Neuromodulation device for treating hippocampus-related brain diseases

Abstract

The present application relates to a neuromodulation device for treating hippocampus-related brain diseases. The neuromodulation device comprises a phototherapy part and a transcranial alternating current stimulation (tACS) part. The phototherapy part irradiates near-infrared light toward at least a frontal lobe or a temporal lobe, such that the near-infrared light acts on at least a part of the hippocampus. The tACS part applies tACS of a second frequency, and an electric field action range covers at least a part of the hippocampus. When the near-infrared light is continuous light, the second frequency is in one of five representative frequency bands of brain waves. When the near-infrared light is pulsed light having a first frequency, the first frequency and the second frequency also satisfy a preset frequency relationship. The preset frequency relationship comprises: a deviation being less than a threshold, or having a preset frequency band coupling relationship. Transcranial electrical stimulation can produce analgesic and relaxing effects, which can reduce the discomfort of a subject during treatment. Therefore, the treatment time can be prolonged and / or the power density of near-infrared light can be increased as needed, so as to improve the therapeutic effect. The photoelectric bimodal stimulation can improve modulation effects on endogenous oscillations of the brain.

Description

Neuromodulation device for treating hippocampus-related brain diseases TECHNICAL FIELD

[0001] The present application relates to the technical field of medical devices, in particular to a neuromodulation device for treating hippocampus-related brain diseases. BACKGROUND

[0002] The hippocampus is located in the medial temporal lobe of the brain and is part of the limbic system, with one in each hemisphere. The hippocampus is closely connected to surrounding structures (such as the amygdala, fornix, and entorhinal cortex) and is mainly responsible for memory formation (especially long-term memory), spatial navigation, and emotional regulation. Hippocampal damage or dysfunction is a common pathological feature of many brain diseases, and the mechanisms include structural damage (atrophy, neuronal death), synaptic plasticity disorders (such as LTP inhibition), and reduced neurogenesis (especially in depression and dementia). For example, hippocampal damage or dysfunction is closely related to depression and dementia. For example, the hippocampus is one of the earliest brain regions to be damaged in Alzheimer's disease (AD), and β-amyloid deposition and tau protein tangles lead to hippocampal atrophy, triggering short-term memory loss and spatial disorientation. For example, chronic stress or trauma can cause hippocampal volume reduction (due to inhibition of neurogenesis and dendritic atrophy), impairing its inhibition of amygdala hyperactivation, triggering hyperarousal and traumatic memory flashbacks, leading to PTSD, and hippocampal dysfunction is associated with symptom severity. For example, Parkinson's disease (PD) patients have reduced hippocampal metabolic activity, and so on.

[0003] As the human body ages, the hippocampus can also be damaged or dysfunctional. With the development of global population aging, hippocampus-related brain diseases such as Alzheimer's disease (AD) often occur in the elderly population, and have become a serious problem. For the elderly, there can be multiple hippocampus-related brain diseases, such as anxiety (or depression, bipolar disorder (BD)), AD, sleep disorders, etc., and emotions are more unstable. Since the various brain regions of humans are interconnected, in addition to the hippocampus as the "hub" being damaged or dysfunctional, the surrounding brain regions associated with it also have lesions. For example, AD lesions involve a wide range of brain regions, including the prefrontal cortex, hippocampus, etc.

[0004] In addition to the drug combination of conventional treatment, in recent years, people try to use photobiomodulation (PBM) to treat various hippocampus-related brain diseases, specifically, by irradiating the brain with a suitable dose of transcranial light (infrared or near-infrared light) of a certain wavelength range, to achieve neural regulation. The light energy of this waveband is mild and has good penetration. Many studies have shown that PBM treatment of AD and other diseases is effective. Further, the mechanism of action of PBM on AD is mainly to improve metabolic function and increase cerebral blood flow, promote nerve growth and synapse generation, increase Aβ clearance rate, activate glial cells, enhance antioxidant stress and anti-inflammatory capacity, etc. However, there are still various problems in actual treatment.

[0005] Taking AD as an example, for the hippocampus deep in the brain, if the power density of the transcranial light is insufficient, it cannot provide sufficient dose to the hippocampus, and excessive increase of the power density will increase the heat accumulation on the scalp or hair (especially the East Asian population with black hair) of the patient, causing discomfort to the AD patient. On the other hand, as the AD progresses, the AD patient not only has memory loss, but also is prone to anxiety and irritability, such as walking non-stop, suddenly standing up, and a considerable proportion of AD patients have chronic pain, and the probability of pain occurrence is positively correlated with the severity of cognitive impairment. Therefore, discomfort during treatment, persistent pain, etc. will lead to resistance to treatment by AD patients.

[0006] The existing PBM neural regulation device for treating AD requires the AD patient to wear a phototherapy head cap for ten minutes to half an hour, and needs to be treated every week. The treatment operation difficulty and the cooperation and compliance of the AD patient are a problem. From the clinical trial under the intervention of a small range of short time professional doctors, to the treatment of AD neural regulation device into the family, convenient, comfortable and effective treatment and disease management for AD patients, there is still a long way to go. SUMMARY

[0007] Therefore, a neural regulation device for treating hippocampus-related brain diseases is needed, which is easy to operate, can provide sufficient dose of transcranial light treatment to the hippocampus and other brain regions associated with brain diseases, and can perform reinforcement treatment on the hippocampus deep in the brain according to the endogenous rhythm of the brain. The discomfort of the subject can be significantly reduced during the treatment process, and the comfort and compliance of the subject during the treatment can be enhanced. Continuous treatment can also achieve mood and pain management of the subject.

[0008] To at least partially solve the problems in the prior art, according to one aspect of the present application, a neuromodulation device for treating hippocampus-related brain diseases is provided, which comprises a light therapy part and a transcranial alternating current stimulation part. The light therapy part comprises a support mechanism and an array of near-infrared light irradiation units arranged on the support mechanism, which is configured to irradiate transcranial near-infrared light to at least the frontal lobe or the temporal lobe of a subject, so that it can act on at least part of the hippocampus. The near-infrared light is continuous light or pulsed light with a first frequency. The transcranial alternating current stimulation part comprises at least one pair of electrodes to apply transcranial alternating current stimulation with a second frequency, and the electric field range of the transcranial alternating current stimulation contains at least part of the hippocampus. In the case of continuous light, the second frequency is in one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band and the fifth frequency band. In the case of pulsed light with a first frequency, the first frequency and the second frequency are each in one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band and the fifth frequency band, and satisfy a preset frequency relationship, wherein the first frequency band is 8-13 Hz, the second frequency band is 13-30 Hz, the third frequency band is 30-100 Hz, the fourth frequency band is 0.5-4 Hz, and the fifth frequency band is 4-8 Hz. The preset frequency relationship includes that the deviation of the first frequency and the second frequency is less than a threshold, or the first frequency and the second frequency have a preset frequency band coupling relationship.

[0009] In some embodiments, the fourth frequency band (0.5-4 Hz) is a representative frequency band of delta waves in brain endogenous oscillation, the fifth frequency band (4-8 Hz) is a representative frequency band of theta waves in brain endogenous oscillation, the first frequency band (8-13 Hz) is a representative frequency band of alpha waves in brain endogenous oscillation, the second frequency band (13-30 Hz) is a representative frequency band of beta waves in brain endogenous oscillation, and the third frequency band (30-100 Hz) is a representative frequency band of gamma waves in brain endogenous oscillation.

[0010] Herein, when describing that the near-infrared light is continuous light, it is intended to mean that the light intensity of the near-infrared light is relatively stable and continuous in time domain, without obvious period. Herein, when describing that the near-infrared light is pulsed light, the pulsed light can include pulsed light caused by instantaneous high light intensity of laser, but is not limited thereto. For example, the near-infrared light emitted by LED and the like has continuous light intensity in time domain, but can form periodic waveforms with rising and falling edges, such as square waveforms, sinusoidal waveforms and the like, which are also included in the scope of pulsed light. The frequency of the waveform is the “frequency” of the pulsed light.

[0011] The neuroregulation device for treating hippocampus-related brain diseases according to the present application can produce a positive therapeutic effect on the brain diseases (such as but not limited to AD) by irradiating the subject's head with near-infrared light in combination with transcranial alternating current stimulation. The transcranial alternating current stimulation in the first to fifth frequency bands can produce analgesic and relaxing effects, reduce the discomfort (such as but not limited to heat pain) of the subject during treatment, enhance the subject's compliance with the treatment, and can also extend the treatment time and / or increase the power density of the near-infrared light as needed to improve the treatment effect, especially for the treatment of deep brain sites such as the hippocampus. Moreover, the transcranial alternating current stimulation, in combination with the continuous treatment of near-infrared light irradiation, can effectively manage the mood and pain of the subject accompanying the brain disease.

[0012] Further, by irradiating the transcranial near-infrared light to at least the frontal lobe or temporal lobe of the subject, which can act on at least part of the hippocampus, and applying transcranial alternating current stimulation (tACS) to at least part of the hippocampus, not only can the metabolic function and cerebral blood flow be improved, nerve growth and synapse generation be promoted, Aβ clearance rate be increased, glial cells be activated, and antioxidant stress and anti-inflammatory capacity be enhanced, but also the endogenous oscillation of the brain can be neuroregulated. The photoelectric dual-mode stimulation can promote each other to improve the treatment effect on the hippocampus-related brain diseases.

[0013] Further, in the case where the near-infrared light is pulsed light having a first frequency, the first frequency of the near-infrared light and the second frequency of the tACS satisfy a preset frequency relationship. The preset frequency relationship can be defined as a deviation of the first frequency and the second frequency being less than a threshold value. In this case, the near-infrared light stimulation and the tACS have a certain degree of frequency band correspondence, which can significantly increase the neural entrainment effect and improve the treatment effect. The preset frequency relationship can also be defined as the first frequency and the second frequency having a preset frequency band coupling relationship. For example, the preset frequency band coupling relationship can be determined according to the frequency band coupling relied on by the normal brain when performing various tasks. For another example, the preset frequency band coupling relationship can also be set according to the frequency band coupling deviated or failed by the diseased brain compared with the normal brain. In this case, the treatment effect can be improved by modulating and repairing the endogenous frequency band coupling of the brain through exogenous frequency band coupling.

[0014] A series of simplified concepts are introduced in the summary, which will be further described in detail in the specific embodiments. The summary part does not mean to try to limit the key features and essential technical features of the claimed technical solutions, nor to determine the protection scope of the claimed technical solutions.

[0015] The advantages and features of the present application will be described in detail below in combination with the drawings. BRIEF DESCRIPTION OF DRAWINGS

[0016] The following drawings for this application are hereby incorporated into this application as part of this application for understanding this application. The drawings for this application and its description show the embodiments of this application, which are used to explain the principles of this application. In the drawings,

[0017] Figure 1A shows a schematic diagram of the use of a neuromodulation device according to a first exemplary embodiment of the present application;

[0018] Figure 1B shows a schematic diagram of the use of a neuromodulation device according to a second exemplary embodiment of the present application;

[0019] Figure 1C shows a schematic diagram of the use of a neuromodulation device according to a third exemplary embodiment of the present application;

[0020] Figure 1D shows a schematic diagram of a near-infrared light irradiation scheme according to a fourth exemplary embodiment of the present application, in which near-infrared light is irradiated to the temporal lobe so as to act on at least part of the hippocampus;

[0021] Figure 1E shows a schematic diagram of a near-infrared light irradiation scheme according to a fifth exemplary embodiment of the present application, in which near-infrared light is irradiated to the frontal lobe so as to act on at least part of the hippocampus;

[0022] Figure 1F shows a schematic diagram of various waveforms of electroencephalogram signals;

[0023] Figures 2A-2C respectively show simulation results of light dose distribution diagrams under the action of 40Hz light therapy at different wavelengths;

[0024] Figures 3A-3D respectively show schematic diagrams of the positions of multiple pairs of electrodes under different schemes;

[0025] Figures 4A-7C respectively show simulation results of intracranial electric field distribution under different schemes shown in Figures 3A-3D;

[0026] Figure 8 shows simulation results of current density at the hippocampus under different schemes shown in Figures 3A-3D;

[0027] Figure 9 shows a schematic diagram of a tACS electrode arrangement according to a sixth exemplary embodiment of the present application;

[0028] Figures 10(a)-10(e) show schematic diagrams of tACS electrode arrangements according to seventh to eleventh embodiments of the present application. DETAILED DESCRIPTION

[0029] In the following description, numerous specific details are provided to provide a thorough understanding of the application. One skilled in the relevant art will recognize, however, that the application can be practiced without one or more of the specific details, or with other methods, components, materials, etc. In other instances, well-known structures, materials, or operations are not shown or described in detail in order to avoid obscuring aspects of the application.

[0030] The terms "first", "second", and similar terms used herein do not necessarily connote an order of importance, but are used to distinguish one element from another, and are used interchangeably with the terms "one", "another", and "at least one". The terms "comprises", "comprising", "includes", "including" and the like can be used herein to indicate the inclusion of one or more elements, components, steps, and the like, but do not preclude the inclusion of one or more other elements, components, steps, and the like. The term "head" used herein refers to organs above the neck (cervical vertebrae) of a human body, including the brain and extracerebral tissues such as the skull, skin, and hair. The term "brain" used herein refers to an organ remaining after the extracerebral tissues are removed, and is intended to mean the cerebrum, but is not limited thereto, and can include the cerebrum, the cerebellum, and the brainstem.

[0031] The term "hippocampus-related brain disease" used herein includes, but is not limited to, any one of Alzheimer's disease (AD), dementia, anxiety, post-traumatic stress disorder (PTSD), cognitive impairment, Parkinson's disease (PDD), Huntington's disease, depression, BD, sleep disorder, amyotrophic lateral sclerosis, autism spectrum disorder, attention deficit disorder in children, schizophrenia, and transient global amnesia.

[0032] The term "dementia" used herein includes dementia caused by various brain diseases, such as, but not limited to, dementia caused by AD, dementia caused by PDD, vascular dementia, frontotemporal dementia, Lewy body dementia, post-traumatic dementia, diabetes-related dementia, and the like. The various "brain diseases" are associated with damage to the hippocampus, such as the degeneration, loss, disorder, and death of neurons, vascular lesions, structural atrophy, abnormal function of neural networks, and the like.

[0033] The expression "for treating Alzheimer's disease" used in the present application is intended to mean that the development of the course of Alzheimer's disease (AD) is alleviated, inhibited, terminated or even reversed, and the course of AD is intended to include the process in which the subject has already developed the clinical symptoms of AD and then develops, and also the process in which the subject has not yet developed the clinical symptoms of AD, but some pathological or physiological phenomena associated with AD have occurred and will develop into AD at a certain probability. That is, the expression "for treating Alzheimer's disease" in the present application includes treating AD that has already occurred, and also includes preventing the occurrence of AD or reducing the probability of the occurrence of AD. Specifically, according to the AD diagnostic criteria of the National Institute on Aging and the Alzheimer's Association (NIA-AA) in 2018, biomarkers can be divided into four categories based on the results of examination of β-amyloid (Aβ) and tau in the brain or cerebrospinal fluid of the population, and head MRI, FDG-PET, and cognitive function can be further divided into six levels. The first level is characterized by normal objective cognitive neuropsychological test, no cognitive complaint, no neurobehavioral symptoms, no cognitive decline or neurobehavioral symptoms reported by the informant, and no follow-up test evidence of cognitive decline; the second level includes subjective cognitive decline (SCD), objective mild cognitive decline (Obj-SCD), and neurobehavioral symptoms; the first level and the second level are collectively referred to as preclinical. The third level is abnormal or impaired in objective cognitive test, but does not reach dementia, i.e., MCI. The fourth to sixth levels are mild, moderate and severe dementia, respectively. The stages of each level in the six levels belong to the course of AD defined in the present application. Further, for subjects carrying genes associated with the risk of AD but currently testing negative for Aβ, such as APOE ε4, ABCA7, CLU, CR1, PICALM, PLD3 and TREM2, medical intervention is performed to reduce the risk of developing AD and slow down the process of developing AD, which is considered "for treating Alzheimer's disease" in the present application.

[0034] In order to at least partially solve the problems existing in the prior art, the present application provides a neuromodulation device for treating hippocampus-related brain diseases.

[0035] As shown in FIG. 1A, the neuromodulation device can include a phototherapy part 5 and a transcranial alternating current stimulation (tACS) part 4, and the phototherapy part 5 can include a support mechanism 1 and an array of near-infrared light irradiation units 3 arranged on the support mechanism 1. The array of near-infrared light irradiation units 3 is configured to irradiate transcranial near-infrared light to at least the frontal lobe or the temporal lobe of the subject, so that it can act on at least part of the hippocampus, and the near-infrared light is continuous light or pulsed light with a first frequency. The tACS part 4 includes at least one pair of electrodes 40 to apply tACS with a second frequency, and the electric field range of the tACS includes at least part of the hippocampus.

[0036] As shown in FIGS. 1A, 1B, and 1C, the light therapy section 5 can irradiate near-infrared light to the frontal lobe, temporal lobe, and parietal lobe of the subject together, that is, the array of near-infrared light irradiation units 3 is distributed with respect to the frontal lobe, temporal lobe, and parietal lobe, so that each of the frontal lobe, temporal lobe, and parietal lobe has a corresponding plurality of near-infrared light irradiation units scattered, thereby delivering a sufficient dose of near-infrared light from each direction of the periphery of the hippocampus, thereby inhibiting the structural and functional impairment of the hippocampus of the brain disease patient and its spread to the periphery. Specifically, near-infrared light, particularly near-infrared light having a wavelength of 650 nm to 1100 nm, can inhibit the structural and functional impairment of the hippocampus associated with various brain diseases in various mechanisms of action.

[0037] For example, one of the mechanisms of action of near-infrared light on the hippocampus is to activate glial cells and enhance antioxidant stress and anti-inflammatory capacity. In the early stages of various diseases such as AD, dementia, anxiety, post-traumatic stress disorder (PTSD), cognitive impairment, Parkinson's disease, Huntington's disease, depression, BD, sleep disorders, amyotrophic lateral sclerosis, etc., the hippocampus is already inflamed (this is one of the early pathological changes), and as the disease progresses, the inflammation of the hippocampus gradually spreads to other brain regions. For example, inflammation of the hippocampus can lead to neurodegenerative changes, affecting memory and cognitive function, leading to worsening of AD, dementia, cognitive impairment diseases. For example, inflammation of the hippocampus can trigger anxiety symptoms, depressive symptoms, etc. by affecting neurogenesis and neural plasticity. In addition, factors such as chronic stress can exacerbate depressive symptoms by increasing inflammation of the hippocampus. For example, PTSD patients have inflammation of the hippocampus, which is related to changes in stress response and neural plasticity; the observed shrinkage of the hippocampus and functional abnormalities in PTSD patients are also related to inflammation. For example, sleep disorders such as sleep deprivation can cause inflammation of the hippocampus, which in turn affects cognitive function and emotional state. By irradiating near-infrared light to the frontal lobe (e.g., dorsolateral prefrontal lobe), temporal lobe (e.g., medial temporal lobe), and parietal lobe (e.g., precuneus) of the subject together, it is possible to hinder the spread of inflammation at the hippocampus to each of the frontal lobe, temporal lobe, and parietal lobe.

[0038] For example, one of the mechanisms of action of near-infrared light on the hippocampus is to activate glial cells and enhance antioxidant stress and anti-inflammatory capacity. In the early stages of various diseases such as AD, dementia, anxiety, post-traumatic stress disorder (PTSD), cognitive impairment, Parkinson's disease, Huntington's disease, depression, BD, sleep disorders, amyotrophic lateral sclerosis, etc., the hippocampus is already inflamed (this is one of the early pathological changes), and as the disease progresses, the inflammation of the hippocampus gradually spreads to other brain regions. For example, inflammation of the hippocampus can lead to neurodegenerative changes, affecting memory and cognitive function, leading to worsening of AD, dementia, cognitive impairment diseases. For example, inflammation of the hippocampus can trigger anxiety symptoms, depressive symptoms, etc. by affecting neurogenesis and neural plasticity. In addition, factors such as chronic stress can exacerbate depressive symptoms by increasing inflammation of the hippocampus. For example, PTSD patients have inflammation of the hippocampus, which is related to changes in stress response and neural plasticity; the observed shrinkage of the hippocampus and functional abnormalities in PTSD patients are also related to inflammation. For example, sleep disorders such as sleep deprivation can cause inflammation of the hippocampus, which in turn affects cognitive function and emotional state. By irradiating near-infrared light to the frontal lobe (e.g., dorsolateral prefrontal lobe), temporal lobe (e.g., medial temporal lobe), and parietal lobe (e.g., precuneus) of the subject together, it is possible to hinder the spread of inflammation at the hippocampus to each of the frontal lobe, temporal lobe, and parietal lobe.

[0039] Specifically, there are sufficient autopsy studies, animal models, brain imaging (PET / fMRI) and genetic studies to support the existence of a complex pathological symptom of reduced mitochondrial metabolism, reduced cerebral blood flow, and inhibited nerve growth and synapse generation in AD, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, dementia, schizophrenia, etc., and near-infrared light irradiation can provide targeted therapeutic effects.

[0040] Further, for depression, BD, PTSD, cognitive impairment, autism spectrum disorder, sleep disorders, evidence can also be provided by brain imaging, blood / cerebrospinal fluid biomarkers, and drug intervention studies. Although there is a certain heterogeneity in different individuals, these diseases also usually have at least one, two, or even three of the pathological symptoms of reduced mitochondrial metabolism, reduced cerebral blood flow, and inhibited nerve growth and synapse generation, so near-infrared light irradiation can also provide certain targeted therapeutic effects.

[0041] Further, regarding attention deficit disorder in children, some children have mitochondrial dysfunction, some subtypes are more prone to mitochondrial dysfunction, and a significant portion of children have reduced blood flow in the prefrontal cortex (PFC) and striatum, and also have abnormal synaptic plasticity and reduced BDNF (brain-derived neurotrophic factor) levels. Some patients with anxiety may have mitochondrial oxidative damage due to long-term stress, some patients have abnormal blood flow in the prefrontal cortex and amygdala, reduced prefrontal regulation, and long-term patients also inhibit neurogenesis near the hippocampus. Transient global amnesia is closely related to reduced cerebral blood flow, especially insufficient blood flow in the hippocampal region. Therefore, near-infrared light irradiation can also provide certain improvement effects for these brain diseases.

[0042] In some embodiments, as shown in FIG. ID and FIG. IE, the array of near-infrared light irradiation units 3 can also irradiate transcranial near-infrared light to at least the frontal lobe or the temporal lobe of the subject, so that the near-infrared light can act on at least part of the hippocampus. By irradiating a sufficient dose of near-infrared light to the frontal lobe (see FIG. IE), or irradiating a sufficient dose of near-infrared light to the temporal lobe (see FIG. ID), the phototherapeutic effect on the hippocampus can also be achieved. As shown in FIG. ID, the array of near-infrared light irradiation units 3 irradiates near-infrared light to the temporal lobe, and the light path of the transcranial transmission of the near-infrared light can intersect at least part of the hippocampus, so that the near-infrared light can be directly delivered to the hippocampus. As shown in FIG. IE, the array of near-infrared light irradiation units 3 irradiates near-infrared light to the dorsolateral prefrontal cortex (DLPFC), and although the DLPFC is spatially some distance away from the hippocampus, the near-infrared light cannot directly reach the hippocampus, but the orbitofrontal cortex can mediate between the DLPFC and the hippocampus, and the phototherapeutic effect of the near-infrared light on the DLPFC can be transmitted to the hippocampus via the orbitofrontal cortex. Therefore, in this context, the near-infrared light is directly delivered to the hippocampus, or does not reach the hippocampus but transmits the phototherapeutic effect to the hippocampus via mediation, both are considered as "able to act on part of the hippocampus".

[0043] In the case that the near-infrared light is continuous light, the second frequency is in one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band and the fifth frequency band. The fourth frequency band is 0.5-4Hz (representative frequency band of δ wave), the fifth frequency band is 4-8Hz (representative frequency band of θ wave), the first frequency band is 8-13Hz (representative frequency band of α wave), the second frequency band is 13-30Hz (representative frequency band of β wave), and the third frequency band is 30-100Hz (representative frequency band of γ wave). Various waveforms can be seen in FIG. 1F.

[0044] The tACS of each of the above frequency bands can induce brain to strengthen the neural oscillation signal of the corresponding frequency or weaken the neural oscillation signal of the related frequency by applying the alternating current of the specific frequency, so as to adjust the pain intensity or achieve the emotional relaxation effect.

[0045] For example, the neural oscillation signals of the α wave frequency band, the β wave frequency band and the γ wave frequency band are closely related to pain processing. In some embodiments, the tACS with the duration of 20-30 minutes, the amplitude of 1mA and the frequency in the α wave frequency band (e.g. 9Hz, 10Hz, 11Hz, etc.) applied to the F3 and F4 positions of the patient can reduce the perception of the waist pain of the patient. In some embodiments, the tACS with the frequency in the α wave frequency band (e.g. 8Hz, 9Hz, 10Hz, 11Hz, etc.) applied to the electrodes near the somatosensory area of the patient is also significantly related to the decrease of the pain perception intensity.

[0046] For example, tACS with theta and beta rhythms applied to the left DLPFC for a certain duration (e.g., 20 min) can significantly increase the contact heat pain threshold during the intervention and for a certain period of time (e.g., 5 min) after the intervention, and the simulated stimulation field applied to the left DLPFC can result in an inverted U-shaped curve relationship between theta rhythms and analgesic effect. Thus, it is confirmed that tACS with frequencies in the theta and beta bands can achieve analgesia, especially for the inhibition of heat pain.

[0047] For example, tACS in the alpha band applied to the frontal lobe and tACS in the beta, theta, and gamma bands applied to the M1 corresponding position to regulate the corresponding band oscillation can significantly reduce the pain perception of the patient.

[0048] For example, the delta band oscillation is closely related to deep sleep and declarative memory consolidation dependent on sleep, and tACS in the delta band such as 0.75 Hz applied to the bilateral prefrontal cortex is conducive to inducing and stabilizing the brain's delta band brain oscillation, thereby improving sleep, reducing stress, and further improving positive emotions.

[0049] Note that studies have shown that tACS can cause rhythmic fluctuations in neuronal membrane potential, affect the timing of spikes, but does not produce action potentials. This effect of tACS is called online effect, which is the direct influence on neuronal activity during stimulation, such as changing the membrane potential of the nerve, enhancing or inhibiting the neural oscillation of a specific frequency. In addition, changes in brain neural oscillation can still be observed several minutes or even 1 hour after the end of long-term or repeated tACS intervention, which is called the offline effect of tACS. For example, the analgesic effect of tACS at different frequencies occurs during treatment in some cases, and does not occur during treatment but appears after treatment and lasts for several to dozens of minutes in some cases.

[0050] Further, tACS in each of the above frequency bands can regulate the endogenous oscillation of the hippocampus, and such regulation has a repairing effect on the hippocampus and an improving effect on various functional disorders.

[0051] For example, tACS in the delta band can increase the synchrony of neuronal activity in the hippocampus, enhance the functional connectivity of the hippocampus, and improve the efficiency of information transmission between the hippocampus and the cortex, which is helpful to improve memory function. For AD patients, tACS in the delta band can enhance the activity of the brain's default mode network (DMN), thereby alleviating the symptoms of cognitive impairment.

[0052] For example, tACS in the theta band can enhance theta oscillation in the hippocampus, which is closely related to memory encoding and retrieval, and can improve the efficiency of memory tasks. For patients with cognitive impairment, tACS in the theta band can enhance the executive function of the brain and improve attention and working memory.

[0053] For example, tACS in the alpha band can modulate neuronal activity in the hippocampus, enhance information transmission between the hippocampus and the cortex, and thus improve information processing efficiency. For patients with depression or anxiety, tACS in the alpha band can modulate the emotional regulation network of the brain, thereby alleviating depressive symptoms.

[0054] For example, tACS in the beta band can modulate neuronal activity in the hippocampus, enhance information transmission between the hippocampus and the cortex, and improve functional connectivity of the brain's motor control network. For patients with Parkinson's disease, tACS in the beta band can enhance the brain's motor control network, thereby alleviating symptoms of movement disorders.

[0055] For example, tACS in the gamma band can enhance gamma oscillations in the hippocampus, which are closely related to memory consolidation and retrieval, thus improving the efficiency of memory task execution, attention, and working memory.

[0056] In summary, by allowing near-infrared light to act on the hippocampus, in combination with tACS in the delta band, theta band, alpha band, beta band, or gamma band, whether the near-infrared light is continuous light or pulsed light, the execution of photoelectric combined therapy can alleviate the subject's pain (including but not limited to thermal pain), relax their mood, improve the subject's compliance with treatment, and tolerance to higher doses. Further, tACS in each band can regulate endogenous oscillations in the hippocampus, in combination with the mechanism of near-infrared light acting on the hippocampus, to optimize the repair effect on the hippocampus and the treatment effect on brain diseases.

[0057] In the case where the near-infrared light is pulsed light with a first frequency, the first frequency and the second frequency are each in one of the first band, the second band, the third band, the fourth band, and the fifth band, and satisfy a preset frequency relationship. By allowing the near-infrared light to have a first frequency, and allowing the first frequency and the second frequency to satisfy a preset frequency relationship, a compound enhanced oscillation stimulus can be provided to the brain. The compound enhanced oscillation stimulus benefits from the photoelectric dual-mode oscillation, and can also benefit from the flexible cooperation of the two frequencies, which can be aligned and enhanced, or coupled and modulated, thereby achieving more refined and targeted regulation of endogenous oscillations in the hippocampus.

[0058] Specifically, the exogenous oscillatory stimulation, via near-infrared light or tACS, can be any one of delta (fourth frequency band), theta (fifth frequency band), alpha (first frequency band), beta (second frequency band), and gamma (third frequency band), and can improve hippocampal function through brain wave entrainment or cell signal regulation. How to improve the endogenous oscillation of the hippocampus has been described in the foregoing in connection with tACS, which is incorporated herein by reference.

[0059] Studies have shown that, in some experimental reports, near-infrared pulsed light with frequencies such as 10 Hz, 20 Hz, and 40 Hz can penetrate deeper into tissues than near-infrared continuous light, and can achieve better effects in reducing the number of Aβ plaques, ATP levels, mitochondrial function, and cognitive improvement. In particular, 40 Hz gamma band near-infrared light has been sufficiently studied to have a good therapeutic effect on hippocampus-related brain diseases including AD.

[0060] The preset frequency relationship includes that the deviation of the first frequency and the second frequency is less than a threshold, or the first frequency and the second frequency have a preset frequency band coupling relationship. Such a preset frequency relationship actually realizes the frequency band alignment or frequency band coupling of near-infrared light and tACS.

[0061] The frequency band alignment of near-infrared light and tACS, for example, the first frequency and the second frequency are in the same one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band, and the fifth frequency band, can significantly increase the neural entrainment effect and improve the regulation effect on the brain endogenous oscillation.

[0062] The frequency band coupling of near-infrared light and tACS can be determined according to the frequency band coupling that the normal brain relies on when performing various tasks. For another example, the preset frequency band coupling relationship can also be set according to the frequency band coupling that the diseased brain deviates from or fails compared with the normal brain. In this case, the brain endogenous frequency band coupling can be modulated and repaired through exogenous frequency band coupling to improve the treatment effect.

[0063] In some embodiments, the photomagnetic signals of the brain can be acquired by near-infrared functional imaging (fnirs), electroencephalography (EEG), functional magnetic resonance imaging (fMRI), deep brain electrodes, electrocorticography, and magnetoencephalography, etc. The photomagnetic signals can be used to determine the frequency band information of the patient's brain deviating or malfunctioning compared to the normal brain. A control unit can be provided in the neuromodulation device, which controls the operation of the phototherapy part and the tACS part according to the photomagnetic signals, such as but not limited to, controlling the working frequency, power parameters, timing parameters, etc. of each part. The control unit can use any of CPU, FPGA, ASIC, DSP chip, SOC (system on chip), MPU (such as but not limited to Cortex), etc. The control unit can be communicatively coupled to a memory and configured to execute computer executable instructions stored therein. The memory can include read-only memory (ROM), flash memory, random access memory (RAM), dynamic random access memory (DRAM) such as synchronous DRAM (SDRAM) or Rambus DRAM, static memory (e.g., flash memory, static random access memory), etc. on which computer executable instructions are stored in any format. The computer executable instructions can be accessed by the control unit, read from the ROM or any other suitable storage location, and loaded into the RAM for execution by the processor to achieve control of the operation of the phototherapy part and the tACS part.

[0064] Please note that when referring to the modulation of endogenous oscillations by tACS or near-infrared light, the effect of the modulation can be either entrainment, i.e. enhancing the endogenous oscillation phenomenon, or suppression, i.e. weakening the endogenous oscillation phenomenon. For example, the oscillation of other frequency bands can be enhanced by applying an exogenous oscillation of other frequency bands, thereby suppressing the oscillation of the target frequency band; or the oscillation of the target frequency band can be induced by applying an exogenous oscillation of the target frequency band that is phase asynchronous, thereby reducing the amplitude of the oscillation of the target frequency band.

[0065] In some embodiments, among the first frequency and the second frequency, one frequency is in the second frequency band and the other frequency is in the third frequency band, thereby forming a beta-gamma band coupling. For example, patients with depression not only have a significant decrease in gamma power in the left temporal lobe and bilateral occipital regions, but also have a decrease in gamma connectivity between the left hemisphere and the right frontal region, and a decrease in beta-gamma coupling in the left temporal lobe region. Therefore, providing photoelectric combined therapy in the form of beta-gamma band coupling can improve the gamma band weakening in the left temporal lobe and bilateral occipital regions of patients with depression, and enhance the beta-gamma coupling in the left temporal lobe region, thereby improving depressive symptoms. For another example, the beta-gamma coupling of the hippocampal LFP signal is involved in the maintenance of working memory, and by regulating its endogenous beta-gamma coupling, the maintenance of working memory can be improved. For another example, in patients with Parkinson's disease, the beta-gamma phase frequency coupling relationship is significantly enhanced, especially in brain regions related to movement, such as the motor cortex and subthalamic nucleus (STN). Based on the beta-gamma phase frequency coupling relationship deviating from the endogenous beta-gamma phase frequency coupling relationship, photoelectric combined therapy can be applied to inhibit or weaken this abnormal enhancement, thereby improving the symptoms of bradykinesia and rigidity in patients.

[0066] In some embodiments, among the first frequency and the second frequency, one frequency is in the second frequency band and the other frequency is in the fourth frequency band, thereby forming a delta-beta band coupling. Non-rapid eye movement sleep (NREM) relies on the delta-beta band coupling during the period to optimize the connection of neural networks, consolidate memories, and alleviate negative emotions such as anxiety and depression. During treatment using the neuroregulation device according to the present application, there are cases where patients feel drowsy or even enter non-rapid eye movement sleep (NREM). In this case, photoelectric combined therapy via the application of delta-beta band coupling helps to strengthen the endogenous delta-beta band coupling during non-rapid eye movement sleep (NREM), increase the synchronous activity between the hippocampus and other brain regions, and improve memory consolidation.

[0067] In some embodiments, one of the first frequency and the second frequency is within a third frequency band and the other is within a fifth frequency band, thereby forming a theta-gamma band coupling. In a working memory task, the optoelectronic combined therapy with the theta-gamma band coupling helps to strengthen the endogenous theta-gamma band coupling oscillation in the brain, effectively improving the performance of the working memory task in the brain. Further, the strengthening of the endogenous theta-gamma band coupling oscillation is an important prerequisite for successfully storing, manipulating and / or recalling information in spatial working memory. For example, the brain of a BD patient exhibits reduced theta-gamma band coupling, which is associated with dysfunction in social cognition. Through the optoelectronic combined therapy with the theta-gamma band coupling, the endogenous theta-gamma band coupling of the patient can be enhanced via neural entrainment, thereby improving the patient's performance in social functioning and executive functioning, such as reaction time in facial emotion recognition. For another example, in the early stage of AD, the theta-gamma band coupling of the patient's brain is impaired. Through the optoelectronic combined therapy with the theta-gamma band coupling, the endogenous theta-gamma band coupling of the patient can be repaired via neural entrainment, thereby improving the performance of the working memory task in the brain while alleviating the pathological symptoms of AD on the endogenous oscillation.

[0068] The construction of the neuromodulation device according to the present application will be described below with reference to FIGS. 1A, 1B and 1C. The construction in FIGS. 1A, 1B and 1C is suitable for irradiating near-infrared light to the frontal lobe, temporal lobe and parietal lobe of the subject, but this is merely an example; as described above, the neuromodulation device can also be constructed to irradiate near-infrared light to only the temporal lobe or frontal lobe of the subject (see FIGS. 1D and 1E).

[0069] In general, the treatment lasts for tens of minutes to several tens of minutes, and the support mechanism 1 can hold 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 the shoulder. The support mechanism 1 can follow the subject's movement, 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 FIG. IB and FIG. 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 on a stand 11, which can be placed on the ground or a table. In some embodiments, the support mechanism can be configured to be supported on both the subject's body and an object other than the body. For example, the support mechanism can be suspended by an elastic member (e.g., a spring) that can be stretched, while the support mechanism can also be fixed on the subject's body. In one aspect, the elastic member can allow the subject to move within a certain range, and reduce the pressure on the body. In another aspect, 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 region.

[0070] In the illustrated embodiments, the support mechanism 1 is configured as a whole, and the support mechanism 1 can be worn on the subject's head as a whole. In other embodiments not shown, the support mechanism 1 can include a plurality of sub-support mechanisms, which can have the same or different configurations. Each sub-support mechanism can be independently supported or fixed on the subject's body. Alternatively, each sub-support mechanism can be independently supported or fixed on an object other than the body. Alternatively, part of the sub-support mechanisms are supported or fixed on the subject's body, and the other part of the sub-support mechanisms are supported or fixed on an object other than the body.

[0071] The near-infrared light irradiation unit 3 can include any one of any suitable light-emitting devices such as light-emitting diodes (LEDs), laser tubes, etc., or can include light-guiding devices that transmit and emit near-infrared light from the outside world. The near-infrared light irradiation unit 3 can emit continuous near-infrared light toward the head of the subject, or can emit pulsed near-infrared light. Illustratively and non-limitingly, the near-infrared light irradiation unit 3 can further include a light board that carries a plurality of light-emitting devices. The plurality of light-emitting devices can be arranged in a pattern according to a certain rule, for example, the projection of the light-emitting devices on a plane can be arranged according to a circular or polygonal pattern. In some embodiments, the light-emitting devices can be distributed on the light board in a pattern of 1x1, 2x2, 3x3, 4x4, 5x5, 2x3, 3x4, or 4x5, etc. In some embodiments, the light-emitting devices can also be arranged on the light board in a pattern of concentric circles, for example, the innermost circle has 5, the outer circle has 10, and the outermost circle has 15, etc. Alternatively, the plurality of light-emitting devices on the light board can be uniformly distributed, and at least part of the light-emitting devices are arranged near the outer edge of each light board, so as to make full use of the space of the light board and obtain a larger near-infrared light projection area.

[0072] The near-infrared light irradiation unit 3 is arranged in an array.

[0073] As shown in FIG. 1A, 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 as being arranged in a cross-like array. Of course, they can also be densely arranged in the forms shown in FIG. 1B and FIG. 1C. A preferable arrangement can make the near-infrared light intensity of each irradiation area relatively uniform, and there is no irradiation dead angle between each irradiation area.

[0074] Hereinafter, AD is taken as an example of the "hippocampus-related brain disease", but it should be understood that the embodiments can be adaptively adjusted for other "hippocampus-related brain diseases", which will not be described here.

[0075] The array of near-infrared light irradiation units 3 can irradiate transcranial near-infrared light to multiple brain regions involved in AD. The support mechanism 1 can maintain the relative spatial relationship, including but not limited to relative distance, relative position, and relative direction, etc., between each near-infrared light irradiation unit 3 and the head of the subject while the near-infrared light irradiation units 3 irradiate near-infrared light to the head of the subject. In embodiments where the support mechanism 1 can move with the subject, the relative position between the near-infrared light irradiation units 3 and the head can be maintained. The near-infrared light irradiation units 3 can be in contact with the head or have a gap between the head. When the support mechanism 1 is supported or fixed on an external object, the support mechanism 1 can control the distance between the head and the near-infrared light irradiation units 3 to be within a desired distance range with the cooperation of the subject, so that there is a gap between the head and the near-infrared light irradiation units 3. In this way, the head of the subject can freely enter and exit the space surrounded by the near-infrared light irradiation units 3. Moreover, the head of the patient has a movable space during irradiation, so the comfort of the AD patient can be improved, and in turn the compliance of the AD patient treatment can be improved.

[0076] In the case where there is a gap between the near-infrared light irradiation units 3 and the head, the near-infrared light can be sufficiently scattered, and the near-infrared light emitted by adjacent near-infrared light irradiation units 3 has more overlapping parts in the projection area of the head, so that most parts of the head can be irradiated by near-infrared light, thereby improving the treatment effect. If the above gap is not provided, in order to achieve irradiation without dead angle, it can be necessary to increase the arrangement density of the near-infrared light irradiation units 3, which can cause more heat generation, affect the comfort of the patient, and greatly reduce the service life of the near-infrared light irradiation units 3, increase the manufacturing cost and control difficulty. However, if the distance between the array of near-infrared light irradiation units 3 and the head is too large, it can cause excessive divergence of the infrared light, resulting in poor uniformity of the distribution of the average power density, or the superimposed average power density is still insufficient, still cannot obtain a good treatment effect. By controlling the distance between the array of near-infrared light irradiation units 3 and the head, each part of the head can be irradiated by near-infrared light with sufficient and relatively uniform average power density, the required divergence angle range of the near-infrared light irradiation units 3 conforms to the emission angle range of the conventional near-infrared LED (for example, 100□135 degrees), and the arrangement density and spacing of the required near-infrared light irradiation units 3 are also appropriate, so that the manufacturing difficulty and cost are beneficially controlled.

[0077] In particular, the array of near-infrared light irradiation units 3 can be configured to irradiate the transcranial near-infrared light to at least the frontal lobe, the temporal lobe and the parietal lobe of the subject, i.e. to provide sufficient irradiation to the corresponding surface of the head above the frontal lobe, the temporal lobe and the parietal lobe of the subject, so that the irradiated near-infrared light can penetrate the skull and the dura mater to deposit to the frontal lobe, the temporal lobe and the parietal lobe after experiencing the attenuation of the hair and the scalp. The near-infrared light irradiation units 3 can maintain the relative positions among each other and between them and the subject under the support of the support mechanism 1, so that the near-infrared light of at least part of the near-infrared light irradiation units 3 can irradiate to the frontal lobe, the temporal lobe and the parietal lobe of the subject, avoiding the situation that one or more of the above-mentioned lobes cannot receive the irradiation of the near-infrared light. For one or more of the above-mentioned lobes, only a part of the lobe can be allowed to receive the irradiation of the near-infrared light, or the lobe can be allowed to completely receive the irradiation of the near-infrared light. The inventors have found that the therapeutic effect is better when the near-infrared light irradiates at least to the corresponding surface of the head above the frontal lobe, the temporal lobe and the parietal lobe. For example, the progression from no symptoms to full dementia of some subjects is closely related to the pathological phenomena of the following cortex. Aβ plaques first appear in the cortex, then enter the limbic system (including the hippocampus), the diencephalon, the brain stem, and finally reach the cerebellum. The amygdala, the entorhinal cortex, and the parahippocampal gyrus can be early brain regions of tau tangle, while the fusiform gyrus, the inferior temporal lobe cortex, and the middle temporal lobe cortex are relatively late brain regions of tau tangle aggregation. By allowing the near-infrared light to irradiate at least to the frontal lobe, the temporal lobe and the parietal lobe, the deposition of Aβ plaques in the medial prefrontal cortex and the medial parietal lobe region can be reduced, and the abnormal aggregation of tau protein in the entorhinal cortex (near the prefrontal lobe), the middle temporal lobe and the hippocampus located in the medial temporal lobe and even the limbic cortex can also be reduced, thereby inhibiting the progression of the AD course. However, for each of the above three lobes, it is not required that the near-infrared light covers the entire lobe.

[0078] In some embodiments, the array of near-infrared light irradiation units 3 is distributed for the frontal lobe, the temporal lobe and the parietal lobe, so that each of the frontal lobe, the temporal lobe and the parietal lobe has a corresponding scattered plurality of near-infrared light irradiation units 3. As described above, the projections of the near-infrared light emitted by adjacent near-infrared light irradiation units 3 on the head can overlap with each other, thereby avoiding the situation that a lamp panel only irradiates a region, resulting in gaps between different projection regions. Preferably, a plurality of lamp panels can be uniformly arranged for each lobe of a plurality of brain regions, thereby ensuring that there is no missed dead angle.

[0079] Referring to FIGS. 1A-1C, the tACS portion 4 can be configured as follows. The tACS portion 4 can include at least one pair of electrodes 40, including one pair, two pairs, 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 positions of the pairs of electrodes, the position of the electric field in the brain can be changed. In other words, a pair of electrodes refers to electrodes that have a voltage difference to be able to form an electric field in the brain. Therefore, "a pair" does not explicitly limit the number of electrodes in a physical sense, that is, at least one pair of electrodes does not mean that the number of electrodes is even, but there can 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 the electrode can be considered to form two pairs of electrodes with the other two electrodes, respectively.

[0080] Specifically, each pair of electrodes 40 is configured to be detachably disposed on the scalp around the frontal lobe or the temporal lobe of the subject (corresponding or associated) to apply tACS of the second frequency, and the electric field of the tACS has an effective range that at least partially covers the hippocampus.

[0081] The inventors have found that the amyloid of AD is deposited in the frontal, parietal, and temporal cortex, and inflammation is diffused throughout the brain, and also deposited in the deep brain such as the hippocampus, and even in the early stage, the whole brain is inflamed. Both the amyloid of AD and inflammation are scattered among various brain regions. Therefore, the near-infrared light irradiation comprehensively covers the frontal, temporal, and parietal lobes, playing a comprehensive sweeping role; in combination with the tACS targeted and intensive treatment of the hippocampus, the treatment can be particularly effective.

[0082] In some embodiments, at least part of the transmitted near-infrared light is directed toward the hippocampus. As described above, one of the main symptoms of AD is the lesion of the hippocampus. By configuring the support structure 1 to cover the cranial portion, and further causing the array of near-infrared light irradiation units 3 to emit near-infrared light to multiple brain regions of the patient's head, such as at least the frontal, temporal, and parietal lobes, especially including the hippocampus, to comprehensively and thoroughly perform phototherapy on the lesion-involved cortical partitions, a better treatment effect can be achieved.

[0083] In some embodiments, the first frequency and the second frequency can both be the same frequency of 10 Hz, 20 Hz, 40 Hz, and 70-80 Hz. The near-infrared pulsed light of the above frequencies has good function of treating AD, and the tACS of the above frequencies can not only treat AD but also relieve pain. The near-infrared light of the above frequencies, such as the near-infrared light with a center wavelength of 650-700 nm, or the near-infrared light with a center wavelength of 760-860 nm, or the near-infrared light with a center wavelength of 870-1100 nm, has good therapeutic effect on AD patients, and in combination with the tACS of the above frequencies, the discomfort of the patients during treatment can be reduced, and the patients can be more relaxed during treatment. In some exemplary embodiments, the tACS at 10 Hz, 40 Hz, or 70-80 Hz is used to increase the release of β-endorphin in the brain of the AD patient. For example, when the frequency of the alternating current is set to each of 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, the tACS test is performed on a voluntary individual subject for 5-10 minutes at an amplitude of about 10 mA, and the β-endorphin concentration in the cerebrospinal fluid sample is tested. It is found that the β-endorphin in the subject is increased.

[0084] The release of β-endorphin significantly reduces the pain, so even if the treatment is longer or the stimulation intensity is higher, for example, the light power density reaches 40 mW / cm 2 and above, even 100-150 mW / cm 2 , and even 150-250 mW / cm 2 , for example, the total stimulation current of tACS reaches 5 mA, even 10 mA, even 15 mA, and the AD patient does not have obvious pain or at least a calm or more pleasant mood relative to before the stimulation.

[0085] In some embodiments, the total stimulation current of the tACS unit 4 can reach 15 mA. Ordinary people can generally accept 15 mA of current, and more than that can cause serious discomfort. However, with tACS, the total stimulation current of the alternating current signal with charge balance, especially the sine wave waveform, can itself reduce the discomfort caused by the current, so the current that ordinary people can accept can be increased to 15 mA without causing strong discomfort. The alternating current of 15 mA with a suitable frequency can not only ensure the stimulation intensity but also produce an analgesic effect so that the subject does not feel discomfort, and because the alternating current of the suitable frequency has a mood regulation effect itself, the compliance of the patient receiving the combined reinforcement treatment of AD is increased.

[0086] In some embodiments, the near-infrared light irradiated by the phototherapy unit can be a single wavelength (also referred to as a first wavelength) with a center wavelength of 760-860 nm, or a single wavelength (also referred to as a second wavelength) with a center wavelength of 650-700 nm. It can also have dual wavelengths, for example, simultaneously including a first wavelength with a center wavelength of 760-860 nm and a second wavelength with a center wavelength of 650-700 nm. The dual wavelength configuration can provide the desired targeted treatment. For near-infrared light with a center wavelength of 760-860 nm, both cells without cytochrome-c oxidase CCO expression and cells with CCO expression can provide good treatment effects. For the aspect of neuroprotection, 670 nm has been proven to be effective for retinal function recovery, and for inhibiting nerve damage caused by CCO, near-infrared light with a wavelength of 650-700 nm is suitable. Near-infrared light with a wavelength of 780-810 nm can promote angiogenesis and promote blood flow. For the aspect of anti-inflammatory treatment, light with a wavelength of about 650 nm can convert the microglial cell phenotype from M1 to M2, which has an anti-inflammatory effect. The brain regions that are neurogenic microenvironments are the subgranular zone of the hippocampal dentate gyrus and the subventricular zone (SVZ) of the lateral ventricle, and near-infrared light with a wavelength of 808 nm, 810 nm has been proven to be able to promote neurogenesis in the neurogenic microenvironment, thereby improving the symptoms of the sharp decline in hippocampal neurogenesis caused by AD.

[0087] FIGS. 2A-2C show simulation results of the distribution of irradiation power levels in the brain obtained by performing irradiation on the head of a subject using a pulsed light source with a center wavelength of 660 nm, 810 nm and 1064 nm respectively at 40 Hz and time-averaged irradiation power normalized to 1, where the abscissa and ordinate are the y-axis and z-axis respectively in mm, and the corresponding values on the color bar are the log values of the ratio of the irradiation power to the normalized irradiation power of 1. It can be seen that the penetration depth of 810 nm and 1064 nm light is deeper than that of 660 nm.

[0088] In one embodiment, the second frequency of tACS can be 70-80 Hz, especially 75 Hz, 76.5 Hz, or 78 Hz, at which the analgesic effect (immediate increase in endorphin in cerebrospinal fluid after stimulation) provided by tACS is most obvious. At the same time, near-infrared pulsed light irradiation of the same frequency is provided, and the light power density and total stimulation current that the subject can tolerate will be relatively high. In another embodiment, the second frequency of tACS and the first frequency of near-infrared pulsed light are both 40 Hz. This multi-physical mode stimulation at this frequency, especially, can promote the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in AD patients, play an active role in p-Tau protein deposition, and accelerate lymphatic clearance of amyloid. Through the photoelectric combined sensory stimulation of 40 Hz transcranial light stimulation and 40 Hz tACS, gamma oscillation can be excited and improved, and the cognitive ability of AD patients can be improved, and the AD course can be delayed. The gamma oscillation of AD patients is impaired, and the entrainment phenomenon can be produced by external current-induced endogenous electroencephalogram oscillation, which can be used to adjust the neural network of the impaired area. tACS at the same frequency band as the abnormal gamma oscillation of AD patients can improve the neural oscillation and brain functional connectivity of the impaired area, and promote the improvement of brain function.

[0089] In some embodiments, the light therapy part and the tACS part 4 are configured to couple the near-infrared light having the first frequency and the tACS having the second frequency in a preset frequency band coupling relationship, in which the frequencies within a lower frequency band of the first frequency and the second frequency have at least one of a phase-amplitude coupling relationship, a phase-phase coupling relationship, and an amplitude-amplitude coupling relationship with the photoelectric stimulation of another frequency.

[0090] For example, the first frequency is in the theta wave frequency band (lower frequency band) and the second frequency is in the gamma wave frequency band, and the power of the alternating current signal in the gamma wave frequency band can be adjusted according to the phase of the near-infrared light in the theta wave frequency band, especially so that the bursts of the alternating current signal in the gamma wave frequency band are coupled with the power peaks of the near-infrared light in the theta wave frequency band, which is beneficial to optimizing the storage, manipulation, and / or recall processing of the brain for spatial working memory.

[0091] For another example, the first frequency is in the delta wave frequency band (lower frequency band) and the second frequency is in the alpha wave frequency band, and the phase of the alternating current signal in the alpha wave frequency band can be adjusted according to the phase of the near-infrared light in the delta wave frequency band.

[0092] In some embodiments, the at least one pair of electrodes can be configured to be detachably disposed on the back of the subject's ears, as shown in FIG. 3A. In some embodiments, the electrodes on the back of the ears can be attached to the mastoid process, so that not only is it easy to attach the electrodes, but it is also easy for the general public to find the mastoid process by hand touch, and to complete the attachment of the electrodes conveniently and confidently. In the embodiment shown in the figure, the total current is 15 mA. The size of the electrode is 3.5 x 3.5 cm, so the current density is 15 mA / 12.25 cm 2 = 1.225 mA / cm 2 . There is no hair behind the ear, it is easy to attach the electrode, it is also more convenient to clean, and the attachment site is intuitive and easy to locate. Simply attach the stimulating electrode to the AD patient, turn on the device, and enjoy the comfortable AD reinforcement therapy. Non-professionals can also operate conveniently.

[0093] FIG. 4A shows the current density distribution on the coronal plane of the subject's head when tACS is performed with the electrode scheme shown in FIG. 3A and a total current of 15 mA. FIGS. 4B and 4C show the current density distribution on the transverse and sagittal planes, respectively. In this case, the frequency of tACS is 40 Hz.

[0094] In some embodiments, the at least one electrode is disposed across the frontal lobe and the periauricular region of the subject when tACS of the second frequency is applied, as shown in FIGS. 3B-3C. The frontal lobe and the periauricular region have sparse hair, making it easy to install the electrodes. The at least one pair of electrodes can be configured to be detachably disposed on the forehead and the back of the subject's ears, respectively, and the total current is still 15 mA.

[0095] In the embodiment shown in FIG. 3B, the electrode disposed on the forehead of the subject is two separate electrodes, which are disposed on the left and right sides of the forehead. The size of the electrode on the forehead and the mastoid process is 3.5 x 3.5 cm, and two electrode pads are attached to the forehead, each forming a pair with the electrode on the mastoid process on the corresponding side. In other words, the two electrodes on the forehead do not form a pair and do not generate a voltage and form a current path between each other. The current of each electrode pad to the mastoid on the corresponding side is equal to the current on the opposite side, which is 7.5 mA. Therefore, the current density of each electrode is 7.5 mA / 12.25 cm 2 = 0.612 mA / cm 2 .

[0096] In the embodiment shown in FIG. 3C, the electrode disposed on the forehead of the subject is a single electrode and is disposed across the left and right sides of the subject's forehead. The size of the electrode on the mastoid process is 3.5 x 3.5 cm, and the size of the electrode on the forehead is 4 x 6 cm. The current density on the forehead is 15 mA / 24 cm 2 = 0.625 mA / cm 2The stimulation circuit of 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. The forehead has no hair, and it is also easy to attach the electrode, and it is more convenient to clean. Further, the combination of tACS of the above frequency band and transcranial light therapy applied to the prefrontal cortex and the posterior ear side has a good regulating effect on the mood of the subject. AD patients can immediately feel the relief of existing pain through the light therapy combined treatment of the present application, and are more willing to cooperate with each treatment. Continuous treatment can well manage pain and mood, and are more willing to insist on treatment.

[0097] In one example embodiment, as shown in FIG. 3D, at least one pair of electrodes includes a plurality of electrodes respectively detachably arranged on the forehead, the posterior ear side and the neck of the subject. The electrode on the forehead and the electrode on the mastoid process of the posterior ear side form a pair of electrodes, and the electrode on the neck and the electrode on the mastoid process form a pair of electrodes. In this way, the current is shunted, and the current density of each electrode is 7.5 mA / 12.25 cm 2 = 0.612 mA / cm 2 .

[0098] In some embodiments, at least one electrode of the at least one pair of electrodes is flexible. As described above, the electrode can be attached to the forehead, the mastoid process of the posterior ear, etc. On the one hand, these parts usually have protrusions or arcs, and the use of conventional rigid electrodes may not be firmly attached and may cause discomfort. On the other hand, for the above relatively loose light therapy part, it is difficult to press the electrode against the head of the subject by the supporting structure. The use of flexible electrodes can facilitate the attachment to the curved surface, so that the electrode can be reliably attached to the skin, and the discomfort caused by the treatment can be reduced. In other words, the flexible electrode can rely on its own deformation ability to improve the attachment to the mastoid process of the posterior ear of the subject. In some embodiments, the electrode can also be attached to the forehead and the mastoid process of the posterior ear using various biocompatible conductive gels.

[0099] In some embodiments, at least one electrode of the at least one pair of electrodes is a transparent electrode. For example, but not limited to, a flexible nanometer metal mesh transparent electrode, a silver nanowire embedded silk fibroin electrode, a nanofiber-based flexible transparent electrode, etc. The transparent electrode can reduce the loss of near-infrared light, so that the hippocampus near the temporal lobe can be subjected to the combined action of transcranial electrical stimulation and near-infrared light irradiation. Here, transparent means at least transparent to the near-infrared light used for treatment, and does not require transparency to all light.

[0100] Preferably, the electrode can use a flexible transparent electrode to be attached to the curved surface of the head, such as the forehead and the mastoid process on both sides, while basically not blocking the transcranial light radiation of the light therapy part, so that the near-infrared light can still efficiently act on the frontal lobe and the temporal lobe, etc.

[0101] In some embodiments, in FIG. 3B, the electrode on the left side of the forehead can form a pair of electrodes with the electrode on the back of the left ear, and the electrode on the right side of the forehead can form a pair of electrodes with the electrode on the back of the right ear. In some embodiments, the electrode on the left side of the forehead can form a pair of electrodes with the electrode on the back of the right ear, and the electrode on the right side of the forehead can form a pair of electrodes with the electrode on the back of the left ear.

[0102] We simulated various tACS schemes using a four-layer spherical head model. The four-layer spherical head model includes scalp, skull, CSF, and brain tissue, and the tACS parameters are set to a sinusoidal wave with a current of 15 mA and a frequency of 40 Hz.

[0103] FIGS. 5A-5C respectively show simulation results of performing tACS using the electrode scheme shown in FIG. 3B, a total current of 15 mA, and a frequency of 40 Hz for tACS, showing the current density distribution in the coronal plane, transverse plane, and sagittal plane of the subject's head.

[0104] FIGS. 6A-6C show simulation results of performing tACS using the electrode scheme shown in FIG. 3C, a total current of 15 mA, and a frequency of 40 Hz for tACS, showing the current density distribution in the coronal plane, transverse plane, and sagittal plane of the subject's head.

[0105] FIGS. 7A-7C show simulation results of performing tACS using the electrode scheme shown in FIG. 3D, a total current of 15 mA, and a frequency of 40 Hz for tACS, showing the current density distribution in the coronal plane, transverse plane, and sagittal plane of the subject's head.

[0106] As can be seen from FIGS. 4A-7C, among the electrode schemes shown in FIGS. 3A, 3B, 3C, and 3D, the frontal lobe, parietal lobe, and occipital lobe all have current density deposition. Moreover, the electrode schemes shown in FIGS. 3B and 3C have stronger current density deposition in the frontal lobe, parietal lobe, and temporal lobe than the electrode schemes shown in FIGS. 3A and 3D. The electrode scheme shown in FIG. 3D has less current density in the brain relative to other schemes due to the large shunt of the current output by the neck electrode through the skin.

[0107] Figure 8 shows the current density at the hippocampus of the subject's head when tACS is performed with the electrode schemes shown in Figures 3A, 3B, 3C and 3D, respectively, and a total current of 15 mA. As can be seen from Figure 8, the three electrode schemes corresponding to Figures 3A, 3B and 3C have a larger current density at the hippocampus, while the electrode scheme shown in Figure 3D has a smaller current density at the hippocampus. Among them, the electrode scheme shown in Figure 3A has the largest current density at the hippocampus, but as can be seen from Figures 4A-4C, the current density at the frontal lobe is not as high as that of the electrode scheme shown in Figure 3B. Therefore, the electrode schemes of Figures 3B and 3C can be used to seek a higher level of current density and tACS effect on the frontal lobe, parietal lobe, temporal lobe and hippocampus.

[0108] In some embodiments, the electrode scheme of Figure 3A can be used to seek tACS with higher current density targeting the hippocampus. Further, the electrode scheme of Figure 3A can be improved to seek tACS with higher current density targeting the hippocampus.

[0109] Specifically, referring to Figure 9, the at least one pair of electrodes includes a first electrode patch 101 disposed at the scalp corresponding to the first temporal lobe, and a set of second electrode patches 1021 disposed at the scalp corresponding to the second temporal lobe. One of the first electrode patch 101 and the set of second electrode patches 1021 is used as a cathode, and the other of the first electrode patch 101 and the set of second electrode patches 1021 is connected to an alternating current source and used as an anode, so that the alternating current flows into the first electrode patch 101 (as shown in Figure 9), or flows from the first electrode patch 101 to the set of second electrode patches 1021 (the current flows in the opposite direction to that shown in Figure 9). In this way, the electric field strength of the hippocampus region near the anode and the cathode can be increased and the current attenuation of the hippocampus region near the anode and the cathode can be reduced, which is also demonstrated by the simulation results of Figures 4A-4C.

[0110] Figure 9 shows an example in which the right side is the first side and the left side is the second side, but it should be noted that the present application is not limited thereto, and the left side can also be the first side and the right side can be the second side. Please note that the present application refers to the scalp corresponding to the temporal lobe, frontal lobe, parietal lobe, etc. in the neocortex as meaning that the application of the electric field at the scalp can act on at least part of the temporal lobe, frontal lobe or parietal lobe via the skull. Specifically, a single small area on the scalp above the ear is attached with an electrode patch to apply an alternating current field, as long as the transcranial alternating current stimulation can act on a part of the temporal lobe, it is considered to be at the scalp corresponding to the temporal lobe. Taking the scalp corresponding to the temporal lobe as an example, after transcranial vertical mapping to the cortex, it can fall outside the space where the temporal lobe is located, and the transcranial alternating electric field applied at this place will have a certain field diffusion, after the diffusion, it can act on at least part of the temporal lobe, so it can be considered as the scalp corresponding to the temporal lobe.

[0111] In some embodiments, the set of second electrode pieces 1021 are not only disposed on the scalp corresponding to the second temporal lobe, but also disposed on the scalp corresponding to at least one of the frontal lobe, the occipital lobe, and the parietal lobe of the first side or the second side, as shown in FIGS. 10(a)-10(e), the second electrode piece 1022 on the scalp corresponding to the frontal lobe, the second electrode piece 1023 on the scalp corresponding to the parietal lobe, the second electrode piece 1024 on the scalp corresponding to the occipital lobe, and the like. In this application, the current intersection of the scalp corresponding to a certain brain region is referred to as "alternating current intersection".

[0112] The electrode arrangement schemes shown in FIGS. 9 and 10 are simulated and compared using a four-layer spherical head model. Please note that in this simulation experiment, the current density at the initial input is 17.2 mA / cm 2 .

[0113] The simulation results show that for the scheme shown in FIG. 9, the current density at the left hippocampus is 0.0135 mA / cm 2 , the current density at the right hippocampus is 0.0135 mA / cm 2 , and the current attenuation factor at the left hippocampus and the right hippocampus is as high as nearly 1300 times; and for the scheme shown in FIG. 10(a), the alternating current intersection exists at the first electrode piece 101 on the scalp corresponding to the right temporal lobe, the current density at the left hippocampus is 0.0294 mA / cm 2 , the current density at the right hippocampus is 0.043 mA / cm 2 , and the current attenuation factor at the left hippocampus is reduced by more than 500 times, the current attenuation factor at the right hippocampus is reduced to 400 times, and the current attenuation factors at the left and right hippocampi are significantly reduced.

[0114] Referring to FIG. 10(b), the first electrode piece 101 on the scalp corresponding to the right temporal lobe is used as an anode, and the alternating current intersection occurs. The electrode arrangement scheme shown in FIG. 10(b) is simulated using a four-layer spherical head model, and the simulation results show that for the experimental scheme shown in FIG. 10(b), the current densities at the left hippocampus and the right hippocampus are 0.0314 mA / cm 2 and 0.0447 mA / cm 2Therefore, based on the simulation verification result, it is shown that the current intensity of the current flowing out from the first electrode sheet 101 and acting on the downstream hippocampus, as shown in FIG. 10(b), is greater than the current intensity of the current flowing into the first electrode sheet 101 and acting on the upstream hippocampus, as shown in FIG. 10(a). Moreover, although the first electrode sheet 101 is arranged at the scalp corresponding to the right temporal lobe, for example, at the right ear postmastoid process, and is used as the anode of the alternating current cross, the current density can be increased for both the right hippocampus and the left hippocampus, and the current density at the right hippocampus is more than 40% higher than that at the left hippocampus. That is, the tACS stimulation intensity for the target side hippocampus can be enhanced by arranging the electrode for the alternating current cross at the scalp corresponding to the target side temporal lobe. Further, the electrode can be arranged as the anode to further improve the current density brought by the alternating current cross and thus improve the electrical stimulation effect.

[0115] In some embodiments, as shown in FIG. 10(c), the set of second electrode sheets can further include a second electrode sheet 1021 arranged at the scalp corresponding to the left temporal lobe and a second electrode sheet 1023 arranged at the scalp corresponding to the parietal lobe. In some embodiments, as shown in FIG. 10(d), the set of second electrode sheets can further include a second electrode sheet 1021 arranged at the scalp corresponding to the left temporal lobe and a second electrode sheet 1024 arranged at the scalp corresponding to the occipital lobe. In some embodiments, as shown in FIG. 10(e), the set of second electrode sheets can further include a second electrode sheet 1021 arranged at the scalp corresponding to the left temporal lobe, a second electrode sheet 1024 arranged at the scalp corresponding to the occipital lobe, and a second electrode sheet 1022 arranged at the scalp corresponding to the frontal lobe. This is only an example and does not limit the specific solutions. Please note that the various electrode arrangements in FIGS. 10(c)-10(e) are described by taking the first electrode sheet 101 as the cathode to collect the current from each second electrode sheet as an example, and the present application is not limited thereto. Each second electrode sheet can also be used as the cathode, and the first electrode sheet 101 can be used as the common anode to feed current to each second electrode sheet, which is not described herein.

[0116] The electrode arrangement scheme A (as shown in FIG. 10(e)), the electrode arrangement scheme B (not shown), and the electrode arrangement scheme C (not shown) are further simulated and verified by using the four-layer ball head model.

[0117] In the electrode arrangement scheme A, the first electrode patch 101 arranged at the right temporal lobe corresponding scalp serves as the cathode, and the second electrode patches 1021, 1024, 1022 arranged at the left temporal lobe corresponding scalp, the occipital lobe corresponding scalp and the frontal lobe corresponding scalp respectively serve as the anodes; in the electrode arrangement scheme B (not shown), the first electrode patch arranged at the right temporal lobe corresponding scalp serves as the cathode, and the second electrode patches arranged at the left temporal lobe corresponding scalp, the parietal lobe corresponding scalp and the frontal lobe corresponding scalp respectively serve as the anodes; in the electrode arrangement scheme C (not shown), the first electrode patch arranged at the right temporal lobe corresponding scalp serves as the cathode, and the second electrode patches arranged at the left temporal lobe corresponding scalp, the parietal lobe corresponding scalp, the frontal lobe corresponding scalp and the occipital lobe corresponding scalp respectively serve as the anodes.

[0118] The simulation results show that, for the electrode arrangement scheme A, the current density at the right hippocampus is 0.0587 mA / cm 2 , the current density at the left hippocampus is 0.0339 mA / cm 2 , and the attenuation multiples at the right and left hippocampi are about 500 times and 300 times respectively.

[0119] For the electrode arrangement scheme B, the current density at the right hippocampus is 0.0587 mA / cm 2 , the current density at the left hippocampus is 0.0339 mA / cm 2 , and the attenuation multiples at the right and left hippocampi are about 500 times and 300 times respectively; for the electrode arrangement scheme C, the current density at the right hippocampus is 0.0757 mA / cm 2 , the current density at the left hippocampus is 0.0407 mA / cm 2 , and the attenuation multiples at the right and left hippocampi are about 450 times and 250 times respectively. From the simulation results, when the second electrode patches at the left temporal lobe corresponding scalp and the frontal lobe corresponding scalp have been arranged and connected to the current source, further increasing the second electrode patches at the corresponding scalps of other brain regions, the attenuation multiple of the current at the hippocampus decreases, and the current densities at the right and left hippocampi both increase significantly.

[0120] It should be noted that, since the simulation is performed by using the four-layer ball head model, the parameters of the same layer ball head model are the same, so the results of the electrode arrangement schemes A and B are the same, but the skull thicknesses of the brain regions of the real head are different, and the simulation results may be slightly different.

[0121] That is, on the basis of arranging the first electrode sheet 101 as a cathode at the scalp corresponding to the temporal lobe on one side, arranging the second electrode sheet at the scalp corresponding to the temporal lobe on the other side and the scalp corresponding to the frontal lobe, and connecting the second electrode sheet to an alternating current source, a second electrode sheet is arranged at the scalp corresponding to the parietal lobe or the occipital lobe and connected to the alternating current source. The third stimulation level to the hippocampus is higher than the second stimulation level, so that the attenuation multiple of the current at the hippocampus is further reduced, and the stimulation intensity to the hippocampus is greater. Moreover, when the second electrode sheet is arranged at the scalp corresponding to the parietal lobe and the scalp corresponding to the occipital lobe and connected to the alternating current source, the attenuation multiple of the current at the hippocampus is smaller, and the stimulation intensity to the hippocampus is further increased.

[0122] Therefore, by configuring each of the second electrode sheets in the set of second electrode sheets, the hippocampus can be provided with stimulation intensity of three different stimulation levels (first stimulation level < second stimulation level < third stimulation level), so as to be suitable for patients in different stages of brain-related diseases and requiring different stimulation intensity levels, for example. When the first stimulation level is to be provided to the hippocampus on the first side, the set of second electrode sheets is arranged only at the scalp corresponding to the temporal lobe on the second side. When the second stimulation level is to be provided to the hippocampus on the first side, the set of second electrode sheets is arranged at the scalp corresponding to the temporal lobe and the scalp corresponding to the frontal lobe on the second side. When the third stimulation level is to be provided to the hippocampus on the first side, the set of second electrode sheets is arranged at the scalp corresponding to the temporal lobe, the scalp corresponding to the frontal lobe, and at least one of the scalp corresponding to the parietal lobe and the scalp corresponding to the occipital lobe on the second side.

[0123] In some embodiments, the tACS unit 4 can be configured to adjust the ratio of the current intensity between each pair of electrodes. In the early stage of AD, asymmetry of bilateral hippocampal atrophy can be found by MRI detection, usually the right hippocampus is more atrophied than the left hippocampus, which provides a reference for the identification of the early stage of AD. During the development of the AD course, the atrophy of the hippocampus on both sides also develops asymmetrically. The tACS unit 4 is configured to be able to adjust the current intensity of each pair of electrodes, and accordingly adjust the current intensity of the current loop acting on the hippocampus on both sides, so that under the same total stimulation current, the hippocampus on both sides can be stimulated specifically, the stimulation dose to the hippocampus on the side with more atrophy is increased, the clearance of β-amyloid protein in the hippocampus is accelerated, and thus the development of the AD course is delayed.

[0124] In some example embodiments, the support mechanism 1 can include a headgear. The headgear can have a certain degree of stretchability to fit the head sizes of different subjects, and be fixed to the head of the subject through such stretchability. However, different subjects can cause the position of the near-infrared light irradiation unit 3 to move. In this case, the headgear can be made in multiple sizes so that the headgear can stretch 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 headgear cannot be changed, but is fixed to the head of the subject by an auxiliary fixing member such as an elastic band. In some embodiments, the headgear can also be supported on other parts of the body other than the head, or can be supported or fixed by the support 11. The subject can accommodate the head in the headgear without touching the headgear. In some embodiments, the support mechanism can also be configured in an umbrella shape, a bell shape, a skeleton type, as long as the near-infrared light irradiation unit 3 can be held at a desired position around the head of the subject.

[0125] In some embodiments, referring back to FIG. IB, the support mechanism 1’ is configured as a head cap, which leaves a gap between the head cap and the head of the subject when the head of the subject is accommodated in the head cap, so that the head can move. Unlike the head cap that is fitted to the shape of the head of the patient, the head cap leaves a gap between the head cap and the head of the patient, so that the patient can move his head in the movable gap according to his own will or involuntarily due to the course of the disease. This loose and open design of the head cap does not constrain the head of the patient, and is particularly friendly to the elderly who are emotionally agitated, anxious, resistant or even afraid of closed or crowded spaces, so as to significantly improve the treatment compliance of AD patients. Specifically, the head cap can be used for continuous wearing by patients with AD and psychological barriers to closed or crowded spaces during treatment. This psychological barrier to closed or crowded spaces can be caused by the patient himself due to age or mental illness other than AD, or caused by AD. This design of the head cap can also be widely applicable to the behavioral characteristics of patients at different stages of AD. For example, for early AD patients, the judgment ability decreases and is often suspicious and easily irritated. The wearing of such a head cap with sufficient freedom and openness is easily accepted by the patient and is not easily irritated, so that the patient can cooperate with the continuous light treatment. For example, for patients with moderate AD, the mood fluctuates dramatically, is impatient and restless, and the head of some patients will frequently and unconsciously sway slightly. This open head cap allows the patient’s head to sway slightly unconsciously without causing the head cap to shake. Therefore, it is not necessary to forcibly stop this slight sway, which increases the comfort of the patient and reduces the workload of medical staff, while avoiding the transmission of the sway of the patient’s head to the head cap, which affects the light treatment effect. Therefore, in other embodiments, the head cap can be used for continuous wearing by AD patients with emotional agitation and anxiety during treatment.

[0126] This design of closing the openings at the bottom but being loose allows the head cap to make AD patients of various stages more willing to accept treatment, and single irradiation can last longer, such as 20 minutes, 30 minutes or even longer for each irradiation, thereby further improving the treatment effect; and avoiding leakage of near-infrared light in various directions during irradiation, thereby further improving the safety of treatment.

[0127] In some embodiments, the inventors have found that, by setting the distance between the array of near-infrared light irradiation units 3 and the head to be within 10 cm, the movable gap in the lateral direction during treatment is controlled to be in the order of several cm, for example, 4-5 cm, 3-4 cm, 2-3 cm, etc. The inventors have confirmed through clinical experiments that this is a range that is psychologically comfortable for patients, and that it allows patients to have sufficient freedom of movement, and does not cause patients to feel too empty and anxious about the head not being accurately positioned.

[0128] As shown in FIG. 1A, in some embodiments, the support mechanism 1 adopts a skeleton structure, can be worn on the head of the subject, and has a hollow region 2, so that the head of the subject is fully exposed to the external environment through the hollow region 2. As described above, the subject can walk and move during treatment. The skeleton support mechanism 1 can avoid the subject's resistance and fear of a fully enclosed head cap. It is especially friendly to the elderly who are emotionally agitated, anxious, resistant, or even afraid of closed or crowded spaces. The wearable support mechanism 1 can allow the subject to move in a small range or even walk freely during treatment, thereby significantly improving the treatment compliance of AD patients. The skeleton structure of the support mechanism 1 can also reduce the weight and have better ventilation. In some embodiments, the heat dissipation channel can be simplified or not specially set, and discomfort caused by heat accumulation is also reduced.

[0129] In some embodiments, as shown in FIG. 1C, the support mechanism 1” can include an external support frame at a first distance or more from the head of the subject. The support frame can be supported or fixed on an external object. The subject can move more freely compared to the head cap support mechanism 1’ shown in FIG. 1B, thereby reducing the feeling of oppression to the subject and further improving the compliance of treatment.

[0130] In the description of the present application, it should be understood that the orientation words such as “front”, “back”, “up”, “down”, “left”, “right”, “lateral”, “vertical”, “vertical”, “horizontal”, and “top”, “bottom”, etc. indicate the orientation or positional relationship shown in the drawings, which is only for the convenience of describing the present application and simplifying the description. Without the opposite description, these orientation words do not indicate and imply that the devices or devices must have a specific orientation or be constructed and operated in a specific orientation, and therefore cannot be understood as a limitation on the scope of protection of the present application; the orientation words “inner” and “outer” refer to the inner and outer of the contour of each component itself.

[0131] For purposes of the description hereinafter, the terms "upper", "lower", "right", "left", "rear", "front", "vertical", "horizontal", and derivatives thereof shall relate to the application as it is oriented in the drawing figures. However, it is to be understood that the application can assume various alternative orientations and, accordingly, such terms are not to be taken as limitations of the present application. Additionally, terms such as "first", "second", "third", etc. are used herein for purposes of description and do not necessitate or require any actual relationship between items. Embodiments of the application will suitably contemplate changes in orientation in addition to the applications specifically as shown in the figures.

[0132] It is also important to note that while the use of the terms "for example", "may" and "for instance" herein indicates that several embodiments of the application are contemplated, in some embodiments of the application, only "one of these embodiments are implemented while in other embodiments of the application, "one of these embodiments is implemented. The terms of degree such as "about" and "substantially" as used herein refer to a range of values that one of ordinary skill in the art would consider equivalent to the recited value (e.g., one of ordinary skill in the art would include the recited value in the range of values). For example, "about 90%," as defined herein, means in a range of 85% to 95%.

[0133] The application has been described herein by way of example only with reference to the accompanying drawings, which are provided illustrative of specific embodiments of the application. However, it is to be understood that variations and modifications of the specific embodiments can be made by those skilled in the art without departing from the scope of the application. Accordingly, it is intended that the application not be limited to the described embodiments, but that it include all modifications and alternatives coming within the scope of the present application. The scope of the application is limited only by the following claims and the equivalents thereof.

Claims

1. A neuromodulation device for treating a hippocampus-related brain disease, characterized by, The neuromodulation device comprises a transcranial alternating current stimulation unit and a near-infrared light irradiation unit, The near-infrared light irradiation unit is configured to irradiate transcranial near-infrared light to at least the frontal lobe or the temporal lobe of the subject, so that the near-infrared light can act on at least part of the hippocampus, and the near-infrared light is continuous light or pulsed light with a first frequency. The transcranial alternating current stimulation unit comprises at least one pair of electrodes for applying transcranial alternating current stimulation with a second frequency, and the electric field range of the transcranial alternating current stimulation includes at least part of the hippocampus. In the case of continuous light, the second frequency is in one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band, and the fifth frequency band; in the case of pulsed light with a first frequency, the first frequency and the second frequency are each in one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band, and the fifth frequency band, and satisfy a preset frequency relationship, wherein the first frequency band is 8-13 Hz, the second frequency band is 13-30 Hz, the third frequency band is 30-100 Hz, the fourth frequency band is 0.5-4 Hz, and the fifth frequency band is 4-8 Hz. The preset frequency relationship includes that the deviation of the first frequency and the second frequency is less than a threshold, or the first frequency and the second frequency have a preset frequency band coupling relationship.

2. The neuromodulation apparatus of claim 1, wherein, The hippocampus-related brain disease includes any one of Alzheimer's disease (AD), dementia, anxiety, post-traumatic stress disorder (PTSD), cognitive impairment, Parkinson's disease, Huntington's disease, depression, bipolar disorder (BD), sleep disorder, amyotrophic lateral sclerosis, autism spectrum disorder, attention deficit disorder in children, schizophrenia, and transient global amnesia.

3. The neuromodulation apparatus of claim 1, wherein, In the case of pulsed light with a first frequency, the first frequency and the second frequency are in the same one of the first frequency band, the second frequency band, the third frequency band, the fourth frequency band, and the fifth frequency band.

4. The neuromodulation apparatus of claim 1, wherein, In the case of pulsed light with a first frequency, the first frequency and the second frequency have any one of the following preset frequency band coupling relationships: One frequency is in the second frequency band, and the other frequency is in the third frequency band. One frequency is in the second frequency band, and the other frequency is in the fourth frequency band. One frequency is in the third frequency band, and the other frequency is in the fifth frequency band.

5. The neuromodulation apparatus of claim 1, wherein, The first frequency and the second frequency are the same one of 10 Hz, 20 Hz, 40 Hz, and 70-80 Hz.

6. The neuromodulation apparatus of any one of claims 1-5, wherein, The at least one pair of electrodes comprises a first electrode patch arranged at the scalp corresponding to the first temporal lobe, and a group of second electrode patches arranged at the scalp corresponding to the second temporal lobe, one of the first electrode patch and the group of second electrode patches is used as a cathode, and the other of the first electrode patch and the group of second electrode patches is connected to an alternating current source and used as an anode, so that the alternating current flows into the first electrode patch or flows from the first electrode patch to the group of second electrode patches.

7. The neuromodulation apparatus according to any one of claims 1-5, wherein, The second set of electrode pieces are arranged on the scalp corresponding to at least one of the frontal lobe, the occipital lobe, and the parietal lobe on the first side or the second side.

8. The neuromodulation apparatus of any of claims 1-5, wherein, The transcranial alternating current stimulation increases the release of β-endorphin in the brain of the subject.

9. The neuromodulation apparatus of claim 8, wherein, The total stimulation current of the transcranial alternating current stimulation part is a sine wave, and the amplitude can reach 5mA, or the amplitude can reach 15mA.

10. The neuromodulation apparatus of claim 3, wherein, The light therapy part and the transcranial alternating current stimulation part are configured to couple the near-infrared light with the first frequency and the transcranial alternating current stimulation with the second frequency in a preset frequency band coupling relationship, the frequency in the lower frequency band of the first frequency and the second frequency has at least one of a phase-amplitude coupling relationship, a phase-phase coupling relationship, and an amplitude-amplitude coupling relationship with the other frequency of the photoelectric stimulation.

11. The neuromodulation apparatus of any of claims 1-5, wherein, The at least one electrode is arranged across the frontal lobe and the periauricular region of the subject when the transcranial alternating current stimulation with the second frequency is applied.

12. The neuromodulation apparatus of any of claims 1-5, wherein, The at least one electrode is arranged across the frontal lobe and the periauricular region of the subject, specifically including any one of the following: At least one pair of electrodes is configured to be detachably arranged on the back of the ears of the subject. At least one pair of electrodes is configured to be detachably arranged on the forehead and the back of the ears of the subject, wherein the electrode arranged on the forehead of the subject is a single electrode arranged across the left and right sides of the forehead of the subject, or two separate electrodes arranged on the left and right sides of the forehead.

13. The neuromodulation apparatus of any of claims 1-5, wherein, The array of near-infrared light irradiation units is distributed for the frontal lobe, the temporal lobe, and the parietal lobe, so that each of the frontal lobe, the temporal lobe, and the parietal lobe has corresponding scattered near-infrared light irradiation units.

14. The neuromodulation apparatus of any one of claims 1-5, wherein, At least one electrode of the at least one pair of electrodes is flexible; and / or at least one electrode of the at least one pair of electrodes is a transparent electrode.

15. The neuromodulation apparatus of any one of claims 1-5, wherein, The transcranial alternating current stimulation part is configured to adjust the proportion of the current intensity between each pair of electrodes.

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