Transcranial physical stimulation apparatus for treating diseases related to target site of brain

Abstract

The present application provides a transcranial physical stimulation apparatus for treating diseases related to a target site of the brain. The transcranial physical stimulation apparatus at least comprises a phototherapy part and an alternating current transcranial electrical stimulation part. The phototherapy part irradiates transcranial near-infrared light onto at least a frontal lobe and a temporal lobe of the head of a subject, or irradiates transcranial near-infrared light within an irradiation range containing the target site and a peripheral brain region thereof. The alternating current transcranial electrical stimulation part comprises a first scalp electrode pair and a second scalp electrode pair. A pair of electrodes constituting the first scalp electrode pair forms an electric field of a first frequency and acts on the target site, and a pair of electrodes constituting the second scalp electrode pair forms an electric field of a second frequency and acts on the target site. The second frequency is greater than the first frequency, and the ratio of the frequency difference to the first frequency is 8% or less, and the frequency difference is within the range of 1 Hz to 80 Hz. The apparatus performs, by means of near-infrared light, comprehensive, gentle, and comfortable transcranial physical treatment on a plurality of disease-related brain regions, and performs, by means of transcranial alternating current, precise targeted treatment on a disease-related target site; the two cooperate synergistically to enable a better therapeutic effect.

Description

A transcranial physical stimulation device for treating a disease related to a target site of the brain TECHNICAL FIELD

[0001] The present application relates to a transcranial physical stimulation device for treating a disease of the brain, in particular to a transcranial physical stimulation device for treating a disease related to a target site of the brain. BACKGROUND

[0002] With the development of population aging, the diseases including Alzheimer's disease (AD), dementia, cognitive impairment, Parkinson's disease (PD), and depression (MD), anxiety, post-traumatic stress disorder (PTSD), bipolar disorder (BD), sleep disorder (SD), attention deficit disorder in children, and other family genetic diseases such as Huntington's disease (HD) that have a high incidence due to various reasons are widely present in people over 65 years old, and are becoming a common challenge to society and family. The pathogenesis of these diseases is not fully clear, but in general, most of them are associated with abnormal neurons. For example, AD, the most widely recognized major pathological features include extracellular neuroinflammatory plaques formed by β-amyloid deposition and intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein aggregation, and a large number of neurons degenerate and disappear.

[0003] In the treatment of the above-mentioned diseases, in recent years, transcranial alternating current stimulation (tACS) as a relatively safe non-invasive brain stimulation technique, low-intensity alternating current of a specific frequency is applied to the target area of the brain through the electrode installed on the scalp, and then the endogenous oscillation in the brain is regulated, for example, the abnormal gamma oscillation in AD patients, to induce the recovery of functional connectivity between brain regions.

[0004] Although the pathogenesis of the above diseases is not clear, it is known that the lesions involve a wide range of brain regions, including the prefrontal lobe, temporal lobe, hippocampus, etc. After all, tACS is a kind of electrical stimulation, and patients with AD and the like generally have low acceptance of tACS for a wide range of brain regions, and a large number of electrode arrangements on the patient's head will increase the patient's stress, especially for patients with or accompanied by mental and behavioral symptoms such as depression and anxiety, the compliance of treatment may be worse. The hair on the patient's head also brings difficulties to the arrangement of a large number of electrodes, and the use of conductive gel similar to electroencephalogram electrodes will further increase the patient's discomfort and resistance. The dose of tACS for a certain brain region is likely to act on the area that is not expected to be affected by the dose of tACS, and doctors will worry about the specific electric field distribution of tACS in the intracranial cavity, whether it meets the actual needs of the patient. Therefore, the existing tACS technology for treating brain diseases cannot customize a comprehensive treatment plan according to the disease to be treated and the target site and the more extensive brain region associated with the disease, the comprehensive treatment plan can meet both the dose requirement at the target site and the treatment / adjunct treatment requirement of the related brain region, can constrain the electric field of a certain frequency band to target the target site, and make the patient feel comfortable during the treatment process. SUMMARY

[0005] In view of the above technical problems existing in the prior art, the present application is proposed. The present application aims to provide a transcranial physical stimulation device for treating diseases related to the target site of the brain, which is easy to operate, and when intending to treat brain diseases including Alzheimer's disease, on the one hand, it can ensure that the target site associated with the disease such as the hippocampus is treated with a sufficient dose, and on the other hand, it is precisely controllable and does not involve other sites that are not expected to produce adverse effects, and at the same time, it can also provide comprehensive and safe transcranial physical treatment for the more extensive brain region associated with the disease, and the whole treatment process is mild and comfortable, and will not bring too much discomfort and additional stress to the patient, and the acceptance and treatment effect are better, and the treatment efficiency is also higher.

[0006] According to a first aspect of the present application, a transcranial physical stimulation device for treating a disease related to a target site in the brain is provided, which at least comprises a phototherapy part and an alternating transcranial electrical stimulation part, the phototherapy part is configured to irradiate transcranial near-infrared light to at least the frontal lobe and the temporal lobe of the head of the subject, or to irradiate transcranial near-infrared light in an irradiation range containing the target site and its surrounding brain regions; the alternating transcranial electrical stimulation part comprises a first pair of scalp electrodes and a second pair of scalp electrodes, the first pair of scalp electrodes comprises a first electrode and a second electrode, a first electric field of a first frequency is formed between the first electrode and the second electrode and acts on the target site; the second pair of scalp electrodes comprises a third electrode and a fourth electrode, a second electric field of a second frequency is formed between the third electrode and the fourth electrode and acts on the target site, the second frequency is greater than the first frequency, the ratio of the frequency difference to the first frequency is 8% or less and is in the range of 1Hz-80Hz.

[0007] According to a second aspect of the present application, a transcranial physical stimulation device for treating a disease related to a target site in the brain is provided. The phototherapy part further comprises a head cap, a plurality of near-infrared light source assemblies are arranged inside the head cap, and the plurality of near-infrared light source assemblies are configured to emit near-infrared light with a wavelength of 620nm-1080nm to the treatment subject.

[0008] Compared with the prior art, the beneficial effects of the embodiments of the present application are as follows:

[0009] After intending to treat a brain disease such as Alzheimer's disease in a patient and determining a target site associated with the disease, for example, the target site associated with Alzheimer's disease is the hippocampus, on the one hand, through the design of the alternating transcranial electrical two pairs of electrode paste positions (usually by pasting the scalp electrode sheet at 3-4 less hair positions), the electric field frequency and the frequency difference, etc. Parameters, so that both electric fields can act on the specific target site. Moreover, since the two electric fields have a frequency difference and form a relatively low-frequency electric field at the target site, precise low-frequency targeted reinforcement stimulation at the target site is achieved; on the other hand, considering the need to improve the effective radiation dose of the target site and its surrounding brain regions, or the possibility of different disease courses, different degrees of potential adverse conditions such as inflammation or rhythm disorders in other brain regions, therefore, the phototherapy part is also used to perform mild near-infrared light irradiation treatment on the target site and its surrounding brain regions or widely distributed frontal lobe and temporal lobe brain regions in a synergistic manner. In addition, under the condition that the electric field frequency of the alternating transcranial electricity and the near-infrared light frequency are appropriately set, the mechanism of exogenous oscillation-neural entrainment on neurons in the involved brain regions can also be achieved.

[0010] Therefore, the transcranial physical stimulation device of the present application can customize a comprehensive treatment plan for the patient according to the treatment needs of brain diseases, which can not only perform precise targeted stimulation on the target site, but also comprehensively and safely treat different disease courses, different degrees or potential lesions in a wider brain area, and the patient feels more comfortable and has less psychological pressure during the treatment, so the acceptance of the treatment is higher, and the curative effect and treatment efficiency are also higher.

[0011] The above description is only a summary of the technical solutions of the present application. In order to enable the technical means of the present application to be more clearly understood, and to be implemented in accordance with the content of the description, and in order to enable the above description and other purposes, characteristics and advantages of the present application to be more apparent and easy to understand, the following specific embodiments of the present application are described. BRIEF DESCRIPTION OF DRAWINGS

[0012] In the drawings, which are not necessarily drawn to scale, like numerals can describe similar components in different views. Like numerals having different letter suffixes or different numerals can represent different instances of similar components. The drawings illustrate generally, by way of example, various embodiments discussed herein, and are not intended to limit the disclosure to the embodiments depicted. Such embodiments are illustrative and exemplary, but not exhaustive or exclusive, of the methods, apparatuses, systems or non-transitory computer-readable medium having instructions for performing the methods that are contemplated by the disclosure.

[0013] Fig. 1(a) shows a schematic left side view of a transcranial physical stimulation device for treating a target site related disease of the brain according to an embodiment of the present application;

[0014] Fig. 1(b) shows a schematic right side view of a transcranial physical stimulation device for treating a target site related disease of the brain according to an embodiment of the present application;

[0015] Fig. 2(a) shows a first example of electrode configuration of a transcranial physical stimulation device according to an embodiment of the present application;

[0016] Fig. 2(b) shows a second example of electrode configuration of a transcranial physical stimulation device according to an embodiment of the present application;

[0017] Fig. 2(c) shows a third example of electrode configuration of a transcranial physical stimulation device according to an embodiment of the present application;

[0018] Fig. 2(d) shows a fourth example of electrode configuration of a transcranial physical stimulation device according to an embodiment of the present application;

[0019] Fig. 3 shows a superimposed envelope diagram of a simultaneously applied alternating oscillating electric field - a first electric field and a second electric field according to an embodiment of the present application; and

[0020] FIG. 4 shows a diagram of a light therapy portion of a transcranial physical stimulation device relative to a radiation range of the hippocampus according to embodiments of the present application. DETAILED DESCRIPTION

[0021] In order to better understand the technical solutions of the present application, the present application is described in detail below in combination with the drawings and specific embodiments. The embodiments of the present application are described in further detail below in combination with the drawings and specific embodiments, but are not as limitations to the present application.

[0022] The "first", "second", and similar words used in the present application do not represent any order, number, or importance, but are only used for differentiation. The "including" or "containing" and similar words used in the present application mean that the elements before the word cover the elements listed after the word, and do not exclude the possibility of also covering other elements. In the present application, the arrows shown in the figures of each step are only as an example of the execution order, and are not a limitation, the technical solutions of the present application are not limited to the execution order described in the embodiments, each step in the execution order can be combined, can be decomposed, can be exchanged in order, as long as it does not affect the logical relationship of the execution content.

[0023] All terms used in the present application (including technical terms or scientific terms) have the same meaning as understood by ordinary skilled persons in the field to which the present application belongs, unless otherwise specifically defined. It should also be understood that terms defined in, for example, a general dictionary should be interpreted as having meanings consistent with their meanings in the context of the relevant technology, and should not be interpreted in an idealized or excessively formalized sense, unless otherwise explicitly defined herein. The technology and equipment known to those skilled in the relevant art can not be discussed in detail, but in appropriate cases, the technology and equipment should be considered as part of the specification.

[0024] Fig. 1(a) and Fig. 1(b) respectively show a schematic left side view and a schematic right side view of a transcranial physical stimulation device for treating a disease related to a target site of the brain according to embodiments of the present application. The term "brain" used in the present application means an organ left after removing the extracerebral tissues and the like, and is intended to mean mainly the cerebrum, but is not limited thereto, and can include the cerebellum, the brainstem and the like. By "treating a disease related to a target site of the brain", it is intended to mean that the disease is related to a certain site of the brain, and the target site can include, but is not limited to, any one of the basal ganglia, the thalamus, the amygdala, the hippocampus located deep in the brain, and can also include a site in the middle or shallow part of the brain (for example, but not limited to, a certain cortical area, such as the M1 region). The disease related to the target site of the brain includes, but is not limited to, any one of AD, dementia, anxiety, PTSD, cognitive impairment, PD, Huntington's disease, MD, BD, SD, amyotrophic lateral sclerosis, autism spectrum disorder, attention deficit disorder in children, schizophrenia, and transient global amnesia. Among them, "dementia" includes dementia caused by various brain diseases, such as, but not limited to, dementia caused by AD, dementia caused by Parkinson's disease (PDD), vascular dementia (VaD), frontotemporal dementia (FTD), Lewy body dementia (DLB), post-traumatic dementia, diabetes-related dementia, and the like.

[0025] The above-mentioned various brain diseases, especially AD, are closely related to target sites such as hippocampus. A considerable part of brain diseases is also associated with sites such as prefrontal cortex. More specifically, PTSD is also associated with amygdala. PSCI, thalamic dementia is associated with thalamus. VaD is associated with basal ganglia, thalamus, frontal cortex, etc. DLB is associated with brain stem (locus ceruleus, substantia nigra) and extensive cortical areas. FTD is associated with frontal and temporal lobes. PDD is associated with substantia nigra, basal ganglia, thalamus, cortical temporal lobe and limbic system, etc. Motor dysfunction such as PD is associated with lesions of basal ganglia. MD may be associated with multiple target sites including prefrontal cortex, amygdala, hippocampus, etc. The prefrontal cortex is relatively shallow. SD is associated with target sites such as brain stem, hypothalamus, amygdala, hippocampus, frontal lobe (prefrontal cortex), and pineal gland, etc. limbic system. HD is associated with target sites such as basal ganglia and cerebral cortex. A considerable part of children with attention deficit disorder have reduced blood flow in the prefrontal cortex (PFC) and striatum. Some patients with anxiety have abnormal blood flow in the prefrontal cortex and amygdala, reduced prefrontal regulation, and long-term patients have reduced neurogenesis near the hippocampus. Transient global amnesia is closely related to decreased brain blood flow, especially insufficient blood flow in the hippocampus region. Patients with depression, BD, PTSD, cognitive impairment, sleep disorders, amyotrophic lateral sclerosis, autism spectrum disorder, schizophrenia, etc. Research shows that there are complex pathological symptoms such as reduced mitochondrial metabolism, reduced cerebral blood flow, and inhibited neurogenesis and synapse generation associated with the hippocampus.

[0026] In other embodiments, the target site can also be a neural nucleus group formed by a set of functionally similar neural nuclei, such as the raphe nucleus associated with SD and MD, the locus ceruleus associated with SD and anxiety, the substantia nigra associated with PD, the basal nucleus associated with AD (also known as Meynert basal nucleus), the supraoptic nucleus of the hypothalamus associated with SD, and the like, which are not listed here.

[0027] The so-called transcranial physical stimulation device is intended to mean that the physical stimulation such as light, electricity, and magnetism applied through the skull still has a physical stimulation amount after attenuation through the skull, which can act on the brain tissue below the skull, at least the cortex. The brain tissue includes, from shallow to deep, structures such as cerebral cortex, white matter, basal ganglia, thalamus, hypothalamus, etc. For example, the hippocampus is located in the temporal lobe of the brain, close to the medial temporal lobe, and is part of the limbic system. It is located in the deep structure of the brain, but not as deep as the basal ganglia, thalamus or brain stem, and is generally considered to be a subcortical structure in anatomy.

[0028] As shown in FIG. 1(a) and FIG. 1(b), the transcranial physical stimulation device at least includes a light therapy part 101 and an alternating current transcranial electrical stimulation (tACS) part 102. Please note that for the sake of simplicity of the illustration, only the head cap of the light therapy part 101 and the head cap electrode patch of the alternating current transcranial electrical stimulation part 102 are shown, and the structures such as the cables and the host device to which the cables are connected are not shown. For example, the light therapy part 101 can include an array of LED light panels distributed in the head cap to emit transcranial near-infrared light to multiple parts of the subject’s head, and the LED light panels can be powered by an external power supply to light up the LED lamp beads to emit transcranial near-infrared light via the cables. For another example, the light therapy part 101 can include an array of optical fiber bundles introduced in the head cap, and the optical fiber bundles can transmit near-infrared light from an external light source (such as but not limited to a near-infrared light excitation generator) via an optical cable.

[0029] The light therapy part 101 is configured to irradiate transcranial near-infrared light to at least the frontal lobe and the temporal lobe of the subject’s head. It is worth noting that for diseases related to the target part of the brain, before the clinical symptoms appear, or during the development of the disease, the lesion is not only limited to the target part of the brain, but also different degrees of symptoms can occur in the frontal lobe (about 1 / 3 of the surface area of the cerebral hemisphere), the temporal lobe and other parts, therefore, irradiating transcranial near-infrared light to the frontal lobe which occupies a large proportion of the whole brain, and the temporal lobe which is close to / contains important parts such as the hippocampus, amygdala, thalamus, etc. can have different degrees of therapeutic or adjuvant therapeutic effects on a wide range of brain diseases. In other embodiments, the irradiation range of transcranial near-infrared light can also include the parietal lobe and other brain regions, which are not limited by the present application.

[0030] Alternatively, for example in the case where the brain disease to be treated is associated with a specific target part, the light therapy part 101 can also be configured to irradiate transcranial near-infrared light in the irradiation range containing the target part and its surrounding brain regions, thereby treating or preventing the potential adverse conditions, such as inflammation-induced neuronal damage or rhythm disorders, which are often present in the surrounding brain regions of the target part and are not conducive to the related disease, and improving the treatment efficiency and treatment effect of the related brain disease.

[0031] For example, in the hippocampus, one of the mechanisms of near-infrared light is to activate glial cells and enhance the ability to resist oxidative stress and inflammation. In the early stages of AD, dementia, anxiety, PTSD, cognitive impairment, Parkinson's disease, Huntington's disease, depression, BD, sleep disorders, amyotrophic lateral sclerosis, and other diseases, inflammation may occur in the hippocampus (which is one of the early pathological changes), and as the disease progresses, inflammation in the hippocampus may gradually spread to other brain regions. For example, inflammation in the hippocampus can lead to neurodegenerative changes, affecting memory and cognitive function, and exacerbating AD, dementia, and cognitive impairment. For example, inflammation in the hippocampus can trigger anxiety and depressive symptoms by affecting neurogenesis and neural plasticity. In addition, factors such as chronic stress can exacerbate depressive symptoms by increasing inflammation in the hippocampus. For example, inflammation in the hippocampus is observed in PTSD patients, which is related to changes in stress response and neural plasticity; the observed reduction in hippocampal volume and dysfunction in PTSD patients is also related to inflammation. For example, sleep disorders such as sleep deprivation can lead to inflammation in the hippocampus, which in turn affects cognitive function and emotional state. By irradiating the frontal lobe (e.g., the dorsolateral prefrontal cortex), the temporal lobe (e.g., the medial temporal lobe), or further together with the parietal lobe (e.g., the precuneus), near-infrared light can prevent the spread of inflammation in the hippocampus to the frontal lobe, temporal lobe, and parietal lobe.

[0032] For example, the mechanism of near-infrared light on the hippocampus also includes improving metabolic function and increasing cerebral blood flow, promoting neural growth and synapse generation, which is particularly suitable for treating AD, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, dementia, schizophrenia, and also suitable for treating depression, BD, PTSD, cognitive impairment, autism spectrum disorder, sleep disorders, and has some effect on attention deficit disorder in children, anxiety, and transient global amnesia.

[0033] Specifically, there is sufficient support from autopsy studies, animal models, brain imaging (PET / fMRI), and genetic studies for AD, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, dementia, schizophrenia, and other diseases, which have a complex pathological condition of reduced mitochondrial metabolism, reduced cerebral blood flow, and inhibited neural growth and synapse generation, and near-infrared light irradiation can provide targeted therapeutic effects.

[0034] Further, for depression, BD, PTSD, cognitive impairment, autism spectrum disorder, sleep disorder, evidence can also be provided by brain imaging, blood / cerebrospinal fluid biomarkers, drug intervention studies. Although there is a certain heterogeneity in different individuals, these diseases usually also have at least one, two or even three pathological symptoms of reduced mitochondrial metabolism, reduced cerebral blood flow, inhibited neural growth and synapse generation, so near-infrared light irradiation can also provide a certain targeted treatment effect.

[0035] Further, for attention deficit disorder in children, some children have abnormal mitochondrial function, 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 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 cortex regulation, and long-term patients also have inhibited neurogenesis near the hippocampus. Transient global amnesia is closely related to decreased cerebral blood flow, especially insufficient blood flow in the hippocampal region. Therefore, near-infrared light irradiation can also provide a certain improvement effect for these brain diseases.

[0036] It is worth noting that in this application, "irradiating near-infrared light to a certain part" or "irradiating near-infrared light in the irradiation range containing a certain part" can be that the optical path of the near-infrared light transmitted through the skull intersects at least part of the part, so that the near-infrared light can be directly delivered to the part, or in another case, the near-infrared light cannot directly reach the part, but can transmit the phototherapy effect of the near-infrared light to the part through other tissues as a medium, which is not limited in this application.

[0037] Take Alzheimer's disease as an example.

[0038] Alzheimer's disease is a brain disease related to the hippocampus deep in the brain, and extensive Aβ plaque deposition in the cerebral cortex, as well as neurofibrillary tangles caused by tau protein lesions in the cortex, are significant pathological markers of Alzheimer's disease. The deposition of Aβ plaques triggers a chain reaction, which in turn causes the misfolding and assembly of intracellular tau proteins, and further spreads the lesions to more extensive neural circuits and cortex, ultimately leading to the failure of the nervous system and the decline of cognitive ability. Aβ plaques first appear in the cortex, then enter the limbic system (including the hippocampus), the diencephalon, the brainstem, and finally the cerebellum. The amygdala, entorhinal cortex, and parahippocampal gyrus may be early brain regions of tau tangle, while the fusiform gyrus, inferior temporal cortex, and middle temporal cortex are relatively late tau tangle aggregation brain regions. The progression of Aβ plaque deposition and tau protein tangle aggregation also reflects the development of the course of Alzheimer's disease to some extent.

[0039] Further, neuroinflammation plays an important role in the development of Alzheimer's disease. Neuroinflammation refers to the activation of the brain immune response, involving immune cells such as microglia and astrocytes. In a healthy state, neuroinflammation plays a beneficial role in maintaining brain homeostasis and defending against infection or injury; in the brain of patients with Alzheimer's disease, even before symptoms appear, this inflammatory response becomes chronic and dysregulated, leading to harmful consequences such as neuronal damage. Neuroinflammation is closely related to the accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles caused by hyperphosphorylated tau protein. Microglia and astrocytes are resident immune cells in the brain and play a key role in the regulation of neuroinflammation in Alzheimer's disease. After the accumulation of Aβ plaques, microglia and astrocytes will transform from the M1 / A1 phenotype to the M2 / A2 phenotype, thereby losing their protective function, causing the production of pro-inflammatory cytokines and exacerbating neuroinflammation. In addition, the phagocytic function of microglia is impaired, leading to reduced clearance of Aβ plaques and further neurotoxicity. These two glial cells are widely distributed in the brain from the cortex to deep structures such as the hippocampus, which leads to the diffuse distribution of inflammatory mediators during the development of Alzheimer's disease, and inflammation occurs in multiple locations such as the frontal and temporal lobes of the cortex even before symptoms appear.

[0040] Therefore, for such multi-focal and diffuse brain diseases, such as Alzheimer's disease, the light therapy unit 101 according to the embodiments of the present application can not only comprehensively and gently and effectively treat diffuse lesions in the target area and surrounding areas, but also achieve more efficient and thorough treatment, and effectively inhibit the further development of the disease. In the case of Alzheimer's disease, irradiating the frontal and temporal lobes of the subject's head with an appropriate dose of transcranial near-infrared light, optionally, the hippocampal surrounding area can also be included in the near-infrared light irradiation range, which can significantly reduce the accumulation volume and number of Aβ plaques in the cerebral cortex and hippocampus, reduce inflammation levels, up-regulate corresponding stress response proteins in the brain, reduce protein aggregation and neuronal apoptosis, and enhance the phagocytic activity of microglia and other cells on accumulated Aβ plaques, thereby alleviating the progression of Alzheimer's disease.

[0041] As shown in FIG. 1(a) and FIG. 1(b), the head electrode pieces of the alternating current transcranial electrical stimulation unit 102 are in pairs, including a first head electrode pair and a second head electrode pair. The first head electrode pair includes a first electrode e1 and a second electrode e2, and a first electric field E1 of a first frequency f1 is formed between the first electrode e1 and the second electrode e2 and acts on a target site (not shown). The second head electrode pair includes a third electrode e4 and a fourth electrode e3, and a second electric field E2 of a second frequency f2 is formed between the third electrode e4 and the fourth electrode e3 and acts on the target site. Moreover, the second frequency f2 is greater than the first frequency f1, the ratio of the frequency difference Δf (Δf = f2 - f1) to the first frequency f1 (Δf / f1) is 8% or less, and the frequency difference Δf is in the range of 1 Hz - 80 Hz.

[0042] The first electric field E1 and the second electric field E2 are both alternating oscillation electric fields, and have a frequency difference Δf therebetween, so that beat phenomenon can be formed, i.e., a phenomenon produced when two sinusoidal waves or periodic signals of close but not identical frequencies are superimposed. When the frequency difference of the two signals is small, a low-frequency oscillation envelope can be observed, and the frequency of the oscillation is equal to the difference Δf of the frequencies of the two original signals.

[0043] The relationship between the various electric fields will be described in combination with FIG. 3, in which the horizontal axis is a time axis, for example, in ms, and the vertical axis is the electric field intensity of each electric field, for example, in V / m (volt / meter), and the specific numerical ranges of the horizontal and vertical axes are different according to the settings of the electric field frequency and amplitude, which are not specifically limited here. As shown in FIG. 3, the first electric field E1 (i.e., the waveform shown in FIG. 3, which has an oscillation frequency f1) and the second electric field E2 (i.e., the waveform shown in FIG. 3, which has an oscillation frequency f2) can be two sinusoidal signals with very close frequencies, for example, both f1 and f2 are greater than 1000 Hz, or even several thousand Hz, and the frequency difference Δf is several Hz to several tens of Hz. The two signals E1 and E2 are superimposed in the overlapping region, and in the case where the frequency difference Δf is small enough relative to the frequencies f1 and f2, a low-frequency oscillation electric field E (i.e., the waveform shown in FIG. 3) is obtained after superposition, and the envelope curve of the oscillation electric field E has a frequency of Δf, and the intensity distribution of the low-frequency oscillation synthetic wave is also shown. As can be seen from FIG. 3, by changing at least one of f1 and f2, the adjustment of Δf, i.e., the frequency of the low-frequency oscillation, can be achieved.

[0044] ​​​The first electric field E1 and the second electric field E2 in FIG. 3 are applied at the same time, so that more significant low-frequency oscillation can be obtained. However, in some embodiments, the first electric field E1 and the second electric field E2 exist and interact at the target site, but can also not be applied at the same time and can have a phase deviation from each other, so as to obtain low-frequency oscillation of a required amplitude.

[0045] Although the two high-frequency oscillation electric fields E1 and E2 of a higher frequency (for example, f1 can be selected in a relatively safe frequency range of 1000 Hz-2000 Hz) are applied, cells in a region where the two electric fields do not overlap will not be activated, and neurons will not react to this. More specifically, neurons only react to low-frequency signals of <1 kHz (or <600 Hz) and are completely unaffected by high-frequency signals of >1 kHz, so that high-frequency electric field signals of >600 Hz, especially >1 kHz, can reach the target site without affecting neurons in superficial or peripheral regions such as the cortex, subcortex, and the like. The position of the pair of electrode sheets is controlled to control the electric field E1 and the electric field E2 to overlap at the target site, so that the two high-frequency electric field signals are superimposed at the target site to obtain a low-frequency oscillation electric field E of a frequency of Δf. When Δf is exactly in a frequency range that can effectively act on neurons, the low-frequency oscillation electric field E can achieve the treatment effect of regulating brain endogenous oscillation, forming neural entrainment, and regulating neural activity and inducing recovery of functional connections between brain regions.

[0046] It is found in practice that when the frequency difference Δf is lower than 1 Hz, the effect on brain tissues such as neurons is often not very obvious, and the treatment effects include δ waves (frequency range 1 Hz-4 Hz) that can induce deep sleep, θ waves (frequency range 4 Hz-8 Hz) that have a relaxing meditation effect, α waves (frequency range 8 Hz-13 Hz) that promote the effect of relaxed wakefulness, β waves (frequency range 14 Hz-30 Hz), and γ waves (frequency range 30 Hz-100 Hz) that are associated with rapid cognitive processing, concentration, perception, and memory formation.

[0047] Taking the above frequency bands into consideration, in the embodiments of the present application, Δf is limited to a range of 1 Hz-80 Hz. For example, when f1 is selected to be 1000 Hz, Δf is selected to be any value in the range of 1 Hz-80 Hz, and Δf / f1 is less than 8%. When f1 is selected to be 2000 Hz, Δf can be as low as 1 Hz and as high as 80 Hz. When Δf is set to be 80 Hz, Δf / f1 is 4%. Other frequency values of f1 are not listed here, as long as the range of Δf and Δf / f1 can be determined in the process of determining f1 and Δf.

[0048] By the high frequency electric field signal, enough energy can be introduced, and the energy is completely ineffective for the cells and neurons of the single high frequency electric field signal path, and is not wasted on the undesired path area, and does not stimulate the undesired area. Instead, the two high frequency electric field signals with a frequency difference Δf form a low frequency oscillating electric field with a frequency difference sensitive to cells and neurons in the overlapping area, thereby efficiently focusing enough energy on the target site located in the overlapping area, such as the hippocampus, thereby ensuring accurate targeting dose.

[0049] Unlike only relying on near-infrared light irradiation to reach the target site such as the hippocampus, the light therapy part 101 of the present application can be coordinated with the alternating transcranial electric stimulation part 102 to irradiate a wide range of brain areas with near-infrared light with mild energy, the irradiation is mild and comfortable, the psychological pressure of the irradiation object is small, and by conveniently pasting a few head skin electrode pieces, the alternating transcranial electric stimulation can be targeted and intensified on the target site such as the hippocampus. In this way, not only the diseased tissues in the diffuse shallow layer and the periphery of the target site are treated, but also the target site which is concentrated and possibly located in a deeper layer is targeted and intensified. Further, the wide irradiation of the transcranial near-infrared light on the diseased tissues in the diffuse shallow layer and the periphery of the target site can widely reduce or even eliminate the diseases in the diffuse shallow layer, such as reducing inflammatory mediators and reducing Aβ plaque deposition for Alzheimer's disease, and the mechanism of action of exogenous oscillation-neural entrainment on the tissues around the target site, and finally focusing on the target site. The present application has rich treatment mechanisms, and can treat diseased sites at different stages of disease in all directions, and the object feels more comfortable and has less psychological pressure during the treatment process.

[0050] Experimental studies show that high frequency oscillations (HFOs) of 100 Hz-400 Hz are synchronized between brain regions, and the signal frequency of alternating transcranial electricity is about 300 Hz-500 Hz, which is more likely to induce seizures, therefore, the first frequency and the second frequency of the embodiments of the present application avoid this frequency band. The Hodgkin-Huxley model shows that when neurons are continuously stimulated at high frequency, the recovery speed of h gate is slow (time constant τ□ is about 20 ms-30 ms), and cannot fully recover to the resting state between two stimulations, the unrecovered h gate remains closed, resulting in the inactivation of the sodium channel, which cannot be effectively activated by subsequent stimulation. Related experimental studies show that neurons have an absolute refractory period (about 1 ms), therefore, brain neuron cells will not respond to high-frequency alternating transcranial electrical stimulation above 1000 Hz. And in practical applications, due to energy metabolism and membrane potential recovery and other limitations, the effective response frequency of neurons is usually lower than 500 Hz. Therefore, in the embodiments of the present application, preferably, the first frequency can be set to a higher frequency of 600 Hz or above, or 1000 Hz or above, thereby being spaced apart from the frequency band that neurons can respond to, especially being far away from the sensitive frequency band that may induce epilepsy, ensuring that the alternating transcranial electrical signal safely and low-loss reaches the target site without disturbing the neurons along the way.

[0051] Through experimental research, it is found that the first frequency and the second frequency of the two electric fields of alternating current transcranial electric stimulation are not necessarily set as high frequencies such as 1000 Hz, and in the case of relatively low frequencies, a stable beat frequency can also be formed, and the first electric field of the first frequency and the second electric field of the second frequency act as fundamental waves, and the low-frequency electric field with a specific frequency difference formed by superposition of the two can cooperate with the fundamental waves to achieve better treatment effect on specific diseases. In consideration of the fact that 4 Hz-150 Hz can be effective for the treatment of dementia, 4 Hz-150 Hz can be effective for sleep disorders, and the sensitive frequency band of epilepsy is avoided, preferably, the first frequency can be set to 130 Hz to 200 Hz, and the frequency difference is set to 1 Hz-13 Hz. In this way, the low-frequency electric field formed at the overlap covers the delta wave, theta wave and alpha wave three frequency bands with calming and relaxing effects, and can precisely stimulate the target site, which is beneficial to the treatment of various diseases. Taking the hippocampus as an example, the tACS in the delta wave band can increase the synchronization of neuronal activity in the hippocampus, enhance the functional connectivity of the hippocampus, and improve the information transmission efficiency between the hippocampus and the cortex, which is helpful to improve the memory function. For AD patients, the tACS in the delta wave band can enhance the activity of the brain's default mode network (DMN), thereby alleviating the symptoms of cognitive impairment. For example, the tACS in the theta wave band can enhance the theta wave oscillation in the hippocampus, which is closely related to the encoding and retrieval of memory, and can improve the efficiency of memory tasks. For patients with cognitive impairment, the tACS in the theta wave band can enhance the executive function of the brain and improve attention and working memory. For example, the tACS in the alpha wave band can regulate the neuronal activity in the hippocampus and enhance the information transmission between the hippocampus and the cortex, thereby improving the information processing efficiency. For patients with depression or anxiety, the tACS in the alpha wave band can regulate the emotional regulation network of the brain, thereby alleviating depressive symptoms. For example, the tACS in the gamma wave band can enhance the gamma wave oscillation in the hippocampus, which is closely related to the consolidation and retrieval of memory, so as to improve the efficiency of memory tasks, attention and working memory. The tACS in each of the above frequency bands can regulate the endogenous oscillation of the hippocampus, which has a repairing effect on the hippocampus and an improving effect on various functional disorders. In addition, the first electric field and the second electric field can also cause neuronal responses, rhythm synchronization in a wider brain area, thereby playing a therapeutic role in related diseases, and the application of cross-frequency bands can achieve better treatment effect.

[0052] Similarly, in other embodiments, the first frequency can also be set to 30 Hz-100 Hz, that is, covering the healthy and safe gamma wave band, and the frequency difference is set to 1 Hz-13 Hz, that is, covering the delta wave, theta wave or alpha band.

[0053] By way of example only, in experimental studies combining 7T fMRI with calcium imaging techniques, it was found that the prefrontal cortex exhibits a neural oscillation cross-frequency coupling mechanism in working memory tasks, namely Theta-Gamma Cross-Frequency Coupling (TG-CFC), which is mainly achieved through phase-amplitude coupling (PAC), i.e., the phase of theta oscillations (4-8 Hz) regulates the amplitude of gamma oscillations (30-100 Hz). This coupling is particularly pronounced in the prefrontal cortex and hippocampus, and is related to information integration and working memory, cross-brain functional connectivity, neural plasticity, and other brain characteristics. Therefore, tACS that applies theta-gamma oscillation coupling can regulate the theta-gamma cross-frequency coupling in the prefrontal cortex and hippocampus, providing improvements in these aspects. For example, in terms of information integration, theta-gamma cross-frequency coupling allows the brain to synchronize information processing between different brain regions, thereby achieving more efficient information integration and transmission. In terms of memory consolidation, theta-gamma cross-frequency coupling is closely related to memory encoding and consolidation in the hippocampus, and the phase of theta waves provides a time frame for gamma wave activity, thereby facilitating the orderly storage of information. In terms of cognitive function, theta-gamma cross-frequency coupling plays a key role in working memory, attention, and perception, and even helps to alleviate behavioral improvements in patients with depression.

[0054] Other cross-frequency couplings, such as delta-gamma (Delta-Gamma) coupling, are also observed in cognitive tasks such as attention and information integration. Therefore, tACS that applies delta-gamma cross-frequency coupling to associated cortical regions can regulate the delta-gamma cross-frequency coupling of the associated cortical regions, thereby improving performance in cognitive tasks such as attention and information integration.

[0055] For another example, the coupling of alpha waves and high-frequency oscillations such as gamma waves also exists in the cerebral cortex, especially in the sensory and motor cortices, so tACS that applies alpha-gamma (Alpha-Gamma) cross-frequency coupling to the sensory and motor cortices can have a particularly therapeutic effect on diseases related to motor function, such as Huntington's disease. For another example, applying alpha-gamma cross-frequency coupling to the parietal-occipital network can support multiple representations in visual working memory, thus helping to improve visual working memory. Therefore, in other embodiments, when the first frequency is set to 30-100 Hz, the frequency difference can also be set to 8-13 Hz, i.e., the alpha wave frequency band.

[0056] Therefore, in the embodiments of the present application, the gamma wave is taken as the fundamental wave, and the delta wave, theta wave or alpha wave is taken as the beat frequency. In this way, the cross-band stimulation mode is similar to the coupling of the brain's own cross-band oscillation, especially very similar to the cross-band characteristics of the prefrontal cortex itself when working memory, and thus also has effects such as promoting the regulation of prefrontal cortex rhythm, improving brain working memory and high-level cognitive function, etc. Therefore, it has good therapeutic effect on dementia, cognitive impairment, Parkinson's disease directly related to working memory, and other diseases such as PTSD, anxiety, depression, sleep disorders, etc. that may accompany or cause abnormal working memory and cognitive impairment.

[0057] In some embodiments, the light therapy unit 101 irradiates transcranial near-infrared light at a third frequency f3, and the frequency difference Δf of the first electric field and the second electric field can be set to satisfy any one of the following preset relationships. Please note that the near-infrared light mentioned herein with a frequency 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, which has a continuous light intensity in the time domain, but can form a periodic waveform with rising and falling edges, such as a square wave, a sine wave, etc., is also included in the scope of "near-infrared light with a frequency", and the frequency of the waveform is the "frequency" of the "near-infrared light".

[0058] The first preset relationship includes that the third frequency f3 is in the gamma wave frequency range, and the frequency difference Δf is in any one of the delta wave frequency range, theta wave frequency range, alpha wave frequency range and gamma wave frequency range. It has been described in detail above that the tACS for applying delta-gamma cross-band coupling, theta-gamma cross-band coupling and alpha-gamma cross-band coupling can help improve working memory, attention, information integration, cognitive impairment, etc. of the brain, and the near-infrared light-tACS cooperative stimulation for applying these cross-band couplings can also achieve such effects, which are not described here. Especially in the case where the first frequency is 600Hz or more, or 1000Hz or more, such cross-band coupling can be achieved at the target site, thereby achieving rhythm regulation for the target site.

[0059] In some embodiments, the frequency difference Δf of the first electric field and the second electric field can be set to 10Hz.

[0060] In some embodiments, the frequency difference Δf of the first electric field and the second electric field can be set as 40 Hz. Experimental studies have shown that gamma waves such as 40 Hz are very healthy and safe for the brain, so the transcranial near-infrared light in the gamma wave frequency band is used as the background, and is combined with the transcranial alternating current in the gamma wave frequency band, which has different therapeutic effects, to further strengthen the regulation of brain rhythm. For example, the third frequency f3 and the frequency difference Δf can also be set to be in the gamma wave frequency band and as close as possible, for example, both can be set near 40 Hz, and the frequency difference between the two is less than the first threshold. In this way, the action frequency of the light therapy and the action frequency of the transcranial alternating current stimulation are the same or close to the same frequency, which can significantly improve the matching and strengthening of oscillation, improve the neural entrainment effect, and enhance the therapeutic effect. Especially the 40 Hz in the gamma wave frequency band. Taking Alzheimer's disease as an example, the photoelectric combined stimulation at this frequency can improve the condition of Alzheimer's patients in multiple ways: promoting the exchange of cerebrospinal fluid (CSF) and interstitial fluid (ISF) in Alzheimer's patients, playing an active role in p-Tau protein deposition, accelerating the lymphatic clearance of amyloid proteins, inducing endogenous brain electrical oscillation entrainment through external current, stimulating and improving gamma oscillation, specifically regulating the neural network of the damaged area, improving neural oscillation and brain functional connectivity in the damaged area, promoting brain function improvement, improving the cognitive ability of patients, and delaying the disease progression.

[0061] The second preset relationship includes that the third frequency f3 is in the alpha wave frequency range, and the frequency difference Δf is in any one of the delta wave frequency range, the theta wave frequency range, the alpha wave frequency range, and the gamma wave frequency range. For example, the near-infrared light with a frequency in the alpha wave frequency range is combined with the alternating low-frequency oscillation in the delta wave frequency range or the theta wave frequency range and targeting the target site. The brain area low-frequency oscillation induced by low-frequency oscillation neural entrainment can be used to regulate the alpha wave frequency oscillation of the brain area induced by near-infrared light neural entrainment. This cross-frequency coupling is similar to the brain wave cross-frequency coupling in the process of entering the "ready to learn" state, concentrating attention, or memory consolidation in some sleep stages, thereby regulating the memory ability of the brain. In addition, this cross-frequency coupling can promote the neural plasticity of the brain, thereby helping to form and maintain long-term memory.

[0062] When the endogenous oscillation is modulated by the frequency of tACS or near-infrared light in the present application, the effect of modulation can be neural entrainment, that is, to enhance certain endogenous oscillation phenomenon, or inhibition, that is, to weaken certain endogenous oscillation phenomenon. For example, the oscillation of other frequency bands can be strengthened by applying external oscillation of other frequency bands, so as to inhibit the oscillation of the target frequency band; or the oscillation of the target frequency band can be induced by applying external oscillation of the target frequency band in phase asynchrony, so as to reduce the amplitude of the oscillation of the target frequency band. The application of external oscillation stimulation by near-infrared light or tACS can improve the endogenous oscillation of the target site such as hippocampus through brain wave entrainment or cell signal regulation, and repair and improve the function of the relevant site.

[0063] Further, the composite reinforcement oscillation stimulation of multiple frequencies can benefit from the oscillation of the photoelectric dual mode, or can benefit from the flexible cooperation of two frequencies, which can be aligned for reinforcement or coupled for modulation, so as to achieve more refined and targeted modulation effect on the endogenous oscillation of the target site.

[0064] In addition, by allowing the near-infrared light to act on the target site such as hippocampus in cooperation with tACS of different frequency bands, whether the near-infrared light is continuous light or pulsed light, the pain (including but not limited to thermal pain) of the subject can be reduced, the mood of the subject can be relaxed, the compliance of the subject to the treatment can be improved, and the tolerance of the subject to a higher dose can be improved when performing photoelectric combined treatment, and the tACS of each wave frequency can modulate the endogenous oscillation of the target site, cooperate with the mechanism of the near-infrared light acting on the hippocampus, and optimize the repair effect on the target site and the treatment effect on brain diseases.

[0065] The electrode configuration of the transcranial physical stimulation device will be illustrated below in combination with FIG. 1(a), FIG. 1(b) and FIG. 2(a)-FIG. 2(d).

[0066] As described above, the first pair of scalp electrodes includes the first electrode e1 and the second electrode e2, and the second pair of scalp electrodes includes the third electrode e4 and the fourth electrode e3. The first pair of scalp electrodes and the second pair of scalp electrodes can be arranged in any one of the following positional relationships, for example.

[0067] The first positional relationship is shown in FIG. 1(a), FIG. 1(b), FIG. 2(a) and FIG. 2(b). The first electrode e1 and the second electrode e2 are arranged on the two sides of the longitudinal fissure of the brain of the subject, and the third electrode e4 and the fourth electrode e3 are also arranged on the two sides of the longitudinal fissure of the brain of the subject. In this way, the first electric field and the second electric field both cross the two hemispheres of the brain, the overlapping area can be positioned deep in the brain, and the front and back movement can conveniently realize the front and back movement of the overlapping area, and can realize accurate positioning for the neural nuclei such as hippocampus and thalamus which extend in the front and back directions.

[0068] For example, in FIG. 2(a), electrode patch e1 is placed at the left periauricular region, and electrode patch e2 is placed at the right frontoparietal region adjacent to the temporal lobe. Electrode patch e3 is placed at the left periauricular region, separated from electrode patch e1 by the helix. Electrode patch e4 is placed at the right occipitoparietal region adjacent to the temporal lobe. The periauricular region, the frontoparietal region adjacent to the temporal lobe, and the occipitoparietal region adjacent to the temporal lobe are all regions with sparse hair, making it easy to attach the electrode patches and clean them. For example, in some embodiments, the two electrode patches (e1 and e3) at the periauricular region can be placed symmetrically on both sides of the helix, with a distance of 4-6 cm, corresponding to the anterior and posterior portions of the hippocampus. The pair of electrode patches e1-e2 can be connected to a corresponding alternating sinusoidal current source I1 to generate an oscillating first electric field E1 in the brain between the pair of electrode patches. The pair of electrode patches e3-e4 can be connected to a corresponding alternating sinusoidal current source I2 to generate an oscillating second electric field E2 in the brain between the pair of electrode patches. The first electric field E1 and the second electric field E2 can be superimposed at the left elongated target region-hippocampus, and the superimposed region is shown as the white circle in FIG. 2(a). Here, the sinusoidal current source is used as an example, but the waveform of the current is not limited to this and can also include other waveforms such as square waves.

[0069] Please note that FIG. 2(a) is only an example of electrode patch arrangement, and this electrode patch arrangement is particularly suitable for treating Alzheimer's disease and for focused transcranial alternating current stimulation of the hippocampus. As shown in FIGS. 2(a)-2(d), each of the left and right cerebral hemispheres has a hippocampus, which is C-shaped and elongated between the corresponding thalamus and medial temporal lobe. Returning to FIG. 2(a), in the course of Alzheimer's disease, the pathological changes in the hippocampus are usually not symmetrical. By using the electrode patch arrangement shown, the two periauricular electrodes e1 and e3 can be placed on the side to be stimulated, and the two electrodes can be used as anodes, with the anodes closer to the hippocampus to be stimulated, so that the electric field is less diffused, and the electric field strength and current strength acting on the hippocampus can be greater.

[0070] In addition, for each side of the hippocampus, the hippocampus can be stimulated by focusing on different parts. If the main direction of the hippocampus is called longitudinal, then a single hippocampus can be divided into several longitudinal target parts, such as longitudinal front, longitudinal middle, longitudinal back, etc., and the longitudinal target part of the hippocampus is taken as the target part to be stimulated. For example, in electrodes e1 and e3, the former corresponds to the longitudinal front, and the latter corresponds to the longitudinal middle. If the longitudinal front is stimulated, the stimulation current amplitude of electrode e3 is greater than that of electrode e1, that is, the stimulation current of the electrode corresponding to the longitudinal target part is less than that of the electrode corresponding to other parts of the hippocampus. Thus, the focusing area of transcranial electrical stimulation can be guided to the longitudinal front, so as to achieve precise targeted reinforcement therapy for the target part, and even the positioning of the target area can be flexibly adjusted.

[0071] The electrode arrangement in Fig. 2(b) also satisfies the first positional relationship, and it can also achieve the purpose of targeted treatment of the hippocampus. As shown in Fig. 2(b), two anodes e1 and e3 can be arranged near the ear of the side where the hippocampus to be stimulated, and two cathodes e2 and e4 can be arranged near the ear of the opposite side. It can be seen that e2 as the second electrode is in front of e1 as the first electrode, e3 as the fourth electrode is in front of e4 as the third electrode, and e4 as the third electrode is on the opposite side of e1 as the first electrode. In this way, the first electric field E1 and the second electric field E2 of high frequency intersect in a cross manner, and the intersection is the overlapping area, and the overlapping area forms a low-frequency oscillating electric field E. If a part of the hippocampus is to be stimulated, the first electric field E1 and the second electric field E2 of high frequency can be made to intersect and overlap at the stimulation part. This way can form a target area that extends more in the longitudinal direction of the hippocampus and is more limited in the transverse direction perpendicular to the longitudinal direction.

[0072] The electrodes are arranged near the temporal lobe or more forward, such as near the hairline of the temporal lobe, behind the ear, on the forehead, etc. There is less hair, and it is easy to expose (such as shaving a part of the hairline does not affect the appearance much), for example, as shown in Fig. 1(a) and Fig. 1(b), it is more convenient to attach and remove, and it is more convenient and comfortable to wipe off when using conductive gel. And because the electrode patch is arranged in a part with less hair, it is also convenient to adapt according to the position of the target part.

[0073] The second position relationship is shown in Fig. 2(d), in which the first electrode e1 is arranged at a position corresponding to the frontal lobe of the subject's head and is used as the third electrode e4, the second electrode e2 is arranged at a position corresponding to any one of the temporal lobe, the junction of the frontal and temporal lobes, and the junction of the occipital and temporal lobes on one side of the subject's head, and the fourth electrode e3 is arranged at a position corresponding to any one of the temporal lobe, the junction of the frontal and temporal lobes, and the junction of the occipital and temporal lobes on the other side of the subject's head. This electrode arrangement can be particularly targeted to stimulate the hippocampus, the thalamus, and the deep neural nuclei of the brain center.

[0074] As mentioned above, in addition to the hippocampus, the target site can also include neural nuclei, or the target site includes the basal ganglia, the thalamus, the amygdala, etc. Taking the thalamus as an example, as shown in Fig. 2(d), e1 and e4 (corresponding to the first electrode and the third electrode, as positive electrodes) can be replaced by the same electrode and arranged on the left and right sides of the frontal lobe, and two negative electrodes e2 and e3 (as the second electrode and the fourth electrode, respectively) are arranged at the bilateral mastoid process (i.e., the temporal lobe or the junction of the occipital and temporal lobes). It can be seen that the first electrode e1 and the third electrode e4 are in front of the second electrode e2 and the fourth electrode e3, and the second electrode e2 is on the opposite side of the fourth electrode e3. In this way, the overlapping area of the first electric field E1 and the second electric field E2 can be positioned to the thalamus (as shown by the white oval in Fig. 2(d)), so as to achieve targeted and precise treatment of the thalamus. Similarly to the description of Fig. 2(a), in Fig. 2(d), the second electrode e2 and the fourth electrode e3 are not necessarily symmetrically arranged, that is, the distribution of the first electric field E1 and the second electric field E2 can be changed by adjusting the positions of the two electrodes, so that the overlapping area of the two corresponds to different parts of the thalamus, and the size relationship between the amplitudes of the stimulation currents of the second electrode e2 and the fourth electrode e3 can also be set according to the different parts of the thalamus as the target site that is intended to be stimulated, so that the stimulation current of the electrode corresponding to the target site to be stimulated is smaller than the stimulation current of the electrode corresponding to other parts of the thalamus. The specific electrode layout and the amplitudes of the stimulation currents of different electrodes can be set as needed according to theoretical calculations or simulation experimental results, which are not listed here.

[0075] The third position relationship is shown in Fig. 2(c), in which the third electrode e4 and the fourth electrode e3 are arranged on both sides of the longitudinal fissure of the subject's head, and the first electrode e1 and the second electrode e2 are arranged at positions corresponding to the frontal lobe of the subject's head and any one of the temporal lobe, the junction of the frontal and temporal lobes, and the junction of the occipital and temporal lobes on one side of the subject's head, respectively.

[0076] As shown in Fig. 2(c), an anode e3 (as the fourth electrode) and a cathode el (as the first electrode) can also be arranged near the ear of the side where the hippocampus to be stimulated, and the cathode el corresponds to the anode e2 (as the second electrode) which can be arranged on the left and right sides of the forehead, so as to form a first electric field which enters from the forehead and exits from the ear side, and the anode e3 corresponds to the cathode e4 (as the third electrode) which can be arranged on the other side of the temporal lobe. It can be seen that the third electrode e4 is on the opposite side of the first electrode el and behind the fourth electrode e3. Thus, a second electric field with the opposite direction of the first electric field is formed, and in this way, a target area which is inclined relative to the hippocampus and extends more in the transverse direction can be formed.

[0077] The fourth positional relationship (not shown) is that the first electrode el (cathode) and the second electrode e2 (anode) are arranged on both sides of the longitudinal fissure of the subject's head brain, and the third electrode e4 (cathode) and the fourth electrode e3 (anode) are arranged at positions corresponding to the frontal lobe of the subject's head and any one of the positions corresponding to the side temporal lobe, the frontotemporal junction, and the occipitotemporal junction of the subject's head, respectively. This positional relationship is similar to the third positional relationship, and also forms a target area which is inclined relative to the hippocampus and extends more in the transverse direction, but the current flows from the fourth electrode e3 (anode e3) at any one of the positions corresponding to the side temporal lobe, the frontotemporal junction, and the occipitotemporal junction of the subject's head to the side brain, and deposits more energy to the target area, thus having a better stimulation effect on the target area.

[0078] The fifth positional relationship (not shown) is that the first pair of scalp electrodes and the second pair of scalp electrodes are arranged at the forehead and the ear. For example, el and e4 (corresponding to the first electrode and the third electrode, as positive electrodes) can be arranged on the left and right sides of the forehead, respectively, and the two negative electrodes e2 and e3 (as the second electrode and the fourth electrode, respectively) can be arranged at the bilateral postauricular mastoid process, or other scalp positions corresponding to the temporal lobe or the occipitotemporal junction. Specifically, the positions of the electrodes of the first pair of scalp electrodes and the second pair of scalp electrodes can be arranged according to the needs of target site targeted stimulation, which will not be described here.

[0079] The sixth positional relationship is shown in Figs. 1(a), 1(b) and 2(a), wherein the first electrode el is arranged on the scalp near the first side temporal lobe, the second electrode e2 is arranged on the scalp of the second side which is more forward than the first electrode; the third electrode e4 is arranged on the scalp near the second side temporal lobe, and the fourth electrode e3 is arranged on the scalp of the first side which is more forward than the third electrode e4.

[0080] In the above various electrode arrangement modes, in at least one of the first pair of scalp electrodes and the second pair of scalp electrodes, the anode is located at one side of the target part on the head of the subject, so that the anode is closer to the target part to be stimulated, and the energy loss due to diffusion in the brain tissue when the electric field reaches the target part is less, and the electric field intensity and current intensity acting on the target part can be greater. Thus, under the condition that the output energy of the transcranial electrical stimulation part is constant, a better treatment effect can be achieved.

[0081] In some embodiments, the current of the first pair of scalp electrodes 102 and the second pair of electrodes 102 is adjustable in the range of 0-10 mA. Specifically, by adjusting the relative current size of the first pair of scalp electrodes 102 and the second pair of scalp electrodes 102, the position of the target area can be flexibly adjusted. Taking the electrode arrangement mode of Figures 1(a) and 1(b) with the hippocampus as the target part as an example, by adjusting the relative current size of the first pair of scalp electrodes 102 and the second pair of scalp electrodes 102, even the various longitudinal parts of the hippocampus on the side where the target area traverses the electrodes e1 and e3 can be flexibly adjusted.

[0082] In some embodiments, each electrode is a flexible transparent electrode, which is attached to the scalp with a curved shape, such as the forehead, both mastoid processes, and the vicinity of the helix, and does not substantially block the transcranial light radiation of the phototherapy part, so that the transcranial light can still efficiently act on the frontal lobe and temporal lobe, etc. It should be understood that the position of the scalp electrode in the present application, such as the vicinity of the temporal lobe and the frontal lobe, is an important area for near-infrared light irradiation. By using the transmission and close attachment of the flexible transparent electrode, the attenuation of the near-infrared light on the light path of the electrode and the electrode-head connection area can be reduced, thereby ensuring the desired irradiation dose distribution in the important area.

[0083] Various flexible transparent electrodes can be used, such as but not limited to flexible nanometer metal mesh transparent electrodes, silver nanowire embedded silk fibroin electrodes, nanofiber-based flexible transparent electrodes, etc. The flexible transparent electrode can be a 2cm 2 -4cm 2 rounded rectangle or a circle, which can be different according to the exposed area of the scalp to be attached. For example, the flexible transparent electrode on the forehead can use a larger area, and the flexible transparent electrode at the mastoid process can use a smaller area, so as to ensure sufficient adhesion and minimize electrode folding or detachment while ensuring the amount of stimulation current.

[0084] In some embodiments, each electrode is adhered to the scalp via a conductive transparent gel that maintains a transmittance of 70-90% for near-infrared light of 620-1080 nm. For example, a conductive transparent gel that is tack-free yet firm, and pain-free to peel off can be used. Specifically, a conductive transparent gel that is body-temperature triggered to adhere, and automatically and painlessly peeled off when cooled can be employed.

[0085] Such a conductive transparent gel can be prepared based on a polyphenol-protein complexation strategy. For example, first, a polyphenol prepolymer (PGA) rich in phenolic and quinone groups is formed; second, the hydrogen bonding between the GelMA molecular chains is broken by using the multiple interactions of polyphenol groups during the gelation of double-bonded gelatin (GelMA), and the entanglement density of GelMA chains is adjusted to be body-temperature responsive, so that stability is maintained and the molecular chain mobility is enhanced at body temperature. When the hydrogel contacts the human skin, the body temperature triggers the phase transition, achieving efficient and rapid adhesion, and remaining stable for a long time. After simple cooling of the surface of the hydrogel, the hydrogen bonds between the GelMA molecular chains in the network are reformed, the adhesion is reduced, and non-injurious peeling is achieved. Further, the introduction of PGA adjusts the crosslinking mode of the GelMA network, giving the PGA-GelMA hydrogel a mechanical flexibility and high ductility that matches the skin tissue, avoiding injury caused by the pulling of the hydrogel when it is peeled off on the skin surface. In addition, the PGA-GelMA hydrogel also exhibits excellent biological activities such as anti-inflammatory, antioxidant, and anti-allergic activities, which can effectively avoid the skin irritation or allergic phenomena caused by traditional skin adhesives in long-term contact with the skin.

[0086] For another example, a highly transparent, self-adhesive, and thermally responsive conductive hydrogel based on dopamine-triggered gelation can be employed. On the one hand, dopamine acts as an initiator to initiate monomer polymerization to form a polymer skeleton, and on the other hand, it can act as a non-covalent crosslinking agent to dynamically adjust the crosslinking network of the hydrogel by using intermolecular forces. The dopamine content therein is as high as 50%, and it can maintain a transmittance of 70-90% for near-infrared light.

[0087] Now returning to FIG. 1(a) and FIG. 1(b), the phototherapy part 101 further comprises a head cap, and a plurality of near-infrared light source assemblies (as shown in FIG. 4 as 401) are arranged inside the head cap, and the plurality of near-infrared light source assemblies 401 are configured to emit pulsed light to the treatment subject, and the center wavelength of the pulsed light is 620-1080 nm.

[0088] In some embodiments, the irradiation range of the pulsed light of each near-infrared light source assembly 401 contains at least part of the hippocampus, and the power is large enough so that the near-infrared light acts on the deep subdural space and the hippocampus, and overlaps at the hippocampus to form a second overlapping area.

[0089] In some embodiments, the pulse light of each near-infrared light source assembly 401 can be focused to a second overlapping area of irradiation, which can at least partially overlap with the action area of the first electric field or the second electric field (as shown by the white circles in FIGS. 2(a)-2(d)). In this way, it is particularly suitable for the case where the lesion of brain disease develops to a target deep site. Taking Alzheimer's disease as an example, early Aβ plaques are aggregated in the neocortex, and then gradually spread to the hippocampus, and in the middle and late stages, significant deposition is also present in the hippocampus. In this way, the target focusing of the combined execution of focused phototherapy and transcranial alternating current stimulation on the hippocampus can reduce plaque deposition and inflammation in the hippocampus, and the latter can rhythmically regulate endogenous oscillations in the brain to form a neural clamp to achieve neuromodulation; further, the focused irradiation of pulse light in each direction, combined with the target reinforcement of transcranial alternating current stimulation, can ensure sufficient photoelectric synergistic dose of the hippocampus, and can particularly enhance the treatment effect on the middle and late stages of Alzheimer's disease. 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 have better effects on reducing the number of Aβ plaques, ATP levels, mitochondrial function, and cognitive improvement. In particular, near-infrared light in the 40 Hz gamma wave frequency band has been sufficiently studied to have good therapeutic effects on hippocampus-related brain diseases including AD.

[0090] In addition, although exemplary embodiments have been described herein, the scope of their protection is limited by the scope of the claims that follow this disclosure. That said, the claims herein are to be interpreted not only by the language used but also by the descriptions and proffered examples that follow, and by the illustrative examples that are set forth in the section entitled "Detailed Description of Illustrative Embodiments." In this regard, no single feature or combination of features should be deemed indispensable to the claimed subject matter, as the claims follow this disclosure. The inventor(s) reserves the right to amend the claims to particularly point out and distinctly claim what is hereby disclosed.

[0091] The above description is intended to be illustrative, and not restrictive. For example, the above-described examples (or one or more aspects thereof) can be used in combination with each other. Other embodiments can be used in addition to those described specifically herein, particularly to persons skilled in the art upon the reading and understanding of the foregoing description. In addition, in the detailed description above, various features can be grouped together to simplify the application. This should not be interpreted as an intent to require all of the claimed subject matter in any claim. On the contrary, inventive subject matter can be less than all of the disclosed embodiments. Thus, the claims following this disclosure, as examples or embodiments, are hereby incorporated into the detailed description, where each claim is independently a separate embodiment, and these embodiments can be combined with each other in various combinations or permutations. The scope of the application should be determined with reference to the claims that follow, along with the full scope of equivalents to which such claims are entitled.

[0092] The above embodiments are only exemplary embodiments of the present application, and are not intended to limit the present application. The scope of protection of the present application is defined by the claims. Those skilled in the art can make various modifications or equivalent replacements to the present application within the spirit and protection scope of the present application, and such modifications or equivalent replacements should also be considered to fall within the protection scope of the present application.

Claims

1. A transcranial physical stimulation device for treating a disease associated with a target site of the brain, characterized by, The transcranial physical stimulation device comprises at least a phototherapy part and an alternating transcranial electrical stimulation part, the phototherapy part is configured to irradiate transcranial near-infrared light to at least frontal lobe and temporal lobe of the head of the subject, or irradiate transcranial near-infrared light in an irradiation range containing the target part and its surrounding brain area; The alternating transcranial electrical stimulation part comprises a first pair of scalp electrodes and a second pair of scalp electrodes, the first pair of scalp electrodes comprises a first electrode and a second electrode, a first electric field of a first frequency is formed between the first electrode and the second electrode and acts on the target part; The second pair of scalp electrodes comprises a third electrode and a fourth electrode, a second electric field of a second frequency is formed between the third electrode and the fourth electrode and acts on the target part, the second frequency is greater than the first frequency, the ratio of the frequency difference to the first frequency is 8% or less and is within the range of 1 Hz-80 Hz.

2. The transcranial physical stimulation device of claim 1, wherein, The first frequency is 130 Hz to 200 Hz, and the frequency difference is 1 Hz-13 Hz.

3. The transcranial physical stimulation device of claim 1, wherein, The first frequency is 600 Hz or more, or 1000 Hz or more.

4. The transcranial physical stimulation device of claim 1, wherein, The first frequency is 30 Hz-100 Hz, and the frequency difference is 1 Hz-13 Hz.

5. The transcranial physical stimulation device according to any one of claims 1-4, characterized in that, The target part comprises a neural nucleus, or the target part comprises any one of basal ganglia, thalamus, amygdala, and hippocampus.

6. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The target part related disease of the brain comprises any one of Alzheimer's disease, dementia, anxiety disorder, post-traumatic stress disorder, cognitive impairment, Parkinson's disease, Huntington's disease, depression, bipolar disorder, sleep disorder, amyotrophic lateral sclerosis, autism spectrum disorder, attention deficit disorder in children, schizophrenia, and transient global amnesia.

7. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The phototherapy part irradiates transcranial near-infrared light at a third frequency, and the frequency difference between the first electric field and the second electric field satisfies any one of the following preset relationships: The third frequency is within the gamma wave frequency range, and the frequency difference is within any one of the delta wave frequency range, the theta wave frequency range, the alpha wave frequency range, and the gamma wave frequency range; The third frequency is within the alpha wave frequency range, and the frequency difference is within any one of the delta wave frequency range, the theta wave frequency range, the alpha wave frequency range, and the gamma wave frequency range.

8. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The first pair of scalp electrodes and the second pair of scalp electrodes are arranged according to any one of the following positional relationships: The first electrode and the second electrode are arranged on both sides of the longitudinal fissure of the brain of the head of the subject, and the third electrode and the fourth electrode are arranged on both sides of the longitudinal fissure of the brain of the head of the subject; The first electrode is arranged at a position corresponding to the frontal lobe of the head of the subject and is used as the third electrode, the second electrode is arranged at any one of a position corresponding to a temporal lobe of the head of the subject, a position corresponding to a junction of the frontal lobe and the temporal lobe, and a position corresponding to a junction of the occipital lobe and the temporal lobe, and the fourth electrode is arranged at any one of a position corresponding to a temporal lobe of the head of the subject, a position corresponding to a junction of the frontal lobe and the temporal lobe, and a position corresponding to a junction of the occipital lobe and the temporal lobe; The third electrode and the fourth electrode are arranged on both sides of the longitudinal fissure of the brain of the head of the subject, and the first electrode and the second electrode are arranged at a position corresponding to the frontal lobe of the head of the subject and at any one of a position corresponding to a temporal lobe of the head of the subject, a position corresponding to a junction of the frontal lobe and the temporal lobe, and a position corresponding to a junction of the occipital lobe and the temporal lobe; The first electrode and the second electrode are arranged on both sides of the longitudinal fissure of the brain of the head of the subject, and the third electrode and the fourth electrode are arranged at positions corresponding to the frontal lobe and any one of the positions corresponding to the temporal lobe, the junction of the frontal lobe and the temporal lobe, and the junction of the occipital lobe and the temporal lobe of the head of the subject, respectively. The first pair of scalp electrodes and the second pair of scalp electrodes are arranged at the forehead and around the ear. The first electrode is arranged on the scalp near the first temporal lobe, the second electrode is arranged on the scalp more forward than the first electrode, the third electrode is arranged on the scalp near the second temporal lobe, and the fourth electrode is arranged on the scalp more forward than the third electrode.

9. The transcranial physical stimulation device of claim 8, wherein, In at least one of the first pair of scalp electrodes and the second pair of scalp electrodes, the anode is arranged at a position corresponding to the target part of the head of the subject.

10. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The current of the first pair of scalp electrodes and the second pair of scalp electrodes is adjustable in the range of 0-10 mA.

11. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The frequency difference between the first electric field and the second electric field is 40 Hz.

12. The transcranial physical stimulation device according to any one of claims 1-4, wherein, Each electrode is a flexible transparent electrode.

13. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The light therapy unit further comprises a head cap, and a plurality of near-infrared light source assemblies are arranged inside the head cap and configured to emit near-infrared light with a wavelength of 620-1080 nm to the subject.

14. The transcranial physical stimulation device according to any one of claims 1-4, wherein, The target part includes a longitudinal target part of the hippocampus, and the stimulating current of the electrode corresponding to the longitudinal target part is smaller than the stimulating current of the electrode corresponding to other parts of the hippocampus.

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