40 Hz therapy device for treating MCI according to the invention 1.

<Invention 3>
The invention 3 is an explanation of the mouthpiece portion 410 expressed as the LED light source holding portion 35, which is a common term in the invention 1, among the explanations of the LED mouthpiece 400 of the invention A of the embodiment 2. A detailed explanation is given in the explanation of FIG. 3 of the embodiment 2. The invention 3 is as follows.

In the first aspect of the invention, the PBM therapy device 10 is an LED mouthpiece 400,
The LED light source holding unit 35 is a mouthpiece unit 410 including a mouthpiece 460 that is fitted to the upper or lower jaw dentition and fixed in the oral cavity while maintaining the reproducibility of the position and irradiation direction in a mouthpiece coordinate system 420, three or more contrast member insertable points 450 that define a coordinate transformation matrix 440 of two orthogonal coordinate systems, the mouthpiece coordinate system 420 and a skull coordinate system 430, and a connecting member 470 that is arranged on the mouthpiece 460 while maintaining the reproducibility of the position and irradiation direction of the LED light source 30.
A 40 Hz therapy device for treating MCI according to the invention 1.

Incidentally, the "example of directly attaching" the LED light source 30 to the connecting member 470 is described in the description of the invention C of the second embodiment and Figures 8(a) and 8(b) for the mouthpiece part 410 fixed to the lower jaw, and described in paragraph 0152 for the mouthpiece part 410 fixed to the upper jaw. This "example of directly attaching" to either the upper or lower jaw is included in the above-mentioned invention 3.
In addition, since the LED mouthpiece 400 uses multiple LED light sources 30, there may be areas where multiple light beams 40 overlap. It is important for safety reasons to manage the upper limit of the light energy density 140 so that it is equal to or less than a predetermined value of 5 even at a distance of 1 cm from the tip of any optical system 70 of the LED light source 30.

<Invention 4>
Invention 4 relates to the LED board 480 explained in invention B of embodiment 2, and is described in detail in the description of Figure 4. Note that invention B of embodiment 2 and the description of Figure 4(c) in paragraph 0136 also include an explanation of the connection relationship between the connecting member 470 and the LED board 480, so if there is any indication that the description is unclear, it can be corrected. Invention 4 is as follows.

In the mouthpiece portion 410 to be fitted to the upper jaw dentition described in the third aspect of the present invention,
Further provided is an LED substrate unit 480 that holds the position and irradiation direction of the LED light source 30 in the oral cavity so that the irradiation target point 490 is included in the light beam 40.
A 40 Hz therapy device for treating MCI according to invention 3.

<Invention 5>
Invention item 5 relates to a phase control device 150 that treats MCI that has progressed and worsened by simultaneously stimulating (or using in combination) the PBM therapy device 10 and the sensory therapy device 20, which are the technical concept of the present invention.
The contents of invention item 5 correspond mainly to invention item A of embodiment 4, and the word order and other expressions have been changed to make it easier to read, and the fact that "predetermined value 5 is 10 mW/cm2" explained in paragraph 0085 has also been written here to clarify the text. Other detailed explanations are written in the parts corresponding to Figures 6 to 10. Invention item 5 is as follows.

"A PBM therapy device 10 that stimulates the affected area of MCI by irradiating a light beam 40 at a light energy density 140 of a predetermined value 5 or less toward the affected area of MCI by blinking a light source in a wavelength range called a biological window 3 that transmits through biological tissue with a repeating waveform of about 40 Hz, and a sensory therapy device 20 that uses the phenomena of SSVEP and ASSR to induce brain waves of about 40 Hz with visual stimulation by light and auditory stimulation by sound, is equipped with a phase control device 150 that controls the phase of these multiple types of stimuli,

The predetermined value 5 is 10 mW/cm2,
The phase control device 150 phase-synchronizes the phase angles 110 of the multiple types of stimuli generated by the PBM therapy device 10 and the sensory therapy device 20, and outputs a synchronization signal 130 that sets and controls the phase difference 120 of the phase angles 110 of the multiple types of stimuli.
A 40 Hz therapy device for treating MCI.

<Invention 6>
Most of invention item 6 overlaps with invention item 1. However, while invention item 1 mainly describes the case where the PBM therapy device 10 is operated independently, invention item 6 describes the PBM therapy device 10 that performs the separately excited operation 100 in response to a synchronization signal 130 from a phase control device 150. This point is described in invention item B of embodiment 1, invention item D of embodiment 2, invention item D of embodiment 3, and invention item F of embodiment 4, and has been explained in detail in the description of each embodiment.
Incidentally, the PBM therapy device 10 of the present invention performs a separate excitation operation 100 when operated with a synchronization signal 130 from a phase control device 150, and performs a self-excitation operation 105 when used alone without a synchronization signal 130 from the phase control device 150.
Invention item 6 is as follows:

"Invention 5,
The PBM therapy device 10 includes an LED light source 30, an LED light source holder 35, and an LED driving device 50.
The LED light source 30 includes an LED element 60 having an output wavelength in the range of 650 to 1000 nm, which is called the biological window 3 and transmits light through biological tissue, and an optical system 70 for adjusting the directivity.
The LED light source holder 35 is a member that holds the LED light source 30 in the oral cavity or on the scalp and determines the position and emission direction.
The LED driving device 50 is a control device that supplies a driving current to the LED element 60 to irradiate the luminous flux 40 with a light energy density 140 equal to or less than the predetermined value 5 while blinking the luminous flux 40 with a repetitive waveform of about 40 Hz;

The LED driving device 50 also includes a 40 Hz signal source 210, an LED driving circuit 220, an output adjusting means 230, and an output monitoring means 240.
The 40 Hz signal source 210 outputs a command value 250 of a time series waveform of about 40 Hz,
The LED driving circuit 220 receives the command value 250 and supplies a driving current to the LED light source 30;
The output adjusting means 230 adjusts the light energy density 140 continuously and/or discontinuously;
The output monitor means 240 indirectly or directly measures and displays the optical energy density 140.
Along with,
The 40 Hz signal source 210 performs a separate excitation operation 100 in response to the synchronization signal 130 from the phase control device 150.
A 40 Hz therapy device for treating MCI according to invention item 5.

In addition, the area to which the PBM therapy device 10 is irradiated is only the inside of the mouth in the first invention, but in the sixth invention, it is either the inside of the mouth or on the scalp.
The phrase "intraoral or on the scalp" indicates that the types of PBM therapy devices 10 include the LED lance 200 of Example 1, the LED mouthpiece 400 of Example 2, and the LED pad 600 of Example 3. Therefore, multiple types of PBM therapy devices 10 may be used simultaneously in the oral cavity and on the scalp.
That is, the intraoral and on-scalp PBM therapy device 10 can be used simultaneously with the phase control device 150. This is apparent from Figures 7 and 9 and their descriptions.

<Invention 7>
The seventh aspect of the invention clearly indicates that the LED lance 200 can be applied as the PBM therapy device 10. For details of the LED lance 200, please refer to the contents explained in the second aspect of the invention. The seventh aspect of the invention is as follows.

In the sixth aspect of the present invention, the PBM therapy device 10 is an LED lance 200,
The LED light source holding portion 35 is a gripping portion 80 having a rod-shaped member for controlling the position and irradiation direction of the LED light source 30 arranged at the tip or/and the side surface of the tip in the oral cavity.
A 40 Hz therapy device for treating MCI according to invention item 6.

<Invention 8>
Invention item 8 clearly indicates that the LED mouthpiece 400 can be applied as the PBM therapy device 10. For details of the LED mouthpiece 400, please refer to the contents explained in invention item 3. Invention item 8 is as follows.

In the sixth aspect of the present invention, the PBM therapy device 10 is an LED mouthpiece 400,
The LED light source holding unit 35 is a mouthpiece unit 410 including a mouthpiece 460 that is fitted to the upper or lower jaw dentition and fixed in the oral cavity while maintaining the reproducibility of the position and irradiation direction in a mouthpiece coordinate system 420, three or more contrast member insertable points 450 that define a coordinate transformation matrix 440 of two orthogonal coordinate systems, the mouthpiece coordinate system 420 and a skull coordinate system 430, and a connecting member 470 that is arranged on the mouthpiece 460 while maintaining the reproducibility of the position and irradiation direction of the LED light source 30.
A 40 Hz therapy device for treating MCI according to invention item 6.

<Invention Item 9>
In the ninth aspect of the invention, the PBM therapy device 10 is an LED substrate 480 of an LED mouthpiece 400, and for details, please refer to the contents explained in the fourth aspect of the invention. The ninth aspect of the invention is as follows.

In the mouthpiece portion 410 to be fitted to the upper jaw dentition described in the eighth aspect of the present invention,
Further provided is an LED substrate unit 480 that holds the position and irradiation direction of the LED light source 30 in the oral cavity so that the irradiation target point 490 is included in the light beam 40.
A 40 Hz therapy device for treating MCI according to invention item 8.

<Invention 10>
The subject matter of the invention 10 shows that an LED pad 600 can be applied as a PBM therapy device 10 .
This relates to a matrix system 640 that uses multiple LED light sources 30 to expand the light beam 40 in order to improve the therapeutic effect when used in combination with an LED lance 200 that irradiates the deep brain, an LED mouthpiece 400, or a sensory therapy device 20. This mainly corresponds to the invention item B of the third embodiment, and the details are described in the description of FIG.

5C, the LED pad 600 of the matrix type 640 has many overlapping portions of the luminous flux 40 after passing through the transmission plate 630. In the case of the matrix type 640, since the LED pad body 610 has a thickness, it is important for safety to manage the upper limit value of the light energy density 140 so that it is equal to or less than a predetermined value 5 at a position immediately after passing through the transmission plate 630, not at a distance of 1 cm from the tip of the optical system 70 of the LED light source 30.
Invention item 10 is as follows:

In the sixth aspect of the present invention, the PBM therapy device 10 is an LED pad 600,
The LED light source holding unit 35 is an LED pad body 610 of a matrix type 640 having an internal structure in which the LED light sources 30 are arranged lengthwise and widthwise on the bottom surface and a transparent plate 630 is arranged on the ceiling surface to irradiate the light beam 40.
A 40 Hz therapy device for treating MCI according to invention item 6.

<Invention 11>
The invention item 11 shows that the LED pad 600 of the backlight system 650 can be applied as the PBM therapy device 10. The light energy density 140 of the light flux 40 of the backlight system 650 is characterized by being almost uniform. It mainly corresponds to the invention item C of the embodiment 3, and the details are described in the description of FIG. 5.
As shown in Fig. 5(d), the LED pad 600 of the backlight type 650 is irradiated almost uniformly with the light beam 40 after passing through the transmission plate 630 without overlapping, but some unevenness such as unevenness or variation may remain in terms of quality control. In the case of the backlight type 650, it is also important for safety to manage the upper limit value of the light energy density 140 so that it is equal to or less than a predetermined value 5 at a position immediately after passing through the transmission plate 630, not at a distance of 1 cm from the tip of the optical system 70 of the LED light source 30.
Invention item 11 is as follows:

In the sixth aspect of the invention, the PBM therapy device 10 is the LED pad 600,
The LED light source holding unit 35 is an LED pad body 610 of a backlight type 650 having an internal structure in which a backlight 660 consisting of the LED light source 30, a reflector 662, and a light guide plate 664 and/or a diffusion plate 666 is arranged on the bottom surface, and the transmissive plate 630 is arranged on the ceiling surface to irradiate the light beam 40.
A 40 Hz therapy device for treating MCI according to invention item 6.

<Invention 12>
The invention item 12 shows that the sensory therapy device 20 includes a visual stimulation device 800 and an auditory stimulation device 810 which perform separate excitation operation 100, and an audiovisual phase control device 820 which outputs a synchronization signal 130 to the two devices.
The contents of the invention item 12 correspond to the common parts of the invention items C, D, and E in the fourth embodiment, and the descriptions of Figures 7 to 10. The invention item 12 is as follows.

"Invention 5,
The sensory therapy device 20 is composed of a visual stimulation device 800, an auditory stimulation device 810, and an audiovisual phase control device 820.
The visual stimulation device 800 is a light emitter 170 that emits light at a repetition frequency of about 40 Hz, or an LCD sunglasses 180 that controls the transmittance of a lens portion at a repetition frequency of about 40 Hz,
The auditory stimulation device 810 includes at least one of an earphone 168 including a bone conduction earphone 162 as a sound generating body 160 that emits sound at a repetition frequency of about 40 Hz, a headphone 164, and a speaker 166;
The audiovisual phase control device 820 outputs the synchronization signal 130 to set the phase difference 120 between the visual stimulation device 800 and the auditory stimulation device 810 and control the phases of the visual stimulation of light and the auditory stimulation of sound, respectively.
Along with,
The visual stimulation device 800 and the auditory stimulation device 810 perform the separate excitation operation 100 according to the synchronization signal 130 from the audiovisual phase control device 820.
A 40 Hz therapy device for treating MCI according to invention item 5.

<Invention 13>
Invention item 13 describes a type of sensory therapy device 20 that "inputs one synchronization signal 130 to perform a separate excitation operation 100."
The contents of the invention 13 are related to the inventions C and F of the fourth embodiment, but are expressed as simply as possible by omitting the parts that overlap with the invention 12. Details are explained in the description of the fourth embodiment, particularly in Figs. 7 and 8.
Invention item 13 is as follows:

"Invention 12,
The audiovisual phase control device 820 receives one of the synchronization signals 130 from the phase control device 150 and performs the separate excitation operation 100.
A 40 Hz therapy device for treating MCI according to invention item 12.

<Invention 14>
Invention item 14 describes a type of sensory therapy device 20 that "inputs two synchronization signals 130 to perform separate excitation operation 100."
The contents of the invention 14 are related to the inventions D and F of the fourth embodiment, but are expressed as simply as possible by omitting the parts that overlap with the invention 12. Details are explained in the description of the fourth embodiment, particularly in Figs. 8 and 9.
Invention item 14 is as follows:

"Invention 12,
The audiovisual phase control device 820 inputs the two synchronization signals 130 from the phase control device 150 and outputs them as the synchronization signals 130 that control the phases of the visual stimulus of light and the auditory stimulus of sound to the visual stimulation device 800 and the auditory stimulation device 810.
A 40 Hz therapy device for treating MCI according to invention item 12.

<Invention 15>
Invention item 15 describes a type of sensory therapy device 20 that "outputs a reference synchronization signal 830 to perform self-excitation operation 105."
The content of the invention item 15 is related to the invention items F and G of the fourth embodiment, but is expressed as simply as possible by omitting the parts that overlap with the invention item 12. Details are explained in the description of the fourth embodiment, particularly in Figs. 9 and 10.
Invention item 15 is as follows:

"In claim 12,
The audiovisual phase control device 820 performs a self-excitation operation 105 that outputs a reference synchronization signal 830 to the phase control device 150;
The phase control device 150 inputs the reference synchronization signal 830 to perform the separate excitation operation 100, sets the phase difference 120 of the PBM therapy device 10, and outputs the synchronization signal 130.
The 40 Hz therapy device for treating MCI according to claim 12.

<Notes>
One of the features of the MCI treatment device of the present invention is the low light energy irradiated from the oral cavity.
In the prior art, a light energy density of 1000 mW/cm2 (Non-Patent Document 8) was required for oral irradiation of the substantia nigra compacta (behind the hippocampus) for the purpose of treating Parkinson's disease.
On the other hand, in the present invention, for the purpose of treating "forgetfulness" due to MCI, it was discovered that the light energy density can be set to an upper limit of 10 mW/cm2 to 1 mW/cm2 or less (described in paragraphs 0079 to 0085) when irradiating the hippocampus from the oral cavity with a flickering light at a repetition frequency of about 40 Hz. Furthermore, the safety of the treatment is improved by providing an output adjustment means 230 and an output monitoring means 240 for preventing treatment errors.
In any case, sufficient effects can be obtained at an energy density of 10 mW/cm to 1 mW/cm, which is the upper limit, and therefore this is a therapeutic device that can be safely used with low output energy that is beyond the common sense of those skilled in the art in the application of stimulating the hippocampus with light energy from the oral cavity for the purpose of treating the "forgetfulness" associated with MCI.

The 40 Hz therapy adopted by this invention is a "disease-modifying therapy" based on the known mechanism of action of "causing the microglia, immune cells in the brain, to phagocytose amyloid beta and tau protein, which are causative agents of Alzheimer's disease, by stimulating the affected area of MCI (Mild Cognitive Impairment) at 40 Hz, and is effective in preventing Alzheimer's disease at the MCI stage.

Therefore, in this invention, the symptoms of "brain fog" are treated by sensory stimulation using light and sound of approximately 40 Hz (sensory therapy device 20) as in the prior art, and the symptoms of "forgetfulness" are treated by stimulation of approximately 40 Hz in combination with weak light from photobiomodulation (PBM therapy device 10), providing an enhanced function as a "disease-modifying therapy" compared to the prior art.

Furthermore, the present invention can also function as a "neural repair and regeneration therapy" that regenerates damaged cells in the deep brain and temporal lobe, which are areas affected by MCI, by irradiating weak light rays, which is a basic function of photobiomodulation.

In this way, the present invention is a therapeutic device with the major feature of combining photobiomodulation technology with 40 Hz sensory stimulation, which has a proven track record as conventional technology, thereby enhancing the functions of "disease modifying therapy" and "symptom alleviating therapy" while also imparting a new function of "nerve repair and regeneration therapy."
Therefore, the present invention is expected to be of industrial use and contribute not only to the manufacture and sale of medical devices but also to the business fields of various medical services and elderly care.

The LED lance 200 in FIG. 3, the LED mouthpiece 400 in FIG. 4, the LED pad 600 in FIG. 5, and the helmet and phase control device 150 in FIG. 7 for safely treating MCI by integrating multiple treatment instruments by the patient, which are specifically disclosed in each embodiment of the present invention, can be industrially used by those skilled in the art within the scope of design modifications based on the technical concept of the present invention and the disclosure of the embodiments.

If further improvements are made to the method of use in clinical applications and research and development is conducted into treatment techniques, this invention will likely encourage the invention of new and improved products and contribute to industrial applications as one of the basic technologies in related industries.

This invention is a therapeutic device that can be used as a so-called digital medicine for the electromagnetic treatment of neurological disorders. However, if it is planned to be used in conjunction with this invention to explore new ideas for "developing new drugs in conventional medicines that improve the effectiveness of dementia prevention and treatment," it could also contribute to industrial applications through the digital strategies of the existing pharmaceutical industry.

number
3 biological window 5 predetermined value 10 PBM therapy device 20 sensory therapy device 30 LED light source 35 LED light source holder 40 light flux 50 LED driver 60 LED element 65 semiconductor chip 70 optical system 80 gripping part 90 mouthpiece 100 separate excitation operation 105 self-excitation operation 110 phase angle of multiple types of stimuli 120 phase difference 130 synchronization signal 140 light energy density 150 phase control device 160 sound generator 162 bone conduction earphone 164 headphone 166 speaker 168 earphone 170 light emitter 172 LED panel 174 LED light bulb 176 light diffusion glasses 180 LCD sunglasses
200 LED lance 210 40 Hz signal source 220 LED drive circuit 230 Output adjustment means 240 Output monitoring means 250 Command value 260 Self-excited/separately excited switching means 400 LED mouthpiece 410 Mouthpiece section 420 Mouthpiece coordinate system 430 Skull coordinate system 440 Coordinate transformation matrix 450 Contrast member insertable point 460 Mouthpiece 470 Connecting member 480 LED board section 490 Irradiation target point 600 LED pad 610 LED pad main body 620 Head fixing member 625 Connecting member 630 Transmitting plate 640 Matrix system 650 Backlight system 660 Backlight 662 Reflecting plate 664 Light guide plate 666 Diffusing plate 800 Visual stimulation device 810 Auditory stimulation device 820 Audiovisual phase control device 830 Reference synchronization signal

Claims (15)

A therapeutic device for treating symptoms of forgetfulness, comprising:
One or more first light sources having a wavelength range of 650 to 1000 nm that transmits through biological tissue are provided in the oral cavity and are made to blink,
A weak light beam having an instantaneous maximum value of 100 mW/cm2 or less is irradiated to a deep part of the brain such as the hippocampus and/or the left and right temporal regions through biological tissue in the brain including the skull (sphenoid bone, etc.) below the brain, measured at a position 1 cm away from the first light source .
A treatment device for forgetfulness characterized by:
2. The forgetfulness treatment device according to claim 1, wherein the light output generated by each of the first light sources provided in the oral cavity has an instantaneous maximum value of 10 mW/cm2 or less when measured at a position 1 cm away from the first light source.
3. The forgetfulness treatment device according to claim 1, wherein the first light source provided in the oral cavity is made to blink with an arbitrary waveform (e.g., a sine wave, a square wave with a selectable duty ratio, a triangular wave, a stepped waveform, or a waveform specified by storing an output every millisecond in a memory, etc.).
4. The forgetfulness treatment device according to claim 1, wherein the first light source provided in the oral cavity is an LED element that emits light in the oral cavity, or an LED element or a laser light source provided outside the oral cavity that emits light via an optical fiber.
5. The forgetfulness treatment device according to claim 1, wherein the light output of said first light source provided in the oral cavity can be monitored by an output display means.
6. The forgetfulness treatment device according to claim 1, wherein the first light source is installed in the oral cavity and attached to a "tip of a rod-shaped treatment device equipped with a grip" or a "mouthpiece" so that the position and direction of irradiation in the oral cavity can be adjusted or fixed.
In addition to the first light source provided in the oral cavity, a second light source is provided which is fixed to the scalp side of the head using a headband, a hat, a helmet, glasses, goggles or a dedicated device;
The second light source is composed of an LED element or a laser light source that emits light in a wavelength range of 650 to 1000 nm,
7. The forgetfulness treatment device according to claim 1, further comprising: a first light source and a second light source that are caused to blink in phase synchronization with each other.
In addition to the first light source and the second light source, a third light source that "provides a visual stimulus by flashing light" and a stimulus sound source that "provides an auditory stimulus by repeating a stimulus sound" are provided,
The forgetfulness treatment device according to claim 7, further comprising a phase control device capable of setting a phase difference between the phases of the first light source, the second light source, the third light source, and the stimulation sound source blinking or repeating in phase synchronization.
The forgetfulness treatment device according to claim 8, wherein the third light source is a light source that blinks in phase synchronization with the first light source, and is an "illuminant that emits light such as an LED panel or an LED bulb" or an "LCD sunglasses that control the transmittance of the lens portion."
9. The forgetfulness treatment device according to claim 8, wherein the stimulation sound source is a sound source that repeats a stimulation sound in phase synchronization with the first light source, and is a sound source such as a bone conduction earphone, an earphone, a headphone, or a speaker.
the phase in which the first light source blinks;
The phase in which the second light source blinks and the phase in which the stimulus sound source repeats are
9. The forgetfulness treatment device according to claim 8, further comprising a phase control device capable of individually adjusting the phase difference based on the phase at which the third light source blinks.
the phase in which the first light source blinks;
9. The forgetfulness treatment device according to claim 7, further comprising a phase control device capable of changing a phase difference between a phase at which the second light source blinks and a phase at which the second light source blinks.
the phase in which the first light source blinks;
9. The forgetfulness treatment device according to claim 8, further comprising a phase control device capable of changing a phase difference between a phase at which the third light source blinks and a phase at which the third light source blinks.
the phase in which the first light source blinks;
9. The forgetfulness treatment device according to claim 8, further comprising a phase control device capable of changing a phase difference between the phase repeated by the stimulation sound source.
15. The forgetfulness treatment device according to claim 1, further comprising the first light source disposed in the oral cavity, and intended to treat amnesic MCI accompanied by forgetfulness symptoms.

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