Nerve stimulation control device including vibration device

Abstract

The present invention provides a nerve stimulation control device including a vibration device, wherein the nerve stimulation control device can be used as a medical device for improving cognitive function or memory by providing vibration stimulation to cranial nerves or the like. The nerve stimulation control device including the vibration device is characterized in that the vibration device includes a vibration probe, an integrated cone paper damper, an integrated bobbin, and a rubber frame, wherein the vibration probe, the integrated cone damper, and the integrated bobbin have a modular structure assembled through a single connection member, the integrated bobbin is accommodated in the integrated cone paper damper, and the rubber frame has a structure surrounding the integrated cone paper damper and the integrated bobbin.

Description

Neurostimulation control device including a vibration device

[0001] The present invention relates to a neural stimulation control device comprising a vibration device, and in particular, to a neural stimulation control device comprising a vibration device that can be utilized as a medical device for improving cognitive function or memory by providing vibration stimulation to brain nerves, etc.

[0002] Dementia is a disease characterized by a decline in learning and memory caused by various factors; among these, Alzheimer's disease (AD) is known as the most common form of dementia as a representative age-related degenerative brain disease.

[0003] Clinically, AD causes cognitive impairment, language and motor coordination, and behavioral changes, and neuropathological features include extracellular senile plaques composed of extracellular amyloid-βpeptide (Aβ), neuronal cells accompanied by neurofibrillary tangles, extensive loss of synapses, and alteration of the neurotransmitter system.

[0004] In particular, the loss of cholinergic cells in the basal forebrain causes the loss of neurotransmitters such as Acetylcholine (ACh) and acts as a decisive factor in the progression of dementia.

[0005] Recently, based on this cholinergic hypothesis, efforts have been made to treat dementia by inhibiting AcetylCholinesterase (AChE), an enzyme responsible for the degradation of ACh at synaptic sites. Various AChE inhibitors, such as physostigmine, tacrine, donepezil, galanthamine, huperzine A, and rivastigmine, which increase the utilization of ACh at cholinergic synapses in the central nervous system, have been approved by the U.S. Food and Drug Administration and are actually used in the treatment of dementia. Currently, new effective AChE inhibitors are continuously being developed, but their use is being restricted due to reports of serious side effects from synthetic AChE inhibitors.

[0006] Therefore, in recent years, natural-derived AChE inhibitors with relatively low side effects and various alternative medicine methods are being attempted.

[0007] Cholinergic neurons of the central nervous system are known to play a very important role in the regulation of cognitive functions, and ACh, a neurotransmitter of these cholinergic neurons, is synthesized and secreted by Choline Acetyltransferase (ChAT) and is responsible for the regulation of various central and peripheral cognitive functions such as appropriate timing, learning, attention, and memory.

[0008] Therefore, damage to cholinergic neurons is known to reduce the secretion of ACh at synapses, leading to learning and memory impairments. Furthermore, since the duration of action of these AChs is dependent on AChE, the enzyme responsible for the degradation of ACh after its release, inhibition of AChE activity has been used as an important target in the development of treatments for various dementias including AD, traumatic brain injury, and delirium, and has also been considered to be very useful for the treatment of schizophrenia.

[0009] Since ChAT is responsible for the synthesis of ACh, it is used as a very important indicator of the activity of cholinergic neurons in the central and peripheral nervous systems in opposition to AChE. In other words, ChAT activity is directly associated with cognitive impairment and is significantly reduced in the elderly population.

[0010] In this context, to evaluate the effect of improving cognitive function, an animal model of memory impairment due to cholinergic neuronal dysfunction without accompanying degeneration of the neurons themselves is required, and the SCP-induced memory impairment C57BL / 6 mouse model is used as the animal model that best fits this purpose.

[0011] SCPs are non-selective Muscarinic ACh Receptor (MAChR) antagonists that act primarily on M1AChRs and M2AChRs and are known to cause learning and short-term memory impairments in rodents and humans. Therefore, SCP-induced amnesia (forgetfulness) rodent models are commonly used for screening anti-amnestic drugs, with C57BL / 6 mice being the most frequently utilized.

[0012] It is known that neurons in the hippocampus and the frontal cortex are sensitive to SCP, and SCP is also known to significantly inhibit the expression of memory-related genes in the hippocampus, including Brain-Derived Neurotrophic Factor (BDNF), Phosphoinositide 3-Kinase (PI3K), protein kinase B (Akt), extracellular signal regulated kinase (ERK) 1 and 2, cAMP response element-binding protein (CREB), and calcium / calmodulin-dependent protein kinase (CaMK IV).

[0013] Currently, vibration is known to play a very important role in human life, potentially being both harmful and beneficial to the human body. Important parameters of vibration stimulation are frequency and proximity to tissues and organs; despite its diverse clinical applications, the precise effects of vibration stimulation on the human body have not yet been fully elucidated.

[0014] Vibratory stimulation of the whole body or local organs is already commonly applied in clinical practice; in particular, pulse stimulation of the brain has been shown to improve motor skills and reduce memory impairment, and the regenerative effects of vibrational stimulation on skeletal muscle and bone tissue are also well known.

[0015] To date, research on vibratory stimulation has primarily focused on skeletal muscle and bone tissue, and while studies on nervous tissue are relatively scarce, recent research on vibratory stimulation in the nervous system suggests that it can have positive effects on mood, the autonomic nervous system, cognitive function, and brain function. Mechanical signals provide cues that cells can detect as a result of applied force, and stimulation initiates mechanical responses such as stress or intracellular forces; subsequently, cells convert mechanical stimuli into biochemical outputs known as mechanochemical signals.

[0016] In this process, highly complex bioactive reactions occur, such as the release of various growth factors and the activation of mechanically sensitive kinases like Src, FAK, and extracellular signal-regulated kinase (ERK), which activate the secondary total system.

[0017] Therefore, mechanical signal stimulation has been considered to have great potential for regulating biochemical signaling pathways induced by soluble factors for the regulation of stem cell differentiation. In particular, subsonic vibration is known to promote the differentiation of human umbilical cord-derived mesenchymal stem cells into neurons through ERK activation, and 40 Hz auditory stimulation is known to improve cognitive function in AD mouse models.

[0018] The present invention aims to provide a neurostimulation control device comprising a vibration device that can be utilized as a medical device for improving cognitive function or memory by providing vibration stimulation that does not cause stress or side effects, particularly vibroacoustic stimulation.

[0019] The present invention aims to provide a neural stimulation control device comprising a vibration device that can provide vibration tactile sensation with minimized noise generation and easy assembly by designing the cone damper and bobbin, among the main components constituting the vibration device, as an integrated unit, and by adopting a modular structure in which the vibration probe, the integrated cone damper, and the bobbin are assembled with a single connecting member.

[0020] The present invention aims to provide a nerve stimulation control device comprising a vibration device that can compensate for the reduction in vibration tactile sensation transmitted by the compression phenomenon when a vibration probe comes into contact with the human body by configuring the integrated cone damper and lower body, etc., to be wrapped with a rubber frame that acts as a spring.

[0021] The problems to be solved by the present invention are not limited to those mentioned above, and other problems not mentioned will be clearly understood by those skilled in the art from the description below.

[0022] A neurostimulation control device comprising a vibration device according to one embodiment of the present invention may include a vibration device comprising a vibration probe, an integrated cone damper, an integrated bobbin, and a rubber frame, wherein the vibration probe, the integrated cone damper, and the integrated bobbin are a modular structure assembled through a single connecting member, the integrated bobbin is accommodated within the integrated cone damper, and the rubber frame is a structure that surrounds the integrated cone damper and the integrated bobbin.

[0023] Additionally, the vibration probe may include a vibration device comprising a plate portion, a coupling projection portion protruding from one surface of the plate portion, and a first through hole penetrating the center of the plate portion and the coupling projection portion.

[0024] In addition, the integrated cone damper may include a vibration device comprising a body portion in the shape of a tube, and a cone plate having a hollow hole formed therein and a rim area inserted along the circumferential direction of one end portion of the body portion.

[0025] In addition, the integrated bobbin may include a vibration device comprising a support plate portion, a coupling portion formed protruding from one surface of the support plate portion and having a second through hole formed therein, and a bonding type voice coil coupled to the other surface of the support plate portion.

[0026] Additionally, the above connecting member may include a vibration device having male screw threads formed on its outer surface, which penetrates the hollow hole formed in the integrated cone damper while being engaged with the female screw threads formed in the first through hole provided in the vibration probe, and which is engaged with the female screw threads formed in the second through hole provided in the integrated bobbin.

[0027] Additionally, the coupling projection is provided with a first contact end at one end thereof that contacts one surface of the cone plate, and the coupling portion is provided with a second contact end at one end thereof that contacts the other surface of the cone plate, and an insertion end extending from the second contact end and sequentially inserted into the hollow hole and the first through hole, wherein the first contact end and the second contact end have the same outer diameter, and the first through hole has an inner diameter larger than the second through hole, and the connecting member may include a first male screw thread extending from the head portion and having an outer diameter corresponding to the first through hole, and a second male screw thread extending from the first male screw thread and having an outer diameter corresponding to the second through hole.

[0028] Additionally, the vibration device may further include a lower body that is detachably fitted to one side of the body portion of the integrated cone damper, has a tubular shape with one side completely open, and forms an internal receiving space; a magnetic body that is fixedly installed on the other side of the lower body to generate magnetic force; and a cap magnetic body that is installed on one side of the magnetic body to induce the magnetic force of the magnetic body to be concentrated on the bonding type voice coil.

[0029] Additionally, the lower body may include a lower body having a locking groove formed along the circumferential direction on the outer surface of one end, and the body portion of the integrated cone damper may include a pair of cut portions formed at positions facing each other to have an elastic structure, and a locking projection formed on the inner surface of the cut portions to engage with the locking groove.

[0030] Additionally, the rubber frame may include a vibration device having a tubular shape with one side completely open to be fitted and wrapped around the body part and the lower body, and having at least one pair of elastic guide grooves formed along the longitudinal direction at positions facing each other on the outer surface to facilitate fitting and coupling to the body part and the lower body.

[0031] Additionally, an elastic member that acts as a spring in the up and down direction is formed on the other side of the rubber frame, and the elastic member includes a plurality of cross-sections including a connecting cross-section extending from the inner circumference of the other side, a first inclined cross-section extending downwardly from the connecting cross-section, a second inclined cross-section extending upwardly from the first inclined cross-section, a horizontal cross-section extending horizontally from the second inclined cross-section, a lower edge cross-section protruding to the other side from the boundary between the first inclined cross-section and the second inclined cross-section, a central space portion partitioned by the lower edge cross-section, the second inclined cross-section, and the horizontal cross-section, and an outer space portion partitioned by the first inclined cross-section and the second inclined cross-section. The elastic member may include a vibration device formed as a three-dimensional geometric structure in which the plurality of cross-sections are rotated around a virtual central axis of the rubber frame.

[0032] Additionally, the vibration device further includes a substrate installed on a mounting portion provided on one side of the integrated cone damper to output a signal input from the outside to the bonding type voice coil, and the rubber frame may include a vibration device having an opening formed therein that exposes the substrate to the outside when fitted into the integrated cone damper.

[0033] In addition, the above vibration device may include a vibration device that induces vibration stimulation.

[0034] In addition, the above vibration device may include a vibration device that induces vibration stimulation through a direct transmission method.

[0035] In addition, the above-mentioned neurostimulation control device may include a vibration device used for the improvement or treatment of cognitive impairment.

[0036] In addition, the above-mentioned cognitive impairment may include a vibration device including attention deficit hyperactivity disorder (ADHD), cognitive impairment accompanied by sarcopenia, neurodegenerative disease, or mild cognitive impairment.

[0037] In addition, the above-mentioned neurodegenerative disease may include a vibrating device comprising Parkinson's disease, traumatic brain injury, multiple sclerosis, drug addiction, alcohol addiction, neurodegenerative conditions, brain inflammation, multi-organ atrophy, Huntington's disease, amyotrophic lateral sclerosis (ALS), chronic traumatic brain lesion, motor neuron disease, dementia, Creutzfeldt-Jakob disease, or normal pressure hydrocephalus.

[0038] Additionally, the above dementia may include a vibrating device comprising Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, AIDS-induced dementia, mixed dementia, age-related cognitive impairment, or age-related memory impairment.

[0039] In addition, the above-mentioned neurostimulation control device may include a vibration device used for the improvement or treatment of neuropsychiatric symptoms or cognitive impairment accompanying a stroke.

[0040] In addition, the above-mentioned neurostimulation control device may include a vibration device used for the improvement or treatment of neurodevelopmental disorders, post-traumatic stress disorder, or sleep disorders.

[0041] In addition, the above-mentioned neurodevelopmental disorder may include a vibrating device including dyslexia, cerebral palsy, or autism spectrum disorder.

[0042] A neurostimulation control device comprising a vibration device used for the prevention, alleviation, or treatment of cognitive decline or neurodegenerative diseases according to another embodiment of the present invention can deliver non-invasive vibratory stimulation to a brain region of an individual to induce mechanotransductive signaling sensitive to vibration frequency.

[0043] In addition, the non-invasive vibration stimulation may include mechanical vibration stimulation configured to mediate the mechanotransmission signal within a neuron or glial cell by activating mechanosensitive channels at the level of the cell membrane or cytoskeleton.

[0044] In addition, the vibration frequency may have a range of 1 Hz to 150 Hz to include a frequency band that maximizes the mechanical transmission response to the brain region.

[0045] In addition, the above vibration frequency may include frequency bands of 40 Hz and 80 Hz.

[0046] In addition, the mechanical vibration stimulation may be configured to be delivered via auditory or somatosensory pathways to improve interneuronal connectivity, synaptic plasticity, or cerebral perfusion.

[0047] In addition, the above-mentioned mechanical signal may be configured to increase the acetylcholine (ACh) content in the hippocampal tissue of the brain region and decrease acetylcholinesterase (AChE) activity.

[0048] In addition, the above-mentioned mechanical delivery signal may be configured to reduce lipid peroxidation in the cerebral cortex tissue of the brain region and activate the endogenous antioxidant defense system (GSH, SOD, or CAT).

[0049] In addition, the above-mentioned mechanical signal may be configured to increase the mRNA expression of at least one gene selected from the group consisting of BDNF, CREB, ChAT, PI3K, Akt, ERK, or CaMK IV in the hippocampal tissue of the brain region.

[0050] A neurostimulation control device including a vibration device according to the present invention can be utilized as a medical device for improving cognitive function or memory by providing vibration stimulation that does not cause stress or side effects.

[0051] A neurostimulation control device including a vibration device according to the present invention can provide vibration stimulation with minimized noise generation and easy assembly by designing the cone damper and bobbin, among the main components constituting the vibration device, as an integrated unit, and by adopting a modular structure in which the vibration probe, the integrated cone damper, and the bobbin are assembled with a single connecting member.

[0052] A nerve stimulation control device including a vibration device according to the present invention is configured to wrap an integrated cone damper and a lower body, etc., with a rubber frame that acts as a spring, thereby compensating for the reduction of vibration stimulation transmitted due to the compression phenomenon when the vibration probe comes into contact with the human body.

[0053] The effects of the present invention are not limited to those mentioned above, and other unmentioned effects will be clearly understood by those skilled in the art from the description below.

[0054] FIG. 1 is a drawing illustrating a vibration device in a nerve stimulation control device including a vibration device according to the present invention.

[0055] Figures 2 and 3 are disassembled drawings of the vibration device shown in Figure 1.

[0056] Figures 4 and 5 are drawings showing the longitudinal section of the vibration device illustrated in Figure 1.

[0057] FIG. 6 is a cross-sectional view illustrating the upper and lower springs acting on a rubber frame in a nerve stimulation control device including a vibration device according to the present invention.

[0058] FIG. 7 is a diagram illustrating the configuration of a nerve stimulation control device including a vibration device according to the present invention.

[0059] FIG. 8 is a block diagram illustrating the configuration of a nerve stimulation control device including a vibration device according to the present invention shown in FIG. 7.

[0060] FIGS. 9 and 10 are drawings illustrating the experimental design used in an experimental example and the provision of vibration stimulation to an experimental rat through the neural stimulation control device according to the present invention, including a vibration device.

[0061] FIG. 11 is a graph showing the change in body weight of an experimental mouse in an experimental example, in a neural stimulation control device including a vibration device according to the present invention.

[0062] FIGS. 12 and 13 are graphs showing the step delay time of a passive avoidance test of an experimental rat in an experimental example and the escape delay time of an experimental rat in a water maze test, in a neural stimulation control device including a vibration device according to the present invention.

[0063] FIGS. 14 and 15 are photographs showing the overall shape of the brain of an experimental mouse and the overall shape of the adrenal gland of an experimental mouse in an experimental example, in a neural stimulation control device including a vibration device according to the present invention.

[0064] FIGS. 16 to 18 are graphs showing serum corticosterone levels of experimental mice, hippocampal Ach content of experimental mice, and hippocampal AchE content of experimental mice in an experimental example, in a neurostimulation control device including a vibration device according to the present invention.

[0065] FIGS. 19 to 22 are histopathological images of the brain-hippocampus of an experimental mouse, an image of a caspase-3 immunolabeled pyramidal cell in the brain-hippocampus DG region of an experimental mouse, an image of a c-Fos immunopositive pyramidal cell in the brain-hippocampus DG region of an experimental mouse, and a histopathological image of the adrenal gland of an experimental mouse, in a neural stimulation control device including a vibration device according to the present invention.

[0066] FIGS. 23 to 27 relate to an experimental example of a cell experiment in a neural stimulation control device including a vibration device according to the present invention, and include a diagram of the cell experiment configuration for vibration stimulation, a conceptual diagram schematically explaining the overall contents of the vibration cell experiment, and a graph showing the experimental results.

[0067] A neurostimulation control device including a vibration device according to the present invention can be used as a device for improving cognitive function, such as a medical device. However, the device according to the present invention can be used not only as a medical device requiring approval from regulatory agencies in each country, such as the FDA, for use, but also as a consumer product that does not require such regulatory procedures as long as the law permits.

[0068] The terms “cognitive function” or “cognition” as used in the present invention may refer to various functions of the human brain, such as, for example, memory, language ability, the ability to perceive time and space, attention, judgment, and abstract thinking ability.

[0069] Cognitive function can be classified into six categories according to DSM-5. DSM-5 is the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, published by the American Psychiatric Association (APA) as a manual that provides diagnostic criteria for mental disorders, defines various symptoms and disorders related to mental disorders, and presents detailed criteria for diagnosing them.

[0070] The DSM-5 defines cognitive function as a total of six categories, including complex attention, executive function, learning and memory, language, perceptual-motor control, and social cognition. Accordingly, cognitive function in the present invention can be understood as including at least one of the above six cognitive domains.

[0071] The term “Cognitive disorders (CD)” as used in this invention refers to a state of reduced cognitive function, meaning any disorder that significantly impairs an individual’s cognitive function to the extent that they cannot function normally in society without treatment, and may also be referred to as neurocognitive disorders (NCD).

[0072] CD or NCD is a disorder occurring in one or more of the following cognitive functions, including but not limited to one or more of attention disorder, persistent attention disorder, attention deficit hyperactivity disorder (ADHD), working memory disorder, episodic memory disorder, executive function disorder, learning disability, language disorder, psychomotor function disorder, or cognitive impairment accompanied by sarcopenia.

[0073] Representative examples of cognitive impairment include neurodegenerative diseases. The term “neurodegenerative disease” as used in the present invention includes, but is not limited to, Parkinson’s disease (PD), traumatic brain injury (TBI), multiple sclerosis, drug intoxication, alcohol intoxication, neurodegenerative conditions, brain inflammation, multi-organ atrophy, Huntington’s disease, amyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy (CTE), motor neuronosis (e.g., amyotrophic lateral sclerosis, spinal cord injury, spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), Alzheimer’s disease (AD), AIDS-induced dementia, vascular dementia, frontotemporal dementia (FTD), Lewy body dementia (DLB), various types of dementia such as age-related cognitive impairment, age-related memory impairment, or mixed dementia, Creutzfeldt-Jakob disease, or normal pressure hydrocephalus.

[0074] Dementia may be associated with a non-limiting neurological and / or psychiatric condition including brain tumors, brain lesions, epilepsy, multiple sclerosis, Down syndrome, Rett syndrome, progressive supranuclear palsy, frontal lobe syndrome, schizophrenia, traumatic brain injury, or Alzheimer's disease (AD).

[0075] Alzheimer's disease (AD) is the most common neurodegenerative disease in developed countries and is characterized by the accumulation of amyloid plaques. Amyloid plaques consist of neurofibrillary tangles (NFTs) composed of Aβ peptides and tau proteins. Clinically, AD is associated with progressive cognitive impairment, including the loss of memory, function, language ability, judgment, and executive function. In advanced stages, AD can cause severe behavioral symptoms.

[0076] Vascular dementia, also referred to as cerebrovascular dementia, is caused by cerebrovascular disease (e.g., infarction of the cerebral hemispheres). It generally follows a pathway with varying periods of improvement and stepwise deterioration. Vascular dementia may include disorientation, impaired memory, or impaired judgment to an unlimited degree. Vascular dementia can be triggered by various vascular causes, such as ascites, systemic lupus erythematosus, infectious vasculitis (e.g., Lyme disease), recurrent intracerebral hemorrhage, or stroke.

[0077] Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder. Individuals with FTD generally exhibit prominent behavioral and personality changes accompanied by speech disorders.

[0078] Lewy body dementia is a type of dementia that shares characteristics with Alzheimer's disease, Parkinson's disease, and the early development of hallucinations, and may include symptoms such as daily fluctuations in symptom severity.

[0079] The cognitive impairment in the present invention may also include mild cognitive impairment (MCI), which refers to a state in which there is a slight decline in an individual's cognitive function, particularly memory, without causing significant hindrance to performing daily life activities.

[0080] The neurostimulation control device of the present invention may be used to prevent, alleviate, or treat cognitive impairment. In one embodiment, the neurostimulation control device of the present invention may be used for the treatment or use of cognitive impairment by including a characteristic vibration device.

[0081] The terms “treatment,” “treat,” and “treating” as used in the present invention refer to the improvement, prevention, or reversal of a disease or disorder, such as cognitive impairment, in a subject. In one embodiment, the terms “treatment,” “treat,” and “treating” may also refer to the inhibition or delay of the progression of a disease or disorder in a subject.

[0082] In other embodiments, these terms refer to the delay of the onset of a disease or disorder in the subject. In some embodiments, the compounds of the present invention are administered as a preventive measure. In this context, the terms "treatment" and "treat" may correspond to the terms "prevention" and "prevent," which refer to the reduction of the risk of acquiring a specific disease or disorder in the subject.

[0083] The term "object" as used in the present invention refers to a living organism capable of developing cognitive impairment, such as a monkey, cow, sheep, horse, pig, cattle, goat, dog, cat, mouse, rat, or mammal such as a human. In a preferred embodiment, the object is a human.

[0084] The term “neuromodulation” as used in this invention refers to inducing a specific response or improving function by regulating the activity of the nervous system through various stimuli, such as electrical, magnetic, chemical, or vibratory stimuli.

[0085] This can be utilized in the treatment of various neurological and psychiatric disorders through the stimulation of sensory nerves and the central nervous system. Accordingly, neurostimulation modulation plays an important role in improving patients' quality of life by regulating the function of the nervous system through non-invasive or minimally invasive methods, and can be used in various fields such as cognitive improvement, rehabilitation therapy, pain management, or mental health care.

[0086] In one embodiment, the neurostimulation modulation may be non-invasive. As used in the invention, the term "non-invasive" refers to devices, methods, and systems that do not require surgical intervention or manipulation of the body, e.g., injection or implantation of a composition or device. For instance, the stimulation may be visual (e.g., flashing light), auditory (e.g., sound vibration, acoustics), and / or tactile (e.g., mechanical stimulation by force, vibration, or movement).

[0087] In one embodiment, the non-invasive stimulation includes, but is not limited to, tDCS (transcranial direct current stimulation), tACS (transcranial alternating current stimulation), TMS (transcranial magnetic stimulation), Focused Ultrasound, Binaural beat sound, Photobiomodulation, vagus nerve stimulation, Vibroacoustic stimulation, Vibrotactile stimulation, etc. Preferably, the stimulation of the present invention may be a vibrating acoustic stimulation.

[0088] In other embodiments, neurostimulation modulation may be invasive or at least partially invasive. For example, visual, auditory, and / or tactile stimulation may be used with the injection or implantation of a composition (e.g., a photosensitive protein) or a device (e.g., an integrated optical fiber and a solid-state light source).

[0089] In another embodiment, neurostimulation control may involve the combined use of invasive and non-invasive methods.

[0090] In a preferred embodiment, neurostimulation control can be induced through vibratory stimulation, and in particular, through vibroacoustic stimulation.

[0091] The term “Vibroacoustic stimulation (VAS)” as used in this invention refers to a method of stimulating the brain using sound and vibration, and includes a method of stimulating sensory nerves using mechanical vibration on the surface of the skin.

[0092] Acoustic vibration stimulation is combined with music listening and therapy and is commonly composed of low-frequency, sinusoidal sound vibrations (20-150 Hz). Acoustic vibration stimulation is understood to include the therapeutic benefits of physical and auditory perception of music, namely auditory and tactile sounds.

[0093] At this time, vibration is transmitted through a vibration device according to the present invention, and a subject such as a patient can listen to preferred music to aid in achieving a predefined treatment goal. Accordingly, the “acoustic vibration stimulation” used in the present invention can also be understood as integrating physicoacoustic therapy, vibroacoustic therapy, vibrotactile stimulation, low-frequency sound stimulation, and rhythmic sensory stimulation.

[0094] In the present invention, “acoustic vibration stimulation” may also be simply referred to as “vibration stimulation,” and unless otherwise specifically distinguished in the present invention, “vibration stimulation” shall be understood to refer to “acoustic vibration stimulation.”

[0095] This provides sensory information through vibrations of various frequencies and intensities, and simultaneously provides musical stimulation, which can induce a response in the nervous system. In other words, acoustic vibration stimulation stimulates tactile receptors on the skin and further stimulates auditory receptors through sound, thereby inducing neural signals, and these neural signals are transmitted to the central nervous system to induce specific responses.

[0096] Accordingly, acoustic vibration stimulation can be considered a form of neurostimulation modulation and can be used for improving cognitive function, alleviating pain, and neurorehabilitation through the activation of neural circuits.

[0097] Methods of stimulating tactile receptors of the skin through acoustic vibration stimulation may include a direct transmission method in which vibration is transmitted by direct contact with the skin surface, an indirect transmission method in which a gap exists between the skin surface and the stimulation source, etc. In a preferred embodiment of the present invention, acoustic vibration stimulation may refer to a direct transmission method.

[0098] Accordingly, the neural stimulation control device of the present invention can produce effects such as improvement of cognitive function by inducing vibration stimulation, particularly acoustic vibration stimulation, to brain nerves, etc. In one embodiment, the neural stimulation control device of the present invention may induce acoustic vibration stimulation through a direct transmission method. In another embodiment, the neural stimulation control device of the present invention may induce acoustic vibration stimulation through an indirect transmission method.

[0099] In one embodiment, the neurostimulation control device of the present invention may be a head-mounted vitrotactile stimulation system (HVSS). Here, the expression "vitrotactile stimulation" is used to emphasize the stimulation method of stimulating through tactile receptors of the skin among the acoustic vitro stimulation of the present invention, and it goes without saying that the HVSS can also transmit sound such as music. Accordingly, the HVSS may adopt a direct transmission method.

[0100] In one embodiment, the HVSS may have a specific embodiment described in the drawings of the present invention, for example, any one of the configurations in FIGS. 1 to 7. In a preferred embodiment, the HVSS may be a device having a perspective view, an exploded view, and a longitudinal section view shown in FIGS. 1 to 7.

[0101] The HVSS used in Experimental Example 1 of the present invention is also according to a preferred embodiment, and HVSS20 should be interpreted as a system that applies vibration stimulation of about 20 Hz, HVSS40 as a system that applies stimulation of about 40 Hz, and HVSS80 as a system that applies stimulation of about 80 Hz. Similarly, HVSS60 can also be understood as a device having the configuration of a preferred embodiment and a system that applies vibration stimulation of about 60 Hz.

[0102] The term "about" as used in the present invention means within 10%, preferably within 5%, and more preferably within 1% of a given numerical value or range.

[0103] In one embodiment, the present invention provides a neurostimulation control device, method, and system for inducing vibration stimulation. The neurostimulation control device, method, and system according to the present invention can induce vibration stimulation of about 20 to 150 Hz, preferably about 20 to 80 Hz, e.g., about 20, 30, 40, 50, 60, 70, or 80 Hz. Most preferably, it may induce vibration stimulation of about 40 Hz or 80 Hz.

[0104] In another embodiment, the present invention provides a method for controlling neural stimulation in a subject, comprising inducing vibrational stimulation in the subject's brain by using a neural stimulation control device, method, or system.

[0105] In another embodiment, the present invention provides a method for improving cognitive function in a subject, comprising inducing vibrational stimulation in the subject's brain by using a neurostimulation control device, method, or system.

[0106] In another embodiment, the present invention provides a method for preventing, alleviating, and / or treating cognitive impairment in a subject, comprising inducing vibrational stimulation in the subject's brain by using a neurostimulation control device, method, or system.

[0107] In one embodiment, the neural stimulation control according to the present invention, particularly vibration stimulation, may not cause a change in body weight in a subject. In one embodiment, the neural stimulation control according to the present invention, particularly vibration stimulation, may not cause a significant change in absolute and relative brain weight in a subject.

[0108] In one embodiment, the neural stimulation control according to the present invention, particularly vibratory stimulation, may not cause significant changes in the absolute and relative weight of the adrenal gland in the subject. In one embodiment, the neural stimulation control according to the present invention, particularly vibratory stimulation, may not cause significant changes in the blood corticosterone content in the subject.

[0109] In one embodiment, neural stimulation control according to the present invention, particularly vibratory stimulation, can increase the ACh content in hippocampal tissue in a subject and cause a decrease in AChE activity. In one embodiment, neural stimulation control according to the present invention, particularly vibratory stimulation, can decrease MDA content and lipid peroxidation in cerebral cortical tissue in a subject, and increase the activity of endogenous antioxidant GSH, endogenous antioxidant enzyme SDO, and CAT.

[0110] In one embodiment, the neurostimulation control according to the present invention, particularly vibratory stimulation, can increase the expression of ChAT and memory-related genes—BDNF, PI3K, Akt, ERK1 and 2, CREB, and CaMK IV mRNA in hippocampal tissue in a subject.

[0111] In one embodiment, the neural stimulation control according to the present invention, particularly the vibratory stimulation, can cause histopathological changes in the cerebral hippocampus region of a subject, for example, may show an increase in the thickness of hippocampal CA1 to CA2, normal DG region, and the number of c-Fos immune-responsive pyramidal neurons, along with a decrease in the number of cleaved caspase-3 immune-responsive pyramidal neurons in the hippocampal DG region.

[0112] In one embodiment, the neural stimulation control, particularly vibration stimulation, according to the present invention may not cause significant histopathological changes in the adrenal gland of the subject. In one embodiment, the subject may be provided with neural stimulation control, particularly vibration stimulation, for about 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, or longer.

[0113] In one embodiment, the subject may be provided with neurostimulation control, in particular, vibration stimulation, for about 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour.

[0114] Terms and words used in this specification and claims should not be interpreted as being limited to their ordinary or dictionary meanings, but should be interpreted in a meaning and concept consistent with the technical spirit of the invention, based on the principle that the inventor can appropriately define the concept of the terms to best describe his invention.

[0115] FIG. 1 is a drawing illustrating a vibration device in a nerve stimulation control device including a vibration device according to the present invention. FIG. 2 and FIG. 3 are exploded drawings of the vibration device shown in FIG. 1. FIG. 4 and FIG. 5 are drawings illustrating longitudinal cross-sections of the vibration device shown in FIG. 1. FIG. 6 is a cross-sectional view illustrating the upper and lower springs acting on a rubber frame in a nerve stimulation control device including a vibration device according to the present invention. FIG. 7 is a drawing illustrating the configuration of a nerve stimulation control device including a vibration device according to the present invention. FIG. 8 is a block diagram illustrating the configuration of a nerve stimulation control device including a vibration device according to the present invention shown in FIG. 7.

[0116] Referring to FIGS. 1 to 8, the nerve stimulation control device (200) according to the present invention is equipped with a vibration device (100) and can provide stimulation by vibration.

[0117] The vibration device (100) according to the present invention may be configured to include a vibration probe (120), an integrated cone damper (130), an integrated bobbin (140), a lower body (160), a magnetic body (150), a cap magnetic body (155), and a rubber frame (170).

[0118] The vibration probe (120) transmits vibration stimulation generated from the vibration device (100) to the outside to stimulate nerves through the skin or scalp of the human body, and may include a plate portion (121), a coupling projection portion (123) protruding from the lower surface of the plate portion (121), and a first through hole (121a) penetrating the center of the plate portion (121) and the coupling projection portion (123).

[0119] The plate portion (121) may have a plurality of circular grooves (121b) formed on its upper surface, forming concentric circles centered around a first through hole (121a), and the circular grooves (121b) may serve to reduce the contact surface with the body while increasing the vibration stimulation transmission rate or intensity at the contact surface.

[0120] The connecting projection (123) is formed with a tapered structure that narrows as it goes downward from the plate portion (121), and a first contact end (124) that contacts one surface of the cone plate (135) may be provided at the lower end.

[0121] The integrated cone damper (130) may include a body portion (131) in the shape of a tube, and a cone plate (135) in which a rim area is inserted along the circumferential direction from the upper portion of the body portion (131) and a hollow hole (135a) is formed. For example, the cone plate (135) may be joined by insert injection molding on the inner surface of the body portion (131). However, it is not limited thereto.

[0122] While a structure in which the upper bracket, cone damper, and bobbin are joined through a 4-point bolting operation generates noise, the present invention adopts an integrated cone damper (130) in which the 4-point bolting operation is eliminated, thereby enabling the output of AC vibrations (sine wave, square wave, or triangular wave, etc.) generated in the vertical direction by the interaction between the magnetic material and the voice coil without noise.

[0123] The body portion (131) may have a pair of cut portions (132) formed to have an elastic structure in a facing position, and a catch (132a) may be formed on the inner surface of the cut portions (132).

[0124] A mounting portion (133) is installed on one side of the outer surface of the body portion (131), and a board (137) that outputs a signal input from the outside (AMP, etc.) to a bonding type voice coil (145) may be mounted thereon. An input line and an output line may be connected to the board (137).

[0125] The cone plate (135) serves to generate vertical vibrations using a magnetic field generated by the interaction between the magnetic body (150) and the voice coil (145), and may be structured such that a plurality of damper parts (135b) extend from the hollow hole (135a) toward the edge.

[0126] The integrated bobbin (140) is received within the integrated cone damper (130) and may include a support plate portion (141), a coupling portion (143) formed protruding from the upper surface of the support plate portion (141) and having a second through hole (141a) formed therein, and a bonding type voice coil (145) coupled to the lower surface of the support plate portion (141).

[0127] The voice coil (145) can generate a magnetic field by receiving power and interacting with the magnetic body (150). The coupling portion (143) may be provided with a second contact end (143a) at its upper end that contacts the lower surface of the cone plate (135), and an insertion end (143b) that extends from the second contact end (143a) and is sequentially inserted into the hollow hole (135a) and the first through hole (121a).

[0128] Unlike a wound voice coil which is manufactured by winding directly onto a bobbin, a bonded voice coil (145) can be manufactured in advance in a tubular shape using an adhesive resin or the like. The bonded voice coil (145) can be inserted into a circular groove (141b) formed on the lower surface of a support plate (141) and then fixed with an adhesive or the like.

[0129] The integrated bobbin (140) can be manufactured in a compact size compared to the existing bobbin and wound voice coil, and can provide a structure that can stabilize heat generation due to vibration at a rated output of 0.5W by changing the impedance to 3.3 to 8Ω.

[0130] The vibration device (100) according to the present invention may include a modular structure in which a vibration probe (120), an integrated cone damper (130), and an integrated bobbin (140) are assembled through a single connecting member (110). Due to this modular structure, the assembly process can be simplified and the product can be miniaturized.

[0131] The connecting member (110) may be exemplified as a hexagonal wrench bolt having male threads formed on its outer surface, and while fastened to the female threads formed in the first through hole (121a) provided in the vibration probe (120), it may pass through the hollow hole (135a) formed in the integrated cone damper (130) and be fastened to the female threads formed in the second through hole (141a) provided in the integrated bobbin (140).

[0132] The first contact end (124) and the second contact end (143a) may be configured to have the same outer diameter, and the first through hole (121a) may be configured to have an inner diameter larger than that of the second through hole (141a). In this case, the connecting member (110) may be exemplified as being composed of a first male screw thread (112) extending from the head portion (111) and having an outer diameter corresponding to the first through hole (121a), and a second male screw thread (113) extending from the first male screw thread (112) and having an outer diameter corresponding to the second through hole (141a).

[0133] A coupling structure through such a single connecting member (110), that is, the connecting member (110) is sequentially coupled to the first through hole (121a) of the vibration probe (120), the hollow hole (135a) of the integrated cone damper (130), and the second through hole (141a) of the integrated bobbin (140), and at the same time, the second contact end (143a) formed at the top of the coupling part (143) of the integrated bobbin (140) is inserted into the first through hole (121a) of the vibration probe (120) and screw-coupled, and the first contact end (124) of the vibration probe (120) and the second contact end (143a) of the integrated bobbin (140), having corresponding outer diameters, are in contact with each other with the hollow hole (135a) in between, so a vibration stimulus with minimized noise generation can be output.

[0134] The lower body (160) can be detachably fitted and coupled to one side of the body portion (131) of the integrated cone damper (130), and is in the shape of a tube with the upper side completely open and the lower side having a bottom surface (162) with a through hole (162a) formed in the center, and can have a receiving space provided inside.

[0135] A lower body (160) has a magnetic body (150) and a catch groove (161) formed along the circumferential direction on the outer surface of one end, and the catch groove (161) can be coupled to a catch projection (132a) formed on the body part (131) of the integrated cone damper (130).

[0136] The magnetic body (150) is fixedly installed on the bottom surface of the lower body (160) and can perform the role of generating a magnetic field by interacting with the voice coil (145). The magnetic body (150) can be exemplified as a permanent magnet made of a ferromagnetic material, such as a neodymium magnet. The cap magnetic body (155) is fixedly installed on the upper surface of the magnetic body (150) and can perform the role of inducing the magnetic force of the magnetic body (150) to be concentrated on the bonding type voice coil (145).

[0137] The rubber frame (170) is intended to compensate for vibration stimulation reduced by the vibration probe (120) being pressed by contact with the human body through spring action, and can be formed in a tubular shape with one side completely open so as to be fitted and wrapped around the body part (131) and the lower body (160).

[0138] On the outer surface of the rubber frame (170), at least one pair of elastic guide grooves (171) may be formed along the longitudinal direction at opposing positions to facilitate easy fitting to the body part (131) and the lower body (160). On the other side of the rubber frame (170), an elastic part (173) that acts as a spring in the up and down direction may be formed.

[0139] The elastic member (173), when viewed as a longitudinal section structure, may be composed of a connecting section (173a) extending from the inner circumference of the other side, a first inclined section (173b) extending downwardly from the connecting section (173a), a second inclined section (173c) extending upwardly from the first inclined section (173b), a horizontal section (173d) extending horizontally from the second inclined section (173c), and a lower edge section (173e) protruding to the other side from the boundary between the first inclined section (173b) and the second inclined section (173c).

[0140] In the elastic part (173), a central space (173f) divided into a lower edge section (173e), a second inclined section (173c), and a horizontal section (173d), and an outer space (173g) divided into a first inclined section (173b) and a second inclined section (173c) may be formed.

[0141] An opening (172) may be formed in the rubber frame (170) to expose the substrate (137) to the outside when fitted into the integrated cone damper (130).

[0142] The nerve stimulation control device (200) according to the present invention can provide stimulation by vibration using a vibration device (100). The nerve stimulation control device (200) can receive vibrations generated according to changes in the acoustic pressure of a sound source and provide massage or stimulation to the human body.

[0143] Specifically, the nerve stimulation control device (200) may include an acoustic pressure generating unit (250) equipped with a sound source processing unit (210) and a vibration device (100), a vibration device (100) including a vibration probe (120) that transmits vibrations generated from the acoustic pressure generating unit (250) to the outside, and various types of vibration stimulation units (260, 262, 264, 266) equipped for use in massage and stimulation.

[0144] The sound source processing unit (210) may be equipped with a device for sound source playback (not shown), such as a codec, amplifier, and speaker, and may process the sound source so that the vibration device (100) generates vibration using the sound source. The sound source processing unit (210) may output a sound wave signal corresponding to the sound source to the acoustic pressure generating unit (250).

[0145] The sound source processing unit (210) may include a control unit (202), an input unit (212, 230, 232, 234, 236), an output unit (218), a control unit (214, 216), a display unit (206), and a power supply unit (204).

[0146] The input section (212, 230, 232, 234, 236) may include a power switch (212) for supplying and cutting off power, various interface devices for inputting a sound source to the sound source processing section (210), such as a memory card input section (230), a USB input section (232), an AUX input section (234), and a wireless communication input section (236).

[0147] The memory card input section (230) can have various portable storage media in which sound sources are stored, such as SD cards, CF cards, memory sticks, MMC cards, and smart media, inserted, and can input sound sources to the sound source processing section (210).

[0148] The USB input section (232) can be connected to an external USB device, such as an MP3 player, smartphone, personal information terminal (PDA), portable multimedia player (PMP), or USB memory, to input sound sources.

[0149] The AUX input section (234) can input a sound source using wired communication. The wireless communication input section (236) can receive a sound source from the outside or wireless internet using, for example, a Wi-Fi communication network or a Bluetooth wireless communication network.

[0150] Accordingly, the sound source processing unit (210) can receive sound sources that the user wants or likes using various interface devices, and can process the sound sources to output sound wave signals.

[0151] The output unit (218) can output a sound wave signal generated by processing a sound source to the acoustic pressure generating unit (250). The output unit (218) can be connected to the acoustic pressure generating unit (250) through a connector and a connecting cable (242).

[0152] The control unit (214, 216) may include a strength control unit (214) and a frequency control unit (216) provided in the form of a button or a dial knob. The strength control unit (214) can control the strength of acoustic pressure generated from an input internal or external sound source. The frequency control unit (216) can control the key, i.e., the frequency, of the built-in sound source.

[0153] The display unit (206) can be equipped with, for example, a light-emitting diode or a liquid crystal display panel, and can display the operation status of the sound source processing unit (210), such as a power on / off state, a sound source playback state, or a control state.

[0154] The power supply unit (204) can receive AC power through the power input unit (220) and supply power (V) to the sound source processing unit (210).

[0155] The control unit (202) can control and process the general operations of the sound source processing unit (210). The control unit (202) can control the supply of power from the power supply unit (204) when the power switch (212) is pressed.

[0156] The control unit (202) can process to receive a sound source from the input unit (230, 232, 234, 236) and can process to output a sound wave signal to the output unit (218). The control unit (202) can process to play a sound source in response when the sound pressure intensity or frequency is adjusted by the intensity adjustment unit (214) and the frequency adjustment unit (216). The control unit (202) can control to display the operating status of the sound source processing unit (210) through the display unit (206).

[0157] In one embodiment, the acoustic pressure generating unit (250) may be provided in the form of a handle (240) and may be exemplified by having a vibration device (100) inside, but is not limited thereto and can be configured in various forms such as a headband or headphone type that is worn on the head.

[0158] The acoustic pressure generating unit (250) receives an acoustic signal from the output unit (218) of the sound source processing unit (210) and can generate vibrations according to the acoustic pressure fluctuation of the acoustic signal using the vibration device (100).

[0159] The acoustic pressure generating unit (250) transmits vibrations according to acoustic pressure by holding the handle (240) and directly contacting the mounted vibration probe (120, 260 to 266) to a specific part of the human body. At this time, any one of the various vibration probes (120) or various vibration stimulation units (260, 262, 264, 266) may be selectively combined with the acoustic pressure generating unit (250).

[0160] Since the term “vibration probe” used in this invention is a key element for controlling nerve stimulation by inducing vibration stimulation, it is also used interchangeably with “vibration stimulation unit” in this invention.

[0161] The vibration probe (120) is coupled to the vibration device (100) of the acoustic pressure generating unit (250) and can transmit vibration to the vibration stimulation unit (260, 262, 264, 266). The vibration stimulation unit (260, 262, 264, 266) can be provided in various forms so that the nerve stimulation control device (200) can massage or stimulate the human body for various purposes.

[0162] The vibration stimulation parts (260, 262, 264, 266) can be mounted on or detached from the vibration device (100) of the acoustic pressure generating part (250), just like the vibration probe (120). The vibration stimulation parts (260, 262, 264, 266) can be provided in various ways depending on the massage area, stimulation area, or purpose of use of the human body, and any one of them can be selected and mounted on the acoustic pressure generating part (250).

[0163] The vibration stimulation part (260, 262, 264, 266) may be equipped with, for example, a sound wave transmission probe (260) for electric stimulation, a vibration probe (262) for scalp massage, a vibration probe (264) for skin massage, or a vibration probe (266) for hand and foot massage.

[0164] However, it is not limited thereto, and the vibration stimulation parts (260, 262, 264, 266) may be provided as heads that are detachable from the vibration probe (120). Multiple heads may be provided so that they can be used for various purposes.

[0165] The head may be provided, for example, as a head for skin massage, a head for scalp massage, or a head for hand and foot massage. The head may be provided in various materials, for example, silicone, wood, plastic, or metal.

[0166] Each of these heads is mounted on a vibration probe (120) and can transmit vibrations generated from a vibration device (100) to the human body to massage the skin, scalp, or hands and feet.

[0167] Therefore, each of the vibration probe (120) and vibration stimulation parts (260, 262, 264, 266) according to the present invention can be coupled to a connecting member (110), and can receive vibration from an integrated cone damper (130) through the connecting member (110) to provide massage and stimulation to the human body.

[0168] Accordingly, the nerve stimulation control device (200) according to the present invention can stimulate the skin or scalp of the human body by contacting it through various vibration probes (120) or vibration stimulation parts (260, 262, 264, 266) that receive vibrations from an integrated cone damper (130) that generates vibrations using a sound source.

[0169] The neurostimulation control device (200) according to the present invention may be used for the improvement or treatment of cognitive impairment. Cognitive impairment may include attention deficit hyperactivity disorder (ADHD), cognitive impairment accompanied by sarcopenia, neurodegenerative diseases, or mild cognitive impairment.

[0170] Neurodegenerative diseases may include Parkinson's disease, traumatic brain injury, multiple sclerosis, drug intoxication, alcohol intoxication, neurodegenerative conditions, brain inflammation, multi-organ atrophy, Huntington's disease, amyotrophic lateral sclerosis (ALS), chronic traumatic brain lesion, motor neuronosis, dementia, Creutzfeldt-Jakob disease, or normal pressure hydrocephalus.

[0171] Dementia may include Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, AIDS-induced dementia, mixed dementia, age-related cognitive impairment, or age-related memory impairment.

[0172] The neurostimulation control device (200) according to the present invention may be used for the improvement or treatment of neuropsychiatric symptoms or cognitive impairment accompanying a stroke. Neuropsychiatric symptoms accompanying a stroke may include depression, anxiety, or fatigue.

[0173] Stroke is an acute disease in which the brain is damaged due to problems with cerebrovascular vessels, but it can leave behind severe neuropsychiatric symptoms such as depression, anxiety, or chronic fatigue as sequelae. The non-invasive vibratory stimulation according to the present invention can help recover the damaged nervous system by stabilizing neural circuits in the brain, regulating neurotransmitter imbalances, and promoting brain plasticity. Through this, a new alternative treatment method can be provided for patients who experience side effects or do not respond to drug therapy.

[0174] The neurostimulation control device (200) according to the present invention may be used for the improvement or treatment of neurodevelopmental disorders. Neurodevelopmental disorders may include dyslexia, cerebral palsy (CP), or autism spectrum disorder (ASD).

[0175] Neurodevelopmental disorders can refer to a group of conditions in which individuals experience difficulties with specific functions due to problems arising during the development of the central nervous system; for example, dyslexia can be a type of learning disability in which individuals have normal intelligence but struggle to decode and understand written text.

[0176] The acoustic vibration stimulation according to the present invention can improve the brain's information processing ability through sensory stimulation of a specific frequency and strengthen the connectivity of neural circuits related to language processing, thereby contributing to the alleviation of dyslexia symptoms.

[0177] Cerebral palsy (CP) is primarily characterized by impairment of motor function, but in many cases, it may be accompanied by difficulties in cognitive and sensory processing. The vibration stimulation according to the present invention can help improve motor control ability by stimulating proprioceptive senses, and can have a positive effect on enhancing the effectiveness of rehabilitation treatment and improving the quality of life for patients with cerebral palsy by regulating overall brain function.

[0178] Autism Spectrum Disorder (ASD) is characterized by difficulties with social interaction and repetitive behaviors, and can often be accompanied by sensory processing problems such as hypersensitivity or desensitization.

[0179] The controlled vibration stimulation according to the present invention can help with sensory integration to stabilize hypersensitive or unstable sensory systems, thereby reducing the subject's anxiety and inducing them to participate better in social interactions.

[0180] The neurostimulation control device (200) according to the present invention can be used for the improvement or treatment of post-traumatic stress disorder. Post-traumatic stress disorder (PTSD) is an anxiety disorder that occurs after experiencing a traumatic event and may be closely related to the overactivity of specific brain regions (amygdala, hippocampus, etc.).

[0181] The neural stimulation control according to the present invention can be effectively used to alleviate hyperarousal and anxiety symptoms in PTSD patients by stabilizing brain waves and controlling the activity of neural circuits associated with fear memories.

[0182] The neurostimulation control device (200) according to the present invention can be used for the improvement or treatment of sleep disorders, particularly insomnia. The stable and rhythmic vibration stimulation according to the present invention can suppress the overactivity of the sympathetic nervous system and activate the parasympathetic nervous system to induce the body into a relaxed state, which can be utilized as a non-pharmacological treatment method to improve insomnia by reducing anxiety and stress that interfere with sleep and helping to induce natural sleep.

[0183] The neurostimulation control device (200) according to the present invention can improve cognitive function by inducing vibration-frequency-sensitive mechanotransductive signaling in neurons or glial cells in a brain region through non-invasive vibration stimulation of a specific frequency band.

[0184] Non-invasive vibration stimulation may include mechanical vibration stimulation. Mechanical vibration stimulation physically activates mechanosensitive channels located at the level of the cell membrane or cytoskeleton, and the mechanical vibration stimulation may be configured to be converted into biochemical signals, namely mechanotransmission signals, to mediate specific responses within neurons or glial cells.

[0185] The vibration frequency of the non-invasive vibratory stimulation may have a range of 1 Hz to 150 Hz to include a frequency band that maximizes the mechanotransmission response to the brain regions of the individual. In particular, a frequency band within the range of 40 Hz to 80 Hz may have significantly superior memory improvement and neuroprotective effects compared to other frequency bands, for example, a frequency band of 20 Hz, which may suggest that the frequency band effectively induces a mechanotransmission response in the brain.

[0186] Mechanical vibration stimulation can be transmitted to specific areas of the brain through a somatosensory pathway via a vibration probe (120) that is in direct contact with the skin of an individual (object) or through an auditory pathway via sound generated upon stimulation.

[0187] Mechanical transmission signals induced by mechanical vibration stimulation can induce improvements in brain function. Specifically, they can act as a mechanism to enhance neuronal connectivity, synaptic plasticity, or cerebral perfusion.

[0188] For example, specific frequency stimulation (40Hz or 80Hz) can significantly increase the expression of genes closely related to synaptic plasticity, such as BDNF and CREB, and can promote neuronal activation through c-Fos expression. In addition, mechanical vibration stimulation can also contribute to improving cerebral blood flow, which is essential for maintaining the healthy function of the brain's nervous system.

[0189] Mechanical vibration stimulation, which is vibrotactile stimulation, can affect not only nerve or molecular signaling but also brain hemodynamics through mechanical-vascular coupling.

[0190] In fact, studies using localized vibratory stimulation have demonstrated, via positron emission tomography (PET) imaging, an increase in localized cerebral blood flow (rCBF) in specific cortical regions; more recently, it was revealed that applying a frequency-controlled head-mounted vibration system to healthy volunteers resulted in frequency-dependent modulation of cerebral blood flow (CBF) measured by MRI immediately after stimulation.

[0191] These results suggest that mechanical vibrations can physically bind to the neurovascular unit to enhance endothelial activation, vasodilation, and microcirculatory perfusion.

[0192] Such hemodynamic promotion can improve the delivery of oxygen and glucose to the hippocampus and cortical tissues, thereby supporting synaptic metabolism and further amplifying the recovery of cholinergic and antioxidant functions observed in the experiments of the present invention.

[0193] The present invention may include a method for preventing, alleviating, or treating cognitive decline or neurodegenerative diseases in an individual. The method for prevention, alleviation, or treatment according to the present invention may include a step of inducing mechanotransductive signaling sensitive to vibration frequency in at least one brain region of an individual. The step of inducing mechanotransductive signaling may include a step of delivering non-invasive vibratory stimulation to the individual.

[0194] Non-invasive vibration stimulation may include mechanical vibration stimulation, and mechanical vibration stimulation can mediate mechanosensitive signals within neurons or glial cells by activating mechanosensitive channels at the level of the cell membrane or cytoskeleton.

[0195] The method for prevention, alleviation, or treatment according to the present invention may include the step of delivering a vibration stimulus having a vibration frequency in the range of 1 Hz to 150 Hz, and the vibration frequency may include a frequency band that maximizes the mechanical delivery response of a brain region.

[0196] Non-invasive vibratory stimulation is transmitted via auditory or somatosensory pathways and can induce improvements in neuronal connectivity, synaptic plasticity, or cerebral perfusion in an individual.

[0197] FIGS. 9 and 10 illustrate the experimental design used in an experimental example and the provision of vibration stimulation to an experimental rat through the neural stimulation control device according to the present invention, wherein the neural stimulation control device includes a vibration device according to the present invention. FIG. 11 is a graph showing the change in body weight of an experimental rat in an experimental example, wherein the neural stimulation control device includes a vibration device according to the present invention. FIGS. 12 and 13 are graphs showing the step delay time of a passive avoidance test of an experimental rat in an experimental example, and graphs showing the escape delay time of an experimental rat in a water maze test, wherein the neural stimulation control device includes a vibration device according to the present invention. FIGS. 14 and 15 are photographs showing the overall shape of the brain of an experimental rat in an experimental example, and photographs showing the overall shape of the adrenal gland of an experimental rat, wherein the neural stimulation control device includes a vibration device according to the present invention. FIGS. 16 to 18 are graphs showing serum corticosterone levels of an experimental mouse, hippocampal Ach content of an experimental mouse, and hippocampal AchE content of an experimental mouse in an experimental example, in a neurostimulation control device including a vibration device according to the present invention. FIGS. 19 to 22 are histopathological images of the brain-hippocampus of an experimental mouse, images of caspase-3 immunolabeled pyramidal cells in the brain-hippocampal DG region of an experimental mouse, images of c-Fos immunopositive pyramidal cells in the brain-hippocampal DG region of an experimental mouse, and histopathological images of the adrenal gland of an experimental mouse in a neurostimulation control device including a vibration device according to the present invention. FIGS. 23 to 27 relate to an experimental example of a cell experiment in a neurostimulation control device including a vibration device according to the present invention, and are graphs showing a configuration diagram of a cell experiment for vibration stimulation, a conceptual diagram schematically explaining the overall contents of the vibration cell experiment, and experimental results.

[0198] Hereinafter, with reference to FIGS. 9 to 27, an experimental example regarding the effect of improving brain disorders or cognitive function using a neurostimulation control device (200) according to the present invention will be described in detail.

[0199]

[0200] [Experiment Example 1]

[0201] - Experimental animals

[0202] A total of 110 6-week-old male SPF / VAF inbred C57BL / 6NCrlOri mice [OrientBio, Seungnam, Korea; ANNEX I ~ IV] were acclimatized to the laboratory environment for 7 days. Based on body weight (average weight 20.60 ± 0.93 g, 18.80 ~ 23.00 g) and behavioral status, they were divided into 20 mice per group, comprising a total of 5 groups (Table 1) for use in the experiment. All experimental animals were handled in accordance with the Animal Ethics Standards under the prior approval of the Daegu Hani University Animal Ethics Committee. [Approval No. DHU2023-049, November 24, 2023 (ANNEX V)]

[0203]

[0204] - Group separation (Total 5 groups; 20 animals per group)

[0205] Normal media control group (medium oral and intraperitoneal administration control group)

[0206] SCP control group (medium oral and SCP intraperitoneal administration control group)

[0207] HVSS20 (20Hz vibration stimulation and SCP intraperitoneal administration experimental group)

[0208] HVSS40 (40Hz vibration stimulation and SCP intraperitoneal administration experimental group)

[0209] HVSS80 (80Hz vibration stimulation and SCP intraperitoneal administration experimental group)

[0210]

[0211] - Experimental Method

[0212] 1. Causes memory impairment

[0213] According to previous methods [Lee et al., 2014; Kim et al., 2018; Hu et al., 2019; Kim et al., 2022a], SCP hydrobromide (Sigma-Aldrich, St. Louis, MO, USA) was dissolved in physiological saline at a concentration of 0.1 mg / ml, and then injected intraperitoneally into the right lower abdomen using a 1 ml syringe with a 26 G needle at a dose of 10 ml / kg (1 mg / kg) each, 1 hour after vibration stimulation on the 7th, 14th, and 28th days of vibration stimulation, to induce memory impairment.

[0214] In the normal media control group, to apply the same administration and correction stress, only the same volume of sterile physiological saline was administered intraperitoneally in the same manner for the same period instead of SCP solution.

[0215]

[0216] 2. Vibratory stimulation

[0217] Referring to Tables 1 to 3 and Figures 9 and 12, based on [Cho et al., 2012; Martorell et al., 2019; Grosman-Dziewiszek et al., 2022; Suk et al., 2023], vibration tactile stimulation at 20, 40, and 80 Hz was performed for 10 minutes, once daily for 28 days using an HVSS including a cylindrical acrylic cylinder mouse restraint device (ø35×110 mm; JD-R-05A, Jeung Do Bio & Plant Co., Ltd., Seoul, Korea).

[0218] In order to apply the same administration and calibration stress to the normal and SCP control groups, they were calibrated for the same period in a cylindrical acrylic cylinder mouse restraint device contained in a power-off HVSS.

[0219]

[0220]

[0221]

[0222]

[0223] 3. Observation Items

[0224] Body weight, passive avoidance test, water maze test, brain weight and gross morphological examination, ACh content in the hippocampus, AChE activity and changes in ChAT and expression of memory-related genes—BDNF, PI3K, Akt, ERK1 and 2, CREB, CaMK IV—changes in the cerebral cortical antioxidant defense system—lipid peroxidation (MDA content), GSH content, SOD and CAT activity, histopathological changes in the brain hippocampus, adrenal weight and gross morphological changes, changes in blood corticosterone content, and histopathological examination of the adrenal gland. The passive avoidance test and water maze test were performed 28 days after the start of vibratory stimulation by HVSS and 24 hours after the final administration of SCP, respectively.

[0225]

[0226] 4. Histomorphometric evaluation

[0227] Cerebrum: Average thickness of hippocampal CA1–CA3 (μm), normal hippocampal DG region, numerical changes in pyramidal neurons (cells / mm²) with cleaved caspase-3 and c-Fos immune responses

[0228] Adrenal gland: Changes in thickness (μm) of the entire adrenal gland, medulla, and cortex, changes in thickness (μm) of the adrenal cortex glomerular layer, bundle layer, and reticular layer

[0229]

[0230] - Experimental results

[0231] 1. Changes in weight

[0232] Referring to Table 4 and Figure 11, no significant change in body weight or weight gain during the 28-day administration period compared to the normal media control group was observed in any of the SCP treatment groups, and no significant change in body weight or weight gain compared to the SCP control group was observed throughout the entire experiment in all 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS.

[0233]

[0234] During the 28-day administration period, the increase in body weight was 1.47% in the SCP control group compared to the normal media control group, and -0.85%, -0.73%, and 0.24% in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS compared to the SCP control group, respectively.

[0235]

[0236] 2. Manual Avoidance Test

[0237] Referring to Figure 12, a significant (p<0.01) decrease in step-through latency time, i.e., step-through latency time, was observed in the SCP control group compared to the normal media control group, but a significant (p<0.01) increase in step-through latency time was observed in the 40 and 80 Hz vibration stimulation experimental groups using HVSS compared to the SCP control group, to a similar degree.

[0238] Meanwhile, in the 20Hz vibration stimulation experimental group using HVSS, no significant change in retention latency was observed compared to the SCP control group.

[0239] The retention latency period showed a change of -71.00% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of 2.34%, 82.19%, and 80.04%, respectively, compared to the SCP control group.

[0240]

[0241] 3. Underwater maze test

[0242] Referring to Figure 13, a significant (p<0.01) increase in escape latency time was observed in the SCP control group compared to the normal media control group, but a significant (p<0.01) decrease in escape latency time was observed in the 40 and 80 Hz vibration stimulation experimental groups using HVSS compared to the SCP control group, to a similar degree.

[0243] Meanwhile, in the 20Hz vibration stimulation experimental group using HVSS, no significant change in escape latency was observed compared to the SCP control group.

[0244] The escape latency period showed a change of 271.13% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of -0.83%, -48.26%, and -49.51%, respectively, compared to the SCP control group.

[0245]

[0246] 4. Changes in brain weight

[0247] Referring to Table 5 and Figure 14, no significant macroscopic morphological changes in the brain and changes in absolute and relative weight of the brain, excluding significant olfactory bulbs, were observed in the SCP control group compared to the normal media control group, and no significant macroscopic morphological changes in the brain and changes in absolute and relative weight of the brain were observed in the 20, 40, and 80 Hz vibration stimulation experimental groups using all HVSS compared to the SCP control group.

[0248]

[0249] The absolute brain weight showed a change of 0.41% in the SCP control group compared to the normal media control group, and in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 0.12%, -0.29%, and 0.70%, respectively, compared to the SCP control group.

[0250] The relative brain weight showed a change of 0.32% in the SCP control group compared to the normal media control group, and in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of 0.09%, -0.63%, and 0.83%, respectively, compared to the SCP control group.

[0251]

[0252] 5. Changes in adrenal weight

[0253] Referring to Table 5 and Figure 5, no significant macroscopic morphological changes in the left adrenal gland or significant changes in the absolute and relative weight of the adrenal gland compared to the normal media control group were observed in the SCP control group, and no significant macroscopic morphological changes in the adrenal gland or significant changes in the absolute and relative weight of the adrenal gland compared to the SCP control group were observed in the 20, 40, and 80 Hz vibration stimulation experimental groups using all HVSS.

[0254] The absolute weight of the adrenal gland showed a change of 7.14% in the SCP control group compared to the normal media control group, and in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -6.67%, 0.00%, and -6.67%, respectively, compared to the SCP control group.

[0255] The relative weight of the adrenal gland showed a change of 5.65% in the SCP control group compared to the normal media control group, and in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -6.64%, 1.93%, and -5.18%, respectively, compared to the SCP control group.

[0256]

[0257] 6. Changes in blood corticosterone levels

[0258] Referring to Figure 16, no significant change in blood corticosterone content compared to the normal media control group was observed in the SCP control group, and no significant change in blood corticosterone content compared to the SCP control group was observed in the 20, 40, and 80 Hz vibration stimulation experimental groups using all HVSS.

[0259] The blood corticosterone content showed a change of 2.40% in the SCP control group compared to the normal media control group, and in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -0.21%, 1.54%, and -0.48%, respectively, compared to the SCP control group.

[0260]

[0261] 7. Changes in ACh content and AChE activity in hippocampal tissue

[0262] Referring to Figures 17 and 18, in the SCP control group, a significant (p<0.01) decrease in ACh content and an increase in AChE activity were observed in the hippocampal tissue compared to the normal media control group, respectively; however, in the 40 and 80 Hz vibration stimulation experimental groups using HVSS, a significant (p<0.01) increase in ACh content and a decrease in AChE activity were observed in the hippocampal tissue compared to the SCP control group, respectively, to similar degrees.

[0263] Meanwhile, in the experimental group with 20Hz vibration stimulation using HVSS, no significant changes in ACh content and AChE activity in hippocampal tissue were observed compared to the SCP control group.

[0264] The ACh content in hippocampal tissue showed a change of -75.12% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 2.36%, 88.58%, and 88.98%, respectively, compared to the SCP control group.

[0265] AChE activity in hippocampal tissue showed a change of 141.02% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of -5.74%, -32.90%, and -33.26%, respectively, compared to the SCP control group.

[0266]

[0267] 8. Cortical lipid peroxidation and changes in the endogenous antioxidant defense system

[0268] Referring to Table 6, in the SCP control group, a significant (p<0.01) increase in MDA content and lipid peroxidation in the cerebral cortex tissue and a decrease in the activity of the endogenous antioxidant GSH, endogenous antioxidant enzyme SOD, and CAT were observed, respectively, compared to the normal media control group; however, in the 40 and 80 Hz vibration stimulation experimental groups using HVSS, a significant (p<0.01) decrease in MDA content in the cerebral cortex tissue and an increase in GSH content, SOD, and CAT activity were observed to similar degrees, respectively, compared to the SCP control group.

[0269] Meanwhile, in the experimental group with 20Hz vibration stimulation using HVSS, no significant changes in MDA and GSH content and SOD and CAT activity were observed in the cerebral cortex tissue compared to the SCP control group.

[0270]

[0271] The MDA content in the cerebral cortex tissue showed a change of 184.68% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of -2.51%, -36.59%, and -35.09%, respectively, compared to the SCP control group.

[0272] The GSH content in the cerebral cortex tissue showed a change of -77.22% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 3.83%, 112.93%, and 116.87%, respectively, compared to the SCP control group.

[0273] CAT activity within the cerebral cortex tissue showed a change of -78.62% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of 1.98%, 103.92%, and 104.52%, respectively, compared to the SCP control group.

[0274] SOD activity in the cerebral cortex tissue showed a change of -82.61% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of 2.46%, 145.43%, and 142.04%, respectively, compared to the SCP control group.

[0275]

[0276] 9. Changes in mRNA expression of ChAT and memory-related genes—BDNF, PI3K, Akt, ERK1 and 2, CREB, and CaMK IV—in hippocampal tissue

[0277] Referring to Table 7, in the SCP control group, a significant (p<0.01) decrease in the expression of ChAT, BDNF, PI3K, Akt, ERK1 and 2, CREB, and CaMK IV mRNA in hippocampal tissue was observed compared to the normal media control group, but in the 40 and 80 Hz vibration stimulation experimental groups using HVSS, a significant (p<0.01) increase in the expression of ChAT and memory-related genes—BDNF, PI3K, Akt, ERK1 and 2, CREB, and CaMK IV mRNA—in hippocampal tissue was observed to a similar degree compared to the SCP control group.

[0278] Meanwhile, in the 20Hz vibration stimulation experimental group using HVSS, no significant changes in the expression of ChAT, BDNF, PI3K, Akt, ERK1 and 2, CREB, and CaMK IV mRNA in hippocampal tissue were observed compared to the SCP control group.

[0279]

[0280] ChAT mRNA expression in hippocampal tissue showed a change of -68.73% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 1.59%, 83.44%, and 85.03%, respectively, compared to the SCP control group.

[0281] BDNF mRNA expression in hippocampal tissue showed a change of -68.64% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 1.92%, 57.19%, and 56.87%, respectively, compared to the SCP control group.

[0282] PI3K mRNA expression in hippocampal tissue showed a change of -70.52% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 6.71%, 74.83%, and 75.84%, respectively, compared to the SCP control group.

[0283] Akt mRNA expression in hippocampal tissue showed a change of -70.43% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 6.98%, 65.12%, and 63.79%, respectively, compared to the SCP control group.

[0284] ERK1 mRNA expression in hippocampal tissue showed a change of -75.27% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 3.59%, 73.71%, and 74.90%, respectively, compared to the SCP control group.

[0285] ERK2 mRNA expression in hippocampal tissue showed a change of -80.46% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 3.41%, 105.85%, and 105.37%, respectively, compared to the SCP control group.

[0286] CREB mRNA expression in hippocampal tissue showed a change of -70.32% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 7.72%, 75.17%, and 74.50%, respectively, compared to the SCP control group.

[0287] CaMK IV mRNA expression in hippocampal tissue showed a change of -73.37% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 1.82%, 84.31%, and 86.13%, respectively, compared to the SCP control group.

[0288]

[0289] 10. Histopathological changes

[0290] 10.1 Histopathological changes in the hippocampus

[0291] Referring to Table 8 and Figures 19 to 20, in the SCP control group, compared to the normal media control group, there was a significant (p<0.01) decrease in hippocampal CA1–CA2 thickness, normal DG region and c-Fos immune response activation [Wirtshafter, 2005; Fast et al., 2016; Kim et al., 2022b], along with a decrease in the number of pyramidal neurons and cleaved caspase-3 immune response apoptosis in the hippocampal DG region [Kim et al., 2016; [Xu et al., 2016] Although an increase in the number of pyramidal neurons was observed in each group, in the 40 and 80 Hz vibration stimulation experimental groups using HVSS, a significant (p<0.01) decrease in hippocampal CA1~CA2 thickness, normal DG region, and the number of c-Fos immune-responsive pyramidal neurons was observed compared to the SCP control group, along with a similar increase in the number of cleaved caspase-3 immune-responsive pyramidal neurons in the hippocampal DG region.

[0292] Meanwhile, in the 20Hz vibration stimulation experimental group using HVSS, no significant changes in hippocampal CA1–CA2 thickness, normal DG region, c-Fos and cleaved caspase-3 immune response, or the number of pyramidal neurons were observed compared to the SCP control group.

[0293]

[0294] The thickness of the cerebral hippocampus CA1 to CA2 showed a change of -20.17% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of 1.28%, 15.14%, and 14.29%, respectively, compared to the SCP control group.

[0295] The number of normal pyramidal neurons in the DG region of the cerebral hippocampus showed a change of -34.65% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, the numbers showed changes of 1.34%, 34.46%, and 32.53%, respectively, compared to the SCP control group.

[0296] The number of apoptosis pyramidal neurons in the cerebral hippocampal DG region showed a change of 404.00% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of -3.97%, -52.78%, and -53.17%, respectively, compared to the SCP control group.

[0297] The number of pyramidal neurons with c-Fos immune response activation in the DG region of the cerebral hippocampus showed a change of -88.55% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, changes of 3.33%, 446.67%, and 440.00%, respectively, compared to the SCP control group.

[0298]

[0299] 10.2. Histopathological changes of the adrenal gland

[0300] Referring to Table 9 and Figure 22, no significant changes in the thickness of the entire adrenal gland, medulla, cortex, adrenal cortex, plexus, and reticular layer were observed in the SCP control group compared to the normal media control group, and no significant histopathological changes in the adrenal gland were observed in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS compared to the SCP control group.

[0301]

[0302] The total thickness of the adrenal gland showed a change of 1.51% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -1.48%, 0.03%, and -1.31%, respectively, compared to the SCP control group.

[0303] The thickness of the adrenal medulla showed a change of 0.58% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -3.30%, -1.51%, and -3.51%, respectively, compared to the SCP control group.

[0304] The thickness of the adrenal cortex showed a change of 1.93% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -0.67%, 0.72%, and -0.33%, respectively, compared to the SCP control group.

[0305] The thickness of the adrenal cortex glomerular layer showed a change of 0.61% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of 1.35%, 1.59%, and 1.61%, respectively, compared to the SCP control group.

[0306] The thickness of the adrenal cortex bundle layer showed a change of 2.74% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -1.29%, 0.56%, and -0.67%, respectively, compared to the SCP control group.

[0307] The thickness of the adrenal cortex reticular layer showed a change of -0.67% in the SCP control group compared to the normal media control group, but in the 20, 40, and 80 Hz vibration stimulation experimental groups using HVSS, it showed changes of -0.13%, 0.29%, and -1.30%, respectively, compared to the SCP control group.

[0308] Under the experimental conditions described above, vibration stimulation at 40 and 80 Hz by HVSS is considered to provide reliable evidence of relatively superior memory improvement effects in a C57BL / 6 mouse model of SCP-induced memory impairment by regulating the expression of memory-related genes—BDNF, PI3K, Akt, ERK1 and 2, CREB, and CaMK IV—without accompanying severe stress or related side effects, and along with neuroprotective effects through cholinergic neuroactivity and antioxidant effects to similar degrees. Therefore, HVSS, which generates appropriate vibration stimulation, particularly 40 Hz vibration stimulation, has a very high potential to be developed into an effective medical device for improving cognitive function for various memory disorders, including dementia, through further detailed mechanistic studies, various animal experiments, and appropriate human clinical trials.

[0309] Based on the experimental examples examined above, it was confirmed that there is an improvement in memory and a therapeutic effect on cognitive dysfunction at about 20 to 150 Hz, particularly at 40 Hz and 80 Hz, and it was confirmed that the neurostimulation control device of the present invention can be used for medicinal purposes.

[0310] In the foregoing, the configuration and operation of a neurostimulation control device including a vibration device according to the present invention have been illustrated with reference to the detailed description and drawings; however, this is merely an example of an embodiment, and various changes and modifications are possible within the scope of the technical concept of the present invention.

Claims

1. In a neurostimulation control device including a vibration device, The above vibration device is, It includes a vibration probe, an integrated cone damper, an integrated bobbin, and a rubber frame, The above vibration probe, the above integrated cone damper, and the above integrated bobbin are modular structures assembled through a single connecting member, and The above integrated bobbin is accommodated within the above integrated cone damper, and The above rubber frame is a nerve stimulation control device comprising a vibration device having a structure that encloses the above integrated cone damper and the above integrated bobbin.

2. In Paragraph 1, The above vibration probe is, Plate section, A coupling projection protruding from one surface of the above plate portion, and A nerve stimulation control device comprising a vibration device including a first through hole penetrating the center of the plate portion and the coupling projection portion.

3. In Paragraph 2, The above-described integrated cone damper is a nerve stimulation control device comprising a vibration device including a body portion in the shape of a tube, and a cone plate having a hollow hole formed therein and a rim area inserted along the circumferential direction of one end portion of the body portion.

4. In Paragraph 3, The above-mentioned integrated bobbin is, Support plate section, A coupling portion formed protruding from one surface of the above-mentioned support plate portion and having a second through hole formed therein, and A neurostimulation control device comprising a vibration device including a bonding type voice coil coupled to the other surface of the support plate portion.

5. In Paragraph 4, A nerve stimulation control device comprising a vibration device wherein the above connecting member has male screw threads formed on its outer surface and, while being engaged with the female screw threads formed in the first through hole provided in the vibration probe, penetrates the hollow hole formed in the integrated cone damper and is engaged with the female screw threads formed in the second through hole provided in the integrated bobbin.

6. In Paragraph 5, The above coupling projection is provided with a first contact end at one end thereof that contacts one surface of the cone plate, and The above-mentioned coupling portion is provided with a second contact end portion at one end that contacts the other surface of the cone plate, and an insertion end portion that extends from the second contact end portion and is sequentially inserted into the hollow hole and the first through hole. The first contact end and the second contact end have the same outer diameter, and The first through hole has an inner diameter larger than the second through hole, and A nerve stimulation control device comprising a vibration device, wherein the above connecting member includes a first male screw thread extending from the head portion and having an outer diameter corresponding to the first through hole, and a second male screw thread extending from the first male screw thread and having an outer diameter corresponding to the second through hole.

7. In Paragraph 4, The above vibration device is, A lower body that is detachably fitted and coupled to one side of the body portion of the above-mentioned integrated cone damper, has a tubular shape with one side completely open, and forms an internal receiving space. A magnetic body fixedly installed on the other surface of the lower body to generate magnetic force, and A nerve stimulation control device comprising a vibration device further including a cap magnet installed on one surface of the magnetic body to induce the magnetic force of the magnetic body to be concentrated on the bonding type voice coil.

8. In Paragraph 7, The above lower body has a catch groove formed along the circumferential direction on the outer surface of one end, and A pair of cut sections are formed in the body portion of the above-mentioned integrated cone damper to have an elastic structure at positions facing each other, and A nerve stimulation control device comprising a vibration device having a locking projection formed on the inner surface of the above-mentioned incision that engages with the locking groove.

9. In Paragraph 7, The above rubber frame is, A nerve stimulation control device comprising a vibration device having a tubular shape with one side completely open to be fitted and wrapped around the body part and the lower body, and having at least one pair of elastic guide grooves formed along the longitudinal direction at positions facing each other to facilitate fitting and coupling to the body part and the lower body.

10. In Paragraph 1, An elastic part that acts as a spring in the up and down motion is formed on the other side of the above rubber frame, and The above elastic part is, A connecting section extending from the inner surface of the other side, A first inclined section extending downwardly inclined from the above connecting section, A second inclined section extending upwardly from the first inclined section above, A horizontal section extending horizontally from the above second inclined section, A lower edge section protruding to the other side from the boundary between the first inclined section and the second inclined section, A central space portion partitioned by the lower edge cross-section, the second inclined cross-section, and the horizontal cross-section, and It includes a plurality of cross sections including an outer space portion partitioned by the first inclined cross section and the second inclined cross section, and The above elastic part is a nerve stimulation control device comprising a vibration device having a three-dimensional geometric structure formed by rotating the plurality of cross-sections around the virtual central axis of the rubber frame.

11. In Paragraph 4, The above vibration device further includes a substrate installed on a mounting portion provided on one side of the integrated cone damper, which outputs a signal input from the outside to the bonded voice coil. A nerve stimulation control device comprising a vibration device having an opening formed in the rubber frame that exposes the substrate to the outside when fitted into the integrated cone damper.

12. In Paragraph 1, The above vibration device is a neurostimulation control device comprising a vibration device that induces vibration stimulation.

13. In Paragraph 1, The above vibration device is a neurostimulation control device comprising a vibration device that induces vibration stimulation through a direct transmission method.

14. In any one of paragraphs 1 through 13, The above-mentioned neurostimulation control device is a neurostimulation control device comprising a vibration device used for the improvement or treatment of cognitive impairment.

15. In Paragraph 14, The above-mentioned cognitive impairment includes attention deficit hyperactivity disorder (ADHD), cognitive impairment accompanied by sarcopenia, neurodegenerative disease, or mild cognitive impairment, and is a neurostimulation control device including a vibration device.

16. In Paragraph 15, The above neurodegenerative disease includes Parkinson's disease, traumatic brain injury, multiple sclerosis, drug addiction, alcohol addiction, neurodegenerative pathology, brain inflammation, multi-organ atrophy, Huntington's disease, amyotrophic lateral sclerosis (ALS), chronic traumatic brain lesion, motor neuronosis, dementia, Creutzfeldt-Jakob disease, or normal intracranial pressure hydrocephalus, and is a neurostimulation control device including a vibration device.

17. In Paragraph 16, The above dementia includes a neurostimulation control device comprising a vibrating device including Alzheimer's disease, vascular dementia, Lewy body dementia, frontotemporal dementia, AIDS-induced dementia, mixed dementia, age-related cognitive impairment, or age-related memory impairment.

18. In any one of paragraphs 1 through 13, The above-mentioned neurostimulation control device is a neurostimulation control device comprising a vibration device used for the improvement or treatment of neuropsychiatric symptoms or cognitive impairment accompanying a stroke.

19. In any one of paragraphs 1 through 13, The above-mentioned neurostimulation control device is a neurostimulation control device comprising a vibration device used for the improvement or treatment of neurodevelopmental disorders, post-traumatic stress disorder, or sleep disorders.

20. In Paragraph 19, The above neurodevelopmental disorder is a neurostimulation control device including a vibration device comprising dyslexia, cerebral palsy, or autism spectrum disorder.

21. A neurostimulation control device comprising a vibration device used for the prevention, alleviation, or treatment of cognitive decline or neurodegenerative diseases, A neurostimulation control device comprising a vibrating device that delivers non-invasive vibratory stimulation to a brain region of an individual to induce mechanotransductive signaling sensitive to vibration frequency.

22. In Article 21, A neurostimulation control device comprising a vibration device including a mechanical vibration stimulation configured to mediate the mechanical transmission signal within a neuron or glial cell by activating mechanosensitive channels at the level of the cell membrane or cytoskeleton.

23. In Article 21, A neurostimulation control device comprising a vibration device having a range of 1 Hz to 150 Hz such that the vibration frequency includes a frequency band that maximizes the mechanical transmission response to the brain region.

24. In Paragraph 23, The above vibration frequency is a neural stimulation control device comprising a vibration device including frequency bands of 40 Hz and 80 Hz.

25. In Paragraph 22, A neurostimulation control device comprising a vibration device configured to transmit the mechanical vibration stimulation through an auditory or somatosensory pathway to improve interneuronal connectivity, synaptic plasticity, or cerebral perfusion.

26. In Paragraph 21, A neurostimulation control device comprising a vibration device configured such that the above mechanical transmission signal increases the acetylcholine (ACh) content in the hippocampal tissue of the brain region and decreases the activity of acetylcholinesterase (AChE).

27. In Article 21, A neurostimulation control device comprising a vibrating device configured such that the above mechanical transmission signal reduces lipid peroxidation within the cerebral cortex tissue of the brain region and activates an endogenous antioxidant defense system (GSH, SOD, or CAT).

28. In Article 21, A neurostimulation control device comprising a vibrating device configured such that the above mechanical transmission signal increases the mRNA expression of at least one gene selected from the group consisting of BDNF, CREB, ChAT, PI3K, Akt, ERK, or CaMK IV in the hippocampal tissue of the brain region.

Images