Neuromodulatory device for treating Alzheimer's disease

Abstract

A neuromodulator for treating Alzheimer's disease comprises a phototherapy unit and an alternating current transcranial electrical stimulation unit. The array of near-infrared light irradiation units is configured to irradiate transcranial near-infrared light to the frontal lobe, temporal lobe and parietal lobe of the subject, and the electric field action range of the alternating current transcranial electrical stimulation unit includes at least part of the hippocampus; when the near-infrared light is continuous light, the second frequency is in one of the first frequency band, the second frequency band and the third frequency band; when the near-infrared light is pulsed light with a first frequency, the first frequency and the second frequency are in the same frequency band among the first frequency band, the second frequency band and the third frequency band. Transcranial electrical stimulation can produce analgesic and relaxing effects, and can reduce the discomfort of the subject during treatment. Thus, the treatment time and / or the power density of the near-infrared light can be extended as needed to enhance the treatment effect. Photoelectric dual-modal stimulation uses the same range of frequencies, which can significantly increase the neural entrainment effect and improve the treatment effect.

Description

Technical Field

[0001] The present application relates to the field of medical device technology, and in particular, to a neuromodulatory device for treating Alzheimer's disease. Background Art

[0002] With the development of the aging of the global population, Alzheimer's disease (AD), which often occurs in the elderly, has become a serious problem. Epidemiological surveys show that the prevalence of people over 65 years old increases with age. In addition to drugs combined with conventional treatments, people have tried to use photobiomodulation (PBM) to treat AD in recent years, by irradiating the brain with a suitable dose of transcranial light (infrared light or near-infrared light) in a certain wavelength range to achieve neuromodulation. The light energy in this band is mild and has good penetration. Many studies have also proved that PBM is effective in treating AD.

[0003] AD lesions involve a wide range of brain areas, including the prefrontal lobe, temporal lobe, hippocampus, etc. For the hippocampus deep in the brain, if the power density of the transcranial light is insufficient, it will not provide a sufficient dose to the hippocampus, and the excessive increase in power density will increase the accumulation of heat on the patient's scalp or hair (especially East Asians with black hair), causing discomfort to AD patients. On the other hand, as the course of AD patients progresses, AD patients not only suffer from memory loss, but are also prone to anxiety and irritability, such as walking around and standing up suddenly, and a considerable proportion of AD patients have frequent pain, and the probability of pain is positively correlated with the severity of cognitive impairment. Therefore, discomfort during treatment can also cause AD patients to resist treatment.

[0004] Existing neuromodulators for treating AD require AD patients to wear a light therapy cap for more than ten minutes to half an hour, and they need weekly treatment. The difficulty of treatment operation and the cooperation and compliance of AD patients are problems. There is still a long way to go from clinical trials with small-scale and short-term intervention of professional doctors to neuromodulators for treating AD that can enter the home and provide convenient and comfortable long-term treatment and disease management for AD patients. Summary of the invention

[0005] Therefore, there is a need for a neuromodulatory device for treating Alzheimer's disease, which is easy to operate, can perform comprehensive transcranial light therapy on multiple brain regions involved in AD, and can provide intensive treatment for the hippocampus deep in the brain. During the treatment process, it can significantly reduce the subject's discomfort, enhance the subject's comfort and compliance with treatment, and continuous treatment can also achieve emotional and pain management of the subject.

[0006] In order to at least partially solve the problems existing in the prior art, according to one aspect of the present application, a neuromodulatory device for treating Alzheimer's disease is provided. The neuromodulatory device includes a phototherapy unit and an AC transcranial electrical stimulation unit. The phototherapy unit includes a support mechanism and an array of near-infrared light irradiation units arranged on the support mechanism, and the array of near-infrared light irradiation units is configured to irradiate transcranial near-infrared light to the frontal lobe, temporal lobe and parietal lobe of the subject, and the near-infrared light is continuous light or pulsed light with a first frequency. The AC transcranial electrical stimulation unit includes at least one pair of electrodes, and each pair of electrodes is configured to be detachably arranged on the scalp around the frontal lobe or temporal lobe of the subject's head to apply AC transcranial electrical stimulation of a second frequency, and the electric field action range of the AC transcranial electrical stimulation includes at least part of the hippocampus. When the near-infrared light is continuous light, the second frequency is in one of the first frequency band, the second frequency band and the third frequency band; when the near-infrared light is pulsed light with a first frequency, the first frequency and the second frequency are in the same frequency band among the first frequency band, the second frequency band and the third frequency band and the deviation is less than a threshold, wherein the first frequency band is 8-12Hz, the second frequency band is 13-24Hz, and the third frequency band is 25-85Hz.

[0007] By using the neuroregulatory device for treating Alzheimer's disease according to the present application, the head of the subject is irradiated with near-infrared light, and combined with alternating transcranial electrical stimulation, an active therapeutic effect can be played on AD. Alternating transcranial electrical stimulation in the alpha, beta and gamma frequency bands can produce analgesic and relaxing effects, which can reduce the discomfort of the subject during treatment and enhance the subject's compliance with treatment. The treatment time and / or the power density of the near-infrared light can also be extended as needed to enhance the therapeutic effect, especially for deep parts of the brain such as the hippocampus; and, continuous treatment in conjunction with near-infrared light irradiation can achieve effective management of the subject's emotions and pain associated with AD. The electric field action range of alternating transcranial electrical stimulation can also include at least part of the hippocampus, thereby improving the therapeutic effect on the hippocampus deep in the brain. When the near-infrared light is a pulsed light with a first frequency, the photoelectric bimodal stimulation uses the same range of frequencies, which can significantly increase the neural entrainment effect and improve the therapeutic effect.

[0008] A series of simplified concepts are introduced in the summary of the invention, which will be further described in detail in the detailed description. The summary of the invention does not mean to attempt to define the key features and essential technical features of the claimed technical solution, nor does it mean to attempt to determine the scope of protection of the claimed technical solution.

[0009] The advantages and features of the present application are described in detail below in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0010] The following drawings of the present application are hereby used as part of the present application for understanding the present application. The drawings show the implementation methods of the present application and their descriptions, and are used to explain the principles of the present application. In the drawings,

[0011] Figure 1A A schematic diagram showing the use of a neuromodulation device according to a first exemplary embodiment of the present application is shown;

[0012] Figure 1B A schematic diagram showing the use of a neuromodulation device according to a second exemplary embodiment of the present application is shown;

[0013] Figure 1C A schematic diagram showing the use of a neuromodulation device according to a third exemplary embodiment of the present application is shown;

[0014] Figure 2A-2C The simulation results of light dose distribution diagrams at different wavelengths under 40Hz phototherapy are shown respectively;

[0015] Figure 3A-3D Schematic diagrams showing the pasting positions of multiple pairs of electrodes under different schemes are shown respectively;

[0016] Figures 4A-7C They are shown respectively Figure 3A-3D The simulation results of intracranial electric field distribution under different schemes are shown;

[0017] Figure 8 Shows Figure 3A-3D Simulation results of current density in the hippocampus under different schemes shown. DETAILED DESCRIPTION

[0018] In the following description, a large amount of details are provided so that the present application can be thoroughly understood. However, it will be appreciated by those skilled in the art that the following description only shows preferred embodiments of the present application in some embodiments, and the present invention can be implemented without one or more such details. In addition, in order to avoid confusion with the present invention, some technical features well known in the art are not described in detail.

[0019] The words "first", "second" and similar words used in this application do not indicate any order, quantity or importance, but are only used to distinguish. The words "include" or "comprise" and similar words mean that the elements before the word include the elements listed after the word, and do not exclude the possibility of covering other elements. The term "head" used in this application refers to the organs above the neck (cervical spine) of the human body, including the brain and extracerebral tissues such as the skull, skin and hair. The term "brain" used in this application refers to the organs left after the removal of extracerebral tissues, etc., mainly intended to represent the brain, but not limited to this, and may also include the brain, cerebellum and brainstem. The expression "for the treatment of Alzheimer's disease" used in this application is intended to indicate that the development of the course of Alzheimer's disease is alleviated, inhibited, terminated or even reversed. The so-called course of Alzheimer's disease is intended to include the clinical symptoms of AD that have appeared in the subject and the subsequent development process, and also includes the process in which the subject has not yet clearly developed clinical symptoms of AD, but some pathological or physiological phenomena associated with AD and will develop into AD with a certain probability have occurred. That is to say, the expression "for the treatment of Alzheimer's disease" in this application includes the treatment of Alzheimer's disease that has already occurred, as well as the prevention of the occurrence of Alzheimer's disease or the reduction of the probability of the occurrence of Alzheimer's disease. Specifically, according to the 2018 AD diagnostic criteria of the National Institute on Aging and the Alzheimer's Association (NIA-AA), based on the β-amyloid protein (Aβ) and tau in the brain or cerebrospinal fluid of the population, as well as the results of cranial MRI and FDG-PET examinations, biomarkers can be divided into 4 categories, and cognitive function can be further divided into 6 levels. Level 1 is characterized by normal objective cognitive neuropsychological tests, no cognitive complaints, no neurobehavioral symptoms, no informed reports of cognitive decline or neurobehavioral symptoms, and no follow-up test evidence of cognitive decline; Level 2 includes subjective cognitive decline (SCD), objective mild cognitive decline (Obj-SCD) and neurobehavioral symptoms; Level 1 and Level 2 are collectively referred to as preclinical. Level 3 is abnormal or impaired objective cognitive tests, but not reaching dementia, that is, MCI. Levels 4 to 6 are mild, moderate and severe dementia, respectively. Each of these 6 levels belongs to the course of Alzheimer's disease as defined in this application. Furthermore, for subjects who carry genes associated with the risk of AD but whose current test results are negative for Aβ, such as APOE ε4, ABCA7, CLU, CR1, PICALM, PLD3 and TREM2, medical intervention to reduce their risk of AD and slow down their progression to AD are all considered to be "for the treatment of Alzheimer's disease" in this application.

[0020] In order to at least partially solve the problems existing in the prior art, the present application proposes a neuromodulatory device for treating Alzheimer's disease (hereinafter referred to as AD). The neuromodulatory device can perform transcranial light therapy on multiple brain regions involved in AD, and cooperate with transcranial alternating current stimulation (tACS) to perform intensive treatment on the hippocampus deep in the brain. During the treatment process, it can significantly reduce the discomfort of the subject, enhance the comfort and compliance of the subject's treatment, and continuous treatment can also achieve emotional and pain management for AD patients. Moreover, the neuromodulatory device is easy to operate, which makes it possible for it to enter the home to provide convenient and comfortable long-term treatment and disease management for AD patients.

[0021] The neuromodulation device may include a light therapy unit and an alternating current transcranial electrical stimulation unit. Figure 1A As shown, the phototherapy section may include a supporting mechanism 1 and an array of near-infrared light irradiation units 3 disposed on the supporting mechanism 1 .

[0022] Typically, the treatment lasts from several tens of minutes to several dozen minutes, and the support mechanism 1 can keep the near-infrared light irradiation unit 3 at a desired position around the subject's head. In some embodiments, the support mechanism 1 can be supported or fixed to the subject's head, or supported on other parts of the subject's body, such as shoulders. The support mechanism 1 can move with the subject so that the subject can move relatively freely during the irradiation. In some embodiments, the support mechanism can also be supported or fixed on an object other than the subject's body, see Figure 1B and Figure 1C . For example, the support mechanisms 1' and 1'' can be fixed to a wall, or clamped on a suitable object. For another example, the support mechanisms 1' and 1'' can be fixed to a bracket 11, and the bracket 11 can be placed on the ground or on a table. In some embodiments, the support mechanism can be constructed to support both the subject's body and an object other than the body. For example, the support mechanism can be suspended by a retractable elastic member (such as a spring), and the support mechanism can also be fixed to the subject's body. On the one hand, the elastic member can allow the subject to move within a certain range and reduce pressure on the body. On the other hand, the position of the support mechanism relative to the subject's head can remain unchanged, thereby ensuring that the near-infrared light can irradiate the desired brain area.

[0023] In the illustrated embodiment, the support mechanism 1 is constructed as a whole, and the support mechanism 1 can be worn as a whole on the head of the subject. In other embodiments not shown, the support mechanism 1 may include a plurality of sub-support mechanisms, and the plurality of sub-support mechanisms may have the same or different structures. Each sub-support mechanism may be independently supported or fixed on the body of the subject. Alternatively, each sub-support mechanism may be independently supported or fixed on an object outside the body. Alternatively, a portion of the sub-support mechanisms are supported or fixed on the body of the subject, and another portion of the sub-support mechanisms are supported or fixed on an object outside the body.

[0024] The near-infrared light irradiation unit 3 may include any one of any suitable light-emitting devices such as a light-emitting diode LED, a laser tube, etc., and may also include a light-guiding device that transmits and emits near-infrared light from the outside. The near-infrared light irradiation unit 3 may emit continuous near-infrared light to the head of the subject, or may emit pulsed near-infrared light. Exemplarily and not restrictively, the near-infrared light irradiation unit 3 may also include a light board carrying a plurality of light-emitting devices. A plurality of light-emitting devices may be arranged into a pattern according to certain rules, for example, the projection of the light-emitting device on a plane may be arranged in a circular or polygonal pattern. In some embodiments, the light-emitting devices may be distributed on the light board in a pattern of 1×1, 2×2, 3×3, 4×4, 5×5, 2×3, 3×4 or 4×5. In some embodiments, the light-emitting devices may also be arranged on the light board in a concentric circle pattern, for example, the innermost circle is 5, and the outer circles are 10 and 15 respectively. Optionally, the plurality of light-emitting devices on the light board may be evenly distributed, and at least some of the light-emitting devices may be arranged near the outer edge of each light board to make full use of the space of the light board and obtain a larger near-infrared light projection area.

[0025] The near infrared light irradiation units 3 are arranged in an array. Figure 1A As shown in the figure, the near infrared light irradiation units 3 are respectively arranged on the forehead, the top of the head and the left and right sides of the top of the head, which can be considered to be arranged in an array similar to a cross. Figure 1B and Figure 1C The better arrangement can make the near-infrared light intensity of each irradiation area relatively uniform, and there is no blind spot between the irradiation areas.

[0026] The array of near-infrared light irradiation units 3 can irradiate transcranial near-infrared light to multiple brain regions involved in AD. When the near-infrared light irradiation unit 3 irradiates near-infrared light to the head of the subject, the support mechanism 1 can maintain the relative spatial relationship between each near-infrared light irradiation unit 3 and the head of the subject, including but not limited to relative distance, relative position and relative direction. In an embodiment in which the support mechanism 1 can move with the subject, the relative position between the near-infrared light irradiation unit 3 and the head can be maintained. The near-infrared light irradiation unit 3 can be close to the head or there is a gap between the head and the near-infrared light irradiation unit 3. When the support mechanism 1 is supported or fixed on an external object, with the cooperation of the subject, the support mechanism 1 can at least control the distance between the head and the near-infrared light irradiation unit 3 within the desired distance range, so that there is a gap between the head and the near-infrared light irradiation unit 3. In this way, the head of the subject can freely enter and exit the space surrounded by the near-infrared light irradiation unit 3. Moreover, during the irradiation, the patient's head has a movable space, so that the comfort of AD patients can be improved, thereby improving the compliance of AD patients with treatment.

[0027] In the case where there is a gap between the near-infrared light irradiation unit 3 and the head, the near-infrared light can be fully scattered, and the near-infrared light emitted by the adjacent near-infrared light irradiation units 3 has a large overlap in the projection area of ​​the head, so that most parts of the head can be irradiated by the near-infrared light, thereby improving the treatment effect. If the above-mentioned gap is not provided, in order to achieve irradiation without dead angles, it may be necessary to increase the arrangement density of the near-infrared light irradiation unit 3, which may cause more heat generation, affect the patient's comfort, and greatly reduce the service life of the near-infrared light irradiation unit 3, increasing the manufacturing cost and control difficulty. However, if the distance between the array of the near-infrared light irradiation unit 3 and the head is too large, it will cause excessive divergence of infrared light, resulting in poor distribution balance of the average power density, or the average power density after superposition is still insufficient, and still cannot obtain a good treatment effect. By controlling the distance between the array of near-infrared light irradiation units 3 and the head, all parts of the head can be irradiated with near-infrared light with sufficient average power density and relatively uniform distribution. The required divergence angle range of the near-infrared light irradiation units 3 conforms to the emission angle range of conventional near-infrared LEDs (for example, 100-135 degrees), and the required arrangement density and spacing of the near-infrared light irradiation units 3 are also relatively appropriate, so that the manufacturing difficulty and cost are beneficially controlled.

[0028] Specifically, the array of the near-infrared light irradiation unit 3 can be constructed to irradiate the frontal lobe, temporal lobe and parietal lobe of the object through the cranial near-infrared light, that is, to provide sufficient irradiation to the head surface corresponding to the frontal lobe, temporal lobe and parietal lobe of the object, so that the irradiated near-infrared light can penetrate the skull and meninges and deposit on the frontal lobe, temporal lobe and parietal lobe after attenuation by the hair and scalp. The near-infrared light irradiation units 3 can maintain their relative positions with each other and their relative positions with the object under the support of the support mechanism 1, so that at least part of the near-infrared light of the near-infrared light irradiation unit 3 can irradiate the frontal lobe, temporal lobe and parietal lobe of the object, avoiding one or more of the above-mentioned multiple lobes from being unable to receive the irradiation of the near-infrared light. For one or more of the above-mentioned multiple lobes, only a part of the lobe can be irradiated with the near-infrared light, or the lobe can be completely irradiated with the near-infrared light. The inventors have found that the treatment effect is better when the near-infrared light is irradiated to at least the head surface corresponding to the frontal lobe, temporal lobe and parietal lobe. For example, the progression of a subject from asymptomatic to full dementia is closely associated with the following cortical pathology: Aβ plaques accumulate in the medial prefrontal and parietal regions of the neocortex several years before the onset of clinical symptoms of AD, and abnormal aggregation of tau protein begins in the middle temporal lobe, possibly starting from the entorhinal cortex (EC), and then spreads to the hippocampus and limbic cortex. By irradiating at least the frontal, temporal, and parietal lobes with near-infrared light, it is possible to reduce the deposition of Aβ plaques in the medial prefrontal and parietal regions, and to reduce the abnormal aggregation of tau protein in the entorhinal cortex (near the prefrontal lobe), the middle temporal lobe, the hippocampus located in the medial temporal lobe, and even the limbic cortex, thereby inhibiting the progression of AD. However, for each of the three lobes mentioned above, it is not necessary to require that the near-infrared light cover the entire lobe.

[0029] In some embodiments, the array of near-infrared light irradiation units 3 is distributed for the frontal lobe, temporal lobe and parietal lobe, so that the frontal lobe, temporal lobe and parietal lobe each have a correspondingly distributed plurality of near-infrared light irradiation units 3. As described above, the near-infrared light emitted by adjacent near-infrared light irradiation units 3 can overlap each other in the projection area of ​​the head, thereby avoiding the situation where one light board only irradiates one area, resulting in gaps between different projection areas. Preferably, multiple light boards can be evenly arranged for each lobe of multiple brain regions, thereby ensuring that there are no missed blind spots.

[0030] See also Figure 1A-Figure 1C, the neuroregulatory device may also include an AC transcranial electrical stimulation unit 4. The AC transcranial electrical stimulation unit can perform intensive treatment on the hippocampus deep in the brain, and can also significantly reduce the discomfort of AD patients during the treatment process. The AC transcranial electrical stimulation unit 4 may include at least one pair of electrodes 40, including one, two or more pairs of electrodes. There is a voltage difference between any pair of electrodes, which can form a current path in the brain, thereby forming a desired electric field in the brain. Moreover, by adjusting the position of the paired electrodes, the position of the electric field in the brain can be changed. In other words, paired electrodes refer to electrodes that have a voltage difference to form an electric field in the brain. Therefore, "paired" does not explicitly limit the physical number of electrodes, that is, at least one pair of electrodes does not mean that the number of electrodes is an even number, but that there may be an odd number of electrodes, such as three electrodes. For example, there is a voltage difference between one of the three electrodes and the other two electrodes, and it can be considered that the electrode and the other two electrodes form two pairs of electrodes respectively.

[0031] Specifically, each pair of electrodes 40 is constructed to be detachably arranged on the scalp around the frontal lobe or temporal lobe of the subject's head (corresponding or associated) to apply an alternating transcranial electrical stimulation of a second frequency, and the electric field action range of the alternating transcranial electrical stimulation includes at least part of the hippocampus. The hippocampus is located between the thalamus and the medial temporal lobe of the brain. It is part of the limbic system and plays a role in short-term memory, long-term memory and spatial positioning. Hippocampal atrophy is closely related to AD. With the development of AD, the lesions further spread to the frontal lobe and temporal lobe, and the brain slowly atrophies, leading to further loss of memory and loss of self-care ability. The functions of the temporal lobe mainly include auditory perception, language reception, visual memory, declarative (real) memory and emotional control. Specifically, patients with right temporal lobe lesions often lose their understanding of non-verbal auditory stimuli (such as music, etc.), while left temporal lobe lesions affect the patient's perception, memory and organization of language. The frontal lobe is the physiological basis of the most complex human psychological activities. It is responsible for planning, regulating and controlling human psychological activities. It plays an important role in human advanced and purposeful behaviors. It is closely related to advanced cognitive functions such as attention, memory, and problem solving, and is also closely related to personality development.

[0032] The inventors found that the amyloid protein of AD will be deposited in the frontal lobe, parietal lobe and temporal lobe cortex, and the inflammation of the whole brain will diffuse, and then deposited in the deep brain such as the hippocampus, and even in the early stage, it will be a whole brain inflammation. Therefore, near-infrared light irradiation uses comprehensive irradiation covering the frontal lobe, temporal lobe and parietal lobe to play a comprehensive sweeping effect. Combined with AC transcranial electrical stimulation for targeted intensive treatment of the hippocampus, the treatment can be particularly effective.

[0033] In an embodiment where the near-infrared light is continuous light, the second frequency of the AC transcranial electrical stimulation can be in one of the first frequency band, the second frequency band and the third frequency band. The first frequency band is 8-12Hz, the second frequency band is 13-24Hz, and the third frequency band is 25-85Hz. The brain of a normal person will generate brain waves in real time, and the brain waves include alpha waves in the first frequency band of 8-12Hz, beta waves in the second frequency band of 13-24Hz, and gamma waves in the third frequency band of 25-85Hz. The AC frequency of the AC transcranial electrical stimulation is in one of the three frequency bands mentioned above, which can have analgesic and relaxing effects on the subject. Specifically, in the frontal area, the external introduction of AC transcranial electrical stimulation of the alpha band, beta band and gamma band can induce neural oscillation enhancement in the corresponding frequency range in the brain, showing a relief effect on subjective pain perception and / or increasing the patient's pleasure. This can improve the tolerance threshold of the subject to a certain extent, thereby receiving near-infrared light irradiation with a relatively high power density, thereby further strengthening the deposition of light dose in the hippocampus and enhancing the therapeutic effect of near-infrared light. In some embodiments, the alternating current of AC transcranial electrical stimulation can also use a high-frequency signal as a carrier to avoid excessive accumulation of charge on the skin surface and deeper locations, causing tingling.

[0034] In an embodiment where the near-infrared light is a pulsed light with a first frequency, the first frequency and the second frequency are in the same frequency band of the first frequency band, the second frequency band and the third frequency band and the deviation is less than the threshold. Combining whole-brain near-infrared light irradiation with targeted alternating transcranial electrical stimulation of deep parts such as the hippocampus can enhance the therapeutic effect. In addition to the mechanisms of light therapy itself that can improve metabolic function and cerebral blood flow, resist oxidative stress and inflammation, promote nerve growth and synapse formation, and activate glial cells, the alternating transcranial electrical stimulation of this frequency band itself can also have a positive effect on AD. Furthermore, photoelectric bimodal stimulation uses the same range of frequencies, which can significantly increase the neural entrainment effect. Because of the targeted strengthening effect of alternating transcranial electrical stimulation, near-infrared light irradiation and alternating transcranial electrical stimulation achieve a more comprehensive therapeutic effect than simple near-infrared light irradiation at the same power density, and bring relatively less thermal discomfort; for individuals who are particularly sensitive to light power density, near-infrared light irradiation and alternating transcranial electrical stimulation can ensure a good therapeutic effect with a relatively low light power density that they can tolerate.

[0035] In the above two technical solutions, irradiating the head of the subject with near-infrared light in combination with alternating current transcranial electrical stimulation can play a positive therapeutic role in AD. Transcranial electrical stimulation in the alpha, beta and gamma frequency bands can produce analgesic and relaxing effects, which can reduce the discomfort of the subject during treatment. As a result, the treatment time can be extended and / or the power density of the near-infrared light can be increased as needed to enhance the therapeutic effect. The electric field action range of alternating current transcranial electrical stimulation can also include at least part of the hippocampus, thereby enhancing the therapeutic effect on the hippocampus deep in the brain. When the near-infrared light is a pulsed light with a first frequency, the photoelectric dual-modal stimulation uses a frequency in the same range, which can significantly increase the neural entrainment effect and improve the therapeutic effect.

[0036] In some embodiments, at least part of the irradiated near-infrared light is transmitted in a direction toward the hippocampus. As described above, one of the main symptoms of AD is the lesions of the hippocampus. By constructing the support mechanism 1 to cover the skull, the array of near-infrared light irradiation units 3 can emit near-infrared light to multiple brain regions of the patient's head, such as at least the frontal lobe, temporal lobe and parietal lobe, and especially the hippocampus, to perform comprehensive and thoughtful phototherapy on the cortical partitions involved in the lesions, thereby achieving better treatment effects.

[0037] In some embodiments, the first frequency and the second frequency may be equal. Simultaneously applying near-infrared light and AC transcranial electrical stimulation of the same frequency to the subject's head can significantly improve the matching and strengthening of oscillations, enhance neural entrainment, and enhance the therapeutic effect.

[0038] In some embodiments, the first frequency and the second frequency may both be the same frequency of 10Hz, 20Hz, 40Hz and 70-80Hz. The inventors recognize and understand that the near-infrared pulse light of the above frequency has a good function of treating AD, and the AC transcranial electrical stimulation of the above frequency can not only treat AD but also relieve pain. Near-infrared light of the above frequencies, such as near-infrared light with a central wavelength of 630-700nm, or near-infrared light with a central wavelength of 760-860nm, has a good therapeutic effect on AD patients, and in combination with AC transcranial electrical stimulation of this frequency, it can reduce the discomfort of patients during treatment, so that the pain of patients during treatment is reduced and it is easier to maintain a relaxed mood. In some exemplary embodiments, AC transcranial electrical stimulation at 10Hz, 40Hz, or 70-80Hz is used to increase the release of β-endorphin in the brain of AD patients. For example, tACS tests were performed on voluntary individual subjects for 5-10 minutes at an amplitude of approximately 10 mA when the frequency of the alternating current was set at 70 Hz, 70.5 Hz, 71 Hz, 71.5 Hz, 72 Hz, 72.5 Hz, 73 Hz, 73.5 Hz, 74 Hz, 74.5 Hz, 75 Hz, 75.5 Hz, 76 Hz, 76.5 Hz, 77 Hz, 78 Hz, 78.5 Hz, 79 Hz, 79.5 Hz and 80 Hz, and the beta-endorphin concentration in the cerebrospinal fluid samples was tested by an ELISA (enzyme-linked immunosorbent assay) kit, and the results showed that beta-endorphin in the subjects' bodies increased.

[0039] The release of β-endorphin significantly reduces pain perception, even with longer treatment times or with greater stimulation intensities, such as a light power density of 40 mW / cm 2 , even 100-150mW / cm 2 , even 150-250mW / cm 2 For example, when the total stimulation current of AC transcranial electrical stimulation reaches 5mA, even 10mA, or even 15mA, AD patients have no obvious pain, or their emotions are at least calmer or happier than before the stimulation.

[0040] In some embodiments, the total stimulation current of the AC transcranial electrical stimulation unit 4 can reach 15mA. Ordinary people can usually accept a current of 15mA, and exceeding this current may cause severe discomfort. With AC transcranial electrical stimulation, the charge-balanced AC signal itself can reduce the discomfort caused by the current, so the current that ordinary people can accept can be increased to 15mA without causing strong discomfort. 15mA of AC coupled with a suitable frequency can not only ensure the intensity of stimulation, but also produce analgesic effects so that the subject will not feel uncomfortable. At the same time, because the AC stimulation of a suitable frequency itself has an emotional regulation effect, it increases the patient's compliance with the combined intensive treatment of AD.

[0041] In some embodiments, the near-infrared light irradiated by the phototherapy unit may be a single wavelength (also referred to as the first wavelength) with a central wavelength of 760-860nm, or a single wavelength (also referred to as the second wavelength) with a central wavelength of 630-700nm. It may also have dual wavelengths, for example, including a first wavelength with a central wavelength of 760-860nm and a second wavelength with a central wavelength of 630-700nm. The dual-wavelength configuration can provide the required targeted treatment. For near-infrared light with a central wavelength of 760-860nm, good therapeutic effects can be provided for cells that do not express cytochrome-c oxidase CCO, as well as cells that express CCO. For neuroprotection, 670nm has been shown to be effective in restoring retinal function, and for inhibiting neural damage caused by CCO, near-infrared light with a wavelength of 630-700nm is suitable. Near-infrared light with a wavelength of 780-810nm can promote angiogenesis and promote blood flow. For anti-inflammatory treatment, light with a wavelength of 635nm can convert the phenotype of microglia from M1 to M2, and has an anti-inflammatory effect. The brain areas that serve as neurogenic microenvironments are the subgranular layer of the dentate gyrus of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. Near-infrared light of 808nm and 810nm has been shown to promote neurogenesis in the neurogenic microenvironment, thereby improving the symptoms of a sharp decline in hippocampal neurogenesis caused by AD.

[0042] Figure 2A-2C The simulation results of the distribution diagram of the irradiation power level in various parts of the brain obtained by irradiating the head of the subject with a pulse light source at 40Hz, with central wavelengths of 660nm, 810nm and 1064nm respectively and the time-averaged irradiation power normalized to 1 are shown, where the horizontal and vertical axes are the y-axis and z-axis respectively, in units of mm, and the corresponding values ​​on the chromaticity bar are the log values ​​of the ratio of the irradiation power to the irradiation power normalized to 1. It can be seen that the penetration depth of 810nm and 1064nm light is deeper than that of 660nm. The penetration depth of 810nm light is the deepest, and the light is attenuated by about 450 times after passing through the scalp and about 10 after passing through the skull. 4 times, and decayed by about 105 times, and attenuated by nearly 10 at a depth of 4 cm in the white matter 8 times.

[0043] In one embodiment, the second frequency of transcranial alternating current stimulation can be 70-80Hz, especially 75Hz, 76.5Hz, or 78Hz, at which time the analgesic effect provided by transcranial alternating current stimulation (the increase of endorphins in cerebrospinal fluid immediately after stimulation) is most obvious. By providing near-infrared pulsed light irradiation of the same frequency at the same time, the light power density and total stimulation current that the subject can tolerate will be relatively high. In another embodiment, the second frequency of transcranial alternating current stimulation and the first frequency of near-infrared pulsed light are both 40Hz. Multi-physical mode stimulation of this frequency can especially promote the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in AD patients, play a positive role in p-Tau protein deposition, accelerate the lymphatic clearance of amyloid protein, and stimulate and improve gamma oscillations through 40Hz transcranial light stimulation in coordination with 40Hz transcranial alternating current stimulation. Cognitive ability, delay the course of AD. The gamma oscillation of AD patients is impaired. By inducing entrainment of endogenous EEG oscillations through external electric current, the neural network in the damaged area can be specifically regulated. Alternating current transcranial electrical stimulation in the same frequency band as the abnormal gamma oscillation of AD patients can improve the neural oscillations and brain functional connections in the damaged area, and promote improvement of brain function.

[0044] In some embodiments, the phototherapy unit and the AC transcranial electrical stimulation unit 4 are configured to irradiate near-infrared light and apply AC transcranial electrical stimulation in a phase-synchronized manner, respectively. As described above, near-infrared light pulses of the same frequency and transcranial AC electrical stimulation can enhance oscillations and significantly enhance the neural entrainment effect. In addition to the same-frequency enhancement, irradiating near-infrared light at the same frequency and applying AC transcranial electrical stimulation at the same frequency in a phase-synchronized manner can enhance neural oscillations and further significantly enhance the neural entrainment effect.

[0045] In some embodiments, when the current brain wave frequency of the subject is in one of the first frequency band, the second frequency band, and the third frequency band, the second frequency and the first frequency can be in the frequency band. In some embodiments, the current brain wave frequency of the AD patient can be detected by an EEG detection device, especially the frequency that falls in any one of the alpha, beta, and gamma frequency bands, and then the photoelectric combined stimulation of the same frequency band where the frequency is located is applied, so that the second frequency of the AC transcranial electrical stimulation and the first frequency of the transcranial light are both in the frequency band. Furthermore, near-infrared light pulses and AC transcranial electrical stimulation of the same frequency and the same phase can also be applied. In this way, the exogenous oscillation frequency can be made the same as the endogenous EEG oscillation frequency at the time of the current source, thereby enhancing the neural oscillation and neural entrainment effect in this frequency band. In another exemplary embodiment, AD patients with different disease courses will show abnormal neural oscillations in different frequency bands. In the early stages of AD, EEG changes mainly include reduced amplitude and slowing of fast rhythms such as alpha, beta and gamma. The neural oscillation defect frequency of AD patients can be confirmed by an EEG detection device, and transcranial light of the corresponding frequency band can be applied in conjunction with alternating current transcranial electrical stimulation of the corresponding frequency band, so as to specifically regulate the neural oscillations that lack the frequency, specifically induce oscillation entrainment, and then specifically regulate the neural activity in the damaged area.

[0046] In some embodiments, at least one pair of electrodes can be configured to be detachably disposed behind the ears of the subject, such as Figure 3A As shown. In some embodiments, the electrodes behind the ears can be attached to the mastoid area, which not only facilitates full attachment of the electrodes, but also makes it easier for ordinary people to find the mastoid area by hand, and complete the attachment of the electrodes conveniently and confidently. In the embodiment shown in the figure, the total current is 15mA. The size of the electrode is 3.5×3.5cm, so the current density is 15mA / 12.25cm 2 =1.225mA / cm 2 There is no hair behind the ears, so it is easy to attach the electrodes and clean them more conveniently. The attachment site is intuitive and easy to locate. Simply attach the stimulation electrodes to the AD patient and turn on the device to enjoy comfortable AD intensive treatment. Non-professionals can also operate it easily.

[0047] Figure 4A Shown Figure 3A The current density distribution in the coronal plane of the subject's head when performing transcranial alternating current stimulation with the electrode scheme shown and a total current of 15 mA. Figure 4B and Figure 4C The current density distribution in the cross section and sagittal plane are shown respectively. The frequency of transcranial alternating current stimulation is 40Hz.

[0048] In some embodiments, at least one pair of electrodes can be configured to be detachably disposed on the forehead and behind the ear of the subject, respectively. Figure 3B and Figure 3C As shown, the total current is still 15mA. Figure 3B In the embodiment shown, the size of the electrodes at the forehead and mastoid is 3.5×3.5 cm, and two electrode sheets are attached to the forehead, and the two electrode sheets form a pair with the electrodes at the corresponding mastoid. In other words, the two electrodes at the forehead do not form a pair, and no voltage or current path is generated between them. The current from each electrode sheet to the corresponding mastoid is equal to the current on the opposite side, both of which are 7.5 mA. Therefore, the current density of each electrode is 7.5 mA / 12.25 cm 2 =0.612mA / cm 2 .exist Figure 3C In the embodiment shown, the electrode size at the mastoid is 3.5×3.5 cm, and the electrode size at the forehead is 4×6 cm. The current density at the forehead is 15 mA / 24 cm 2 =0.625mA / cm 2 . In this way, the stimulation circuit at the electrode position is also adjacent to and affects the primary motor cortex or the dorsolateral prefrontal cortex, thereby achieving the effect of relieving pain and increasing pleasure. There is no hair on the forehead, so it is also easy to attach electrodes and it is more convenient to clean. Furthermore, applying alternating current transcranial electrical stimulation in the above frequency band to the frontal lobe and behind the ear combined with whole-head phototherapy also has a good regulatory effect on the subject's emotions. Through the combined phototherapy of the present application, AD patients can immediately feel the relief of existing pain and are more willing to cooperate with each treatment. Continuous treatment can manage pain and emotions well, and they are more willing to persist in treatment.

[0049] In an exemplary embodiment, Figure 3D At least one pair of electrodes includes multiple electrodes detachably arranged on the forehead, the back of the ear and the neck of the subject, the forehead electrode and the electrode at the mastoid position behind the ear form a pair of electrodes, and the neck electrode and the electrode at the mastoid position form a pair of electrodes. This allows the current to be split, and the current density of each electrode is 7.5mA / 12.25cm 2 =0.612mA / cm 2 .

[0050] In some embodiments, at least one electrode in at least one pair of electrodes is flexible. As described above, the electrodes can be attached to the forehead, mastoid process behind the ear, and other parts. On the one hand, these parts usually have protrusions or curvatures, and the use of conventional rigid electrodes may result in loose adhesion and discomfort. On the other hand, for the above-mentioned looser phototherapy part, it is difficult to press the electrode against the head of the subject through a supporting mechanism. The use of flexible electrodes can facilitate attachment to curved surfaces, allowing the electrodes to fit reliably to the skin, reducing the discomfort that may be caused by treatment. In other words, the flexible electrode can rely on its own deformation ability to improve the fit with the mastoid process behind the ear of the subject. In some embodiments, the electrodes can also be adhered to the forehead and mastoid process behind the ear using various biocompatible conductive gels.

[0051] In some embodiments, at least one of the at least one pair of electrodes is a transparent electrode. For example, but not limited to, a flexible nano-metal mesh transparent electrode, a silver nanowire embedded silk protein electrode, a nanofiber-based flexible transparent electrode, etc. The transparent electrode can reduce the loss of near-infrared light, so that transcranial electrical stimulation and near-infrared light can work in combination around the hippocampus near the temporal lobe. Transparency here means that it is transparent to at least the near-infrared light used for treatment, and it is not required to be transparent to all light.

[0052] Preferably, the electrodes can be flexible transparent electrodes so that they can be attached to the curved surface of the head, such as the forehead and the mastoid processes on both sides, while basically not blocking the transcranial light radiation of the phototherapy part, so that the near-infrared light can still act efficiently on the frontal lobe and temporal lobe and other parts.

[0053] Figure 3B A scheme of attaching two independent electrodes on the forehead and electrodes behind the two ears is shown. The two independent electrodes on the forehead are arranged on the left and right sides of the forehead, and the electrodes behind the two ears can be attached to the mastoids on both sides. In some embodiments, the electrode on the left side of the forehead can form a pair of electrodes with the electrode behind the left ear, and the electrode on the right side of the forehead can form a pair of electrodes with the electrode behind the right ear. In some embodiments, the electrode on the left side of the forehead can form a pair of electrodes with the electrode behind the right ear, and the electrode on the right side of the forehead can form a pair of electrodes with the electrode behind the left ear. Figure 5A-Figure 5C The use of Figure 3B The current density distribution in the coronal, transverse and sagittal planes of the subject's head when performing transcranial alternating current stimulation with the electrode scheme shown and a total current of 15 mA, wherein the frequency of the transcranial alternating current stimulation is 40 Hz.

[0054] In some embodiments, the electrode disposed at the forehead of the subject may be a single electrode and disposed across the left and right sides of the forehead of the subject, such as Figure 3C shown. Figure 6A-6C Shown Figure 3CThe current density distribution in the coronal, transverse and sagittal planes of the subject's head when performing transcranial alternating current stimulation with the electrode scheme shown and a total current of 15 mA, wherein the frequency of the transcranial alternating current stimulation is 40 Hz.

[0055] from Figures 4A-7C It can be seen that Figure 3A , Figure 3B , Figure 3C and Figure 3D In the electrode scheme shown, current density is deposited in the frontal lobe, parietal lobe, and occipital lobe. Figure 3B and Figure 3C The electrode scheme shown is compared to Figure 3A and Figure 3D The electrode scheme shown has strong current density deposition in the frontal lobe, parietal lobe, and temporal lobe. Figure 3D The electrode scheme shown has a smaller current density in the brain than other schemes because the current output by the neck electrode patch is largely shunted through the skin.

[0056] Figure 8 From top to bottom, the following are shown: Figure 3A , Figure 3B , Figure 3C and Figure 3D Current density at the hippocampus of a subject's head with transcranial alternating current stimulation using the electrode scheme shown and a total current of 15 mA. Figure 8 It can be seen that Figure 3A , Figure 3B , Figure 3C The corresponding three electrode schemes have a larger current density in the hippocampus. Figure 3D The electrode scheme shown has low current density in the hippocampus. Figure 3A In the electrode scheme shown, the current density is greatest in the hippocampus, but the return Figure 4A-4C , we can see that the current density at the frontal lobe is not as good as Figure 3B The electrode scheme shown. Therefore, it can be used Figure 3B and Figure 3C The electrode scheme is used to seek high current density and transcranial alternating current stimulation effects in the frontal lobe, parietal lobe, temporal lobe and hippocampus. Figure 3A The electrode scheme seeks high levels of current density and transcranial alternating current stimulation effects targeting the hippocampus.

[0057] In some embodiments, the AC transcranial electrical stimulation unit 4 can be configured to: adjust the ratio of the current intensity between each pair of electrodes. In the early stage of AD, the asymmetry of bilateral hippocampal atrophy can be found through MRI detection, usually the right hippocampus is more atrophic than the left hippocampus, which provides a reference for the early identification of AD. In the course of AD, the atrophy of the hippocampi on both sides is not completely symmetrical. The AC transcranial electrical stimulation unit 4 is configured to: be able to adjust the current intensity of each pair of electrodes, and correspondingly adjust the current intensity of the current circuit acting on the hippocampi on both sides, so that the hippocampi on both sides can be stimulated in a targeted manner under the same total stimulation current, increase the stimulation dose of the hippocampus on the side with severe atrophy, and accelerate the removal of β-amyloid protein therein, thereby delaying the development of AD.

[0058] In some exemplary embodiments, the support mechanism 1 may include a head cap. The head cap may have a certain degree of elasticity to adapt to the head size of different subjects, and can be fixed on the subject's head through this elasticity. However, when worn by different subjects, the position of the near-infrared light irradiation unit 3 may move. In this case, the head cap can be made into multiple sizes so that the head cap can be stretched within an acceptable range to ensure that the near-infrared light irradiation unit 3 can irradiate the frontal lobe, temporal lobe and parietal lobe. In some embodiments, the shape of the head cap cannot be changed, but is fixed to the subject's head by auxiliary fixings such as elastic bands. In some embodiments, the head cap may also be supported on other parts of the body other than the head, or may be supported or fixed by a bracket 11. The subject can accommodate the head in the head cap without contacting the head cap. In some embodiments, the support mechanism may also be constructed in an umbrella shape, a bell shape, or a skeleton shape, as long as the near-infrared light irradiation unit 3 can be kept in the desired position around the subject's head.

[0059] In some embodiments, referring back to Figure 1B, the support mechanism 1' is constructed as a head cap, and a gap is reserved between the head cap and the head when the head of the subject is accommodated therein, so that the head can move. Unlike adapting to the patient's head shape, a gap is reserved between the head cap and the patient's head for the patient's head to move, so that the patient can move his head in the movable gap according to his own wishes or involuntarily due to the course of the disease. This loose and open head cap design does not restrain the patient's head, and is especially friendly to the elderly who are emotionally agitated, anxious, resistant or even afraid of confined or crowded spaces, thereby significantly improving the treatment compliance of AD patients. Specifically, the head cap can be used for patients with AD who have psychological barriers to confined or crowded spaces to wear continuously during the treatment process. This psychological barrier to confined or crowded spaces can be caused by the patient's own age or psychological diseases other than AD, or it can be caused by suffering from AD. This design of the head cap can also be widely applicable to the behavioral characteristics of patients with different courses of AD. For example, for early AD patients, their judgment ability is reduced and they are often suspicious and irritable. The wearing of such a head cap with sufficient freedom and openness is easy for patients to accept and not easily irritate, so that patients can cooperate with the continuous light therapy. For another example, for patients in the middle stage of AD, their emotions fluctuate violently, they are impatient and restless, and they often walk around. Some patients' heads will frequently shake slightly unconsciously. This open head cap allows the patient's head to have such unconscious slight shaking without causing the head cap itself to vibrate. Therefore, there is no need to forcibly stop such slight shaking, which increases the comfort of the patient and reduces the workload of medical staff. At the same time, it can prevent such shaking of the patient's head from being transmitted to the head cap and affecting the effect of light therapy. Therefore, in some other embodiments, the head cap can be used for AD patients who are emotionally agitated and anxious to wear continuously during treatment.

[0060] In addition to the closed but loose design of the lower opening, the head cap can make AD patients with various disease courses more willing to accept treatment, and a single irradiation can last longer, such as 20 minutes, 30 minutes, or even longer each time, thereby further improving the treatment effect; and avoiding the leakage of near-infrared light in all directions during the irradiation process, thereby further improving the safety of treatment.

[0061] In some embodiments, by setting the distance between the array of near-infrared light irradiation unit 3 and the head to within 10 cm, the lateral movable gap during the treatment process is controlled to a few cm level, such as 4-5 cm, 3-4 cm, 2-3 cm, etc. The inventors conducted psychological investigations and analyses on patients in clinical experiments and confirmed that this is a psychologically comfortable range for patients, which allows patients to have sufficient freedom of movement while not being too spacious to cause patients to feel uneasy and worried about the inaccurate position of the head.

[0062] like Figure 1A As shown, in some embodiments, the support mechanism 1 adopts a skeleton structure, which can be worn on the head of the subject and has a hollow area 2, so that the head of the subject is fully exposed to the external environment through the hollow area 2. As mentioned above, the subject may walk and move during the treatment process. The use of a skeleton-type support mechanism 1 can prevent the subject from having resistance and fear of the fully enclosed head cap, which is especially friendly to the elderly who are emotionally agitated, anxious, resistant to or even afraid of confined or crowded spaces. The wearable support mechanism 1 allows the subject to move in a small range or even walk freely during the treatment process, thereby significantly improving the treatment compliance of AD patients. The support mechanism 1 with a skeleton structure can also reduce weight and has better ventilation. In some embodiments, the setting can be simplified or even no special heat dissipation channel is set, and there is less discomfort caused by heat accumulation.

[0063] In some embodiments, Figure 1C As shown, the support mechanism 1'' may include an external support frame that is at least a first distance from the head of the subject. The support frame may support or be fixed on an external object, and the subject may be Figure 1B The head cap type support mechanism 1' shown can move more freely, thereby reducing the sense of oppression brought to the subject and further improving the compliance of the treatment.

[0064] In the description of the present application, it should be understood that the orientation or positional relationship indicated by directional words such as "front", "back", "up", "down", "left", "right", "lateral", "vertical", "vertical", "horizontal", "top", "bottom", etc. is usually based on the orientation or positional relationship shown in the drawings, and is only for the convenience of describing the present application and simplifying the description. Unless otherwise specified, these directional words do not indicate or imply that the device or device referred to must have a specific orientation or be constructed and operated in a specific orientation, and therefore cannot be understood as limiting the scope of protection of the present application; the directional words "inside" and "outside" refer to the inside and outside relative to the outline of each component itself.

[0065] For ease of description, regional relative terms such as "above", "above", "on the upper surface", "above", etc. may be used here to describe the regional positional relationship between one or more components or features shown in the figure and other components or features. It should be understood that regional relative terms include not only the orientation of the components as described in the figure, but also different orientations in use or operation. For example, if the components in the accompanying drawings are inverted as a whole, the components "above other components or features" or "above other components or features" will include the situation where the components are "below other components or structures" or "below other components or structures". Therefore, the exemplary term "above" may include both "above" and "below". In addition, these components or features may also be positioned at other different angles (e.g., rotated 90 degrees or other angles), and this article is intended to include all of these situations.

[0066] It should be noted that the terms used herein are only for describing specific embodiments and are not intended to limit the exemplary embodiments according to the present application. As used herein, unless the context clearly indicates otherwise, the singular form is also intended to include the plural form. In addition, it should be understood that when the terms "comprise" and / or "include" are used in this specification, it indicates the presence of features, steps, operations, parts, components and / or combinations thereof.

[0067] The present application has been described by the above-mentioned embodiments, but it should be understood that the above-mentioned embodiments are only for the purpose of example and description, and are not intended to limit the present invention to the scope of the described embodiments. In addition, it can be understood by those skilled in the art that the present invention is not limited to the above-mentioned embodiments, and more variations and modifications can be made according to the teachings of the present invention, and these variations and modifications all fall within the scope of the protection claimed by the present invention. The protection scope of the present invention is defined by the attached claims and their equivalents.

Claims

1. A neuromodulator for treating Alzheimer's disease, characterized in that: The neuromodulator includes a phototherapy unit and an alternating current transcranial electrical stimulation unit that work in synergy. The phototherapy unit includes a support mechanism and an array of near-infrared light irradiation units disposed on the support mechanism, wherein the array of near-infrared light irradiation units is configured to irradiate transcranial near-infrared light to the frontal lobe, temporal lobe and parietal lobe of the subject, wherein the near-infrared light is continuous light or pulsed light having a first frequency; The AC transcranial electrical stimulation unit includes at least one pair of electrodes, each pair of electrodes being configured to be detachably disposed on the scalp of the subject's head around the frontal lobe or the temporal lobe to apply AC transcranial electrical stimulation of a second frequency, and the electric field action range of the AC transcranial electrical stimulation includes at least a portion of the hippocampus; When the near-infrared light is continuous light, the second frequency is in one of the first frequency band, the second frequency band and the third frequency band; In the case where the near-infrared light is the pulsed light with the first frequency, the first frequency and the second frequency are in the same frequency band among the first frequency band, the second frequency band and the third frequency band and the deviation is less than a threshold, wherein the first frequency band is 8-12 Hz, the second frequency band is 13-24 Hz, and the third frequency band is 25-85 Hz.

2. The neural regulation device according to claim 1, characterized in that: At least a portion of the irradiated near-infrared light is transmitted in a direction toward the hippocampus.

3. The neural regulation device according to claim 2, characterized in that: The first frequency is equal to the second frequency.

4. The neural regulation device according to claim 3, characterized in that: The first frequency and the second frequency are both the same frequency among 10 Hz, 20 Hz, 40 Hz and 70-80 Hz.

5. The neural control device according to any one of claims 2 to 4, characterized in that: The phototherapy section and the AC transcranial electrical stimulation section are configured to irradiate the near-infrared light and apply the AC transcranial electrical stimulation, respectively, in a phase-synchronized manner.

6. The neuromodulator according to any one of claims 1 to 4, characterized in that: At least one pair of electrodes is configured to be detachably disposed behind the ears of the subject, respectively.

7. The neuromodulator according to any one of claims 1 to 4, characterized in that: At least one pair of electrodes is configured to be detachably disposed on the forehead and behind the ears of the subject, respectively.

8. The neural regulation device according to claim 7, characterized in that: The electrode disposed at the forehead of the subject is a single electrode disposed across the left and right sides of the forehead of the subject, or is two separate electrodes disposed on the left and right sides of the forehead.

9. The neuromodulator according to any one of claims 1 to 4, characterized in that: The array of the near-infrared light irradiation units is distributed for the frontal lobe, the temporal lobe and the parietal lobe, so that the frontal lobe, the temporal lobe and the parietal lobe each have a correspondingly distributed plurality of near-infrared light irradiation units.

10. The neural regulation device according to claim 1, characterized in that: The supporting mechanism is configured as a head cap, and when the head of the subject is accommodated therein, a gap of several centimeters is retained between the head cap and the head.

11. The neural regulation device according to claim 1, characterized in that: The support mechanism adopts a skeleton structure, can be worn on the head of the object and has a hollow area, so that the head of the object is fully exposed to the external environment through the hollow area.

12. The neural regulation device according to claim 1, characterized in that: The support mechanism includes an external support frame that is at a distance greater than a first distance from the head of the subject.

13. The neuromodulator according to any one of claims 1 to 4, characterized in that: The total stimulation current of the AC transcranial electrical stimulation unit can reach 15 mA.

14. The neuromodulator according to any one of claims 1 to 4, characterized in that: The alternating current transcranial electrical stimulation increases the release of beta-endorphin in the brain of the subject.

15. The neuromodulator according to any one of claims 1 to 4, characterized in that: At least one electrode of the at least one pair of electrodes is flexible.

16. The neuromodulator according to any one of claims 1 to 4, characterized in that: At least one electrode of the at least one pair of electrodes is a transparent electrode.

17. The neuromodulator according to any one of claims 1 to 4, characterized in that: The AC transcranial electrical stimulation unit is configured to adjust the ratio of current intensity between each pair of electrodes.

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