Neurofeedback and induction of immune response

Abstract

To provide a method for inducing an immune response in a subject.SOLUTION: Provided is a method for inducing an immune response in a subject, including a step of activating mesolimbic neurons in the subject by applying a neurofeedback, thereby inducing an immune response in the subject.SELECTED DRAWING: Figure 8

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 813,059, filed on March 3, 2019, entitled "Neurofeedback and Induction of Immune Responses", the contents of which are hereby incorporated by reference in their entirety.

[0002] In some embodiments, the present invention is in the fields of neuroimmunology and neuromodulation.

Background Art

[0003] The placebo response related to the neuronal reward system is one of the most fascinating phenomena in modern medicine and is an example of the potential of the mental state to affect one's clinical state and overall well - being. As revealed by the placebo response, deciphering the neuronal mechanisms that mediate the interaction between the brain and the body holds the potential to harness the brain's healing capabilities. Recently, a causal relationship between activation of the reward system and immune function has been reported in mice. This discovery has great potential to improve personal health management and rationalize the use of reward - related brain activation to enhance immune function.

[0004] Biofeedback, a technology developed in the 1960s, individually teaches how to regulate autonomic body functions that are normally considered outside the realm of conscious control. Biofeedback is based on the concept that immediate and continuous feedback of information amplifies conditioned responses so that spontaneous control is achieved. Biofeedback consciously regulates autonomic functions such as heart rate, skin conductance, and the functions of the intestines and bladder. People can be trained to regulate higher-order unconscious biological processes such as pain, motor ability, and anxiety. Brain activity or connectivity training using biofeedback, i.e., brain functionality training, is called neurofeedback (NF). Generally, neurofeedback relates to a brain-computer interface approach, i.e., closing the loop with the brain through a computerized interface. Learning through neurofeedback can include both voluntary and involuntary techniques. It has even become possible to regulate biological processes. Brain activity or connectivity training using biofeedback, i.e., brain functionality training, is called neurofeedback (NF). Generally, neurofeedback relates to a brain-computer interface approach, i.e., closing the loop with the brain through a computerized interface. Learning through neurofeedback can include both voluntary and involuntary techniques. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0005] According to a first aspect, a method for inducing an immune response in a subject is provided, the method comprising activating mesolimbic neurons in the subject by applying neurofeedback, thereby inducing an immune response in the subject. In some embodiments, the mesolimbic neurons are located in the ventral tegmental area (VTA), bilateral ventral striatum (VS), or a combination thereof. MEANS FOR SOLVING THE PROBLEM

[0006] In some embodiments, inducing an immune response includes activating or increasing the immune response. In some embodiments, the immune response is selected from the group consisting of a vaccination response, a humoral response, a cytotoxic response, an innate immune response, and an acquired immune response.

[0007] In some embodiments, inducing an immune response includes activating or increasing the immune response.

[0008] In some embodiments, the immune response is selected from the group consisting of a vaccination response, a humoral response, a cytotoxic response, an innate immune response, and an acquired immune response.

[0009] ​​​​In some embodiments, the increased vaccine efficacy is compared to a control and is determined based on the antibody concentration in plasma, the antibody biological half-life in plasma, or a combination thereof. It is determined.

[0010] In some embodiments, the neurofeedback includes electroencephalography (EEG), functional magnetic resonance imaging (fMRI), or a combination thereof.

[0011] In some embodiments, the subject has an immunodeficiency disease.

[0012] In some embodiments, the subject has an infectious disease.

[0013] In some embodiments, the infectious disease is a viral disease.

[0014] In some embodiments, the subject has cancer.

[0015] In some embodiments, the subject requires vaccination.

[0016] Unless otherwise defined, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In practicing or testing the embodiments of the present invention, methods and materials similar or equivalent to those described herein can be used, but exemplary methods and / or materials are described below . If there is a conflict, the patent specification including the definitions will control. In addition, the materials, methods, and examples are illustrative only and are not necessarily intended to be limiting. It is not necessarily intended to limit.

[0017] Further embodiments and full scope of application of the present invention will become apparent from the detailed description shown below will be. However, various changes and modifications within the spirit and scope of the present invention will become apparent to those skilled in the art from this detailed description, so the preferred embodiments of the present invention are shown while the detailed description and specific examples of the present invention are given only by way of illustration and should be understood.

Brief Description of the Drawings

[0018]

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Mode for Carrying Out the Invention

[0019] In some embodiments, the present invention is a method for inducing an immune response in a subject comprising applying neuromodulation feedback (NF) to up - regulate the midbrain A method including the step of activating limbic neurons, thereby inducing an immune response in a subject. It is directed to a method.

[0020] In some embodiments, the mesolimbic neurons are located in the ventral tegmental area (VTA), bilateral ventral striatum (VS), or a combination thereof.

[0021] In some embodiments, activating the mesolimbic neurons includes co - activating neurons located within the VTA and neurons located within the VS.

[0022] In some embodiments, inducing an immune response increases, elevates, activates, or differentially activates an immune response, or any combination thereof.

[0023] In some embodiments, the immune response includes any response taken by the body to defend itself from pathogens or abnormalities. In one embodiment, the immune response includes a response mediated by or involving immune cells.

[0024] In one embodiment, the immune response includes any response that activates or inhibits the immune system or mediators of the immune system. In another embodiment, activation of the immune response includes activation of immune cells. In another embodiment, activation of immune cells results in proliferation of a subset of immune cells. In another embodiment, activation of immune cells results in increased secretion of immune mediators by the activated cells. In another embodiment, activation of immune cells results in phagocytosis and / or destruction of pathogens, foreign cells, diseased cells, molecules derived or secreted therefrom, or any combination thereof. In another embodiment, activation of immune cells is limited ​ However, it results in the phagocytosis and destruction of neighboring cells such as virus-infected cells. In another embodiment, the activation of immune cells results in the activation of the secretion of antibodies directed against a specific molecule, epitope, pathogen, or any combination thereof.

[0025] In some embodiments, the immune response is a cytotoxic response. As used herein, a cytotoxic response includes the activation of the complement system and refers to a response that results in cell lysis and / or other damage.

[0026] In some embodiments, the immune response is a humoral response, i.e., it includes the production and secretion of antibodies.

[0027] In some embodiments, the immune response is an innate response, i.e., it includes the innate immune system.

[0028] In some embodiments, the immune response is an adaptive immune response, i.e., it includes the adaptive immune response.

[0029] In some embodiments, the immune response is any response that activates B cells, dendritic cells, macrophages, natural killer (NK) cells, T cells, thymocytes, or any combination thereof. In another embodiment, the response that activates the cells as described herein results in the proliferation of cells or other immune cells, the secretion of immune mediators such as cytokines, the migration of immune cells, the activation of the immune cascade, the removal of foreign molecules or cells, or any combination thereof.

[0030] In another embodiment, the immune response is associated with a disease, and the methods described herein It is used to optimize the immune response according to the state.

[0031] In some embodiments, applying the method of the present invention results in an increase in the production, secretion, or both of one or more cytokines. In some embodiments, one or more cytokines are selected from TNFα, INFγ, IL-6, IL-4, and / or any combination thereof.

[0032] In another embodiment, the immune response is related to cancer treatment in which the immune response is triggered against tumor / cancer cells or cancer / tumor antigens. In another embodiment, the method of the present invention for inducing an immune response has a direct positive effect on cancer treatment.

[0033] In some embodiments, the immune response is a vaccination response. In some embodiments, the method of the present invention is aimed at optimizing vaccination. In some embodiments, the optimized vaccination results in an increased vaccination effect.

[0034] The term "efficacy" as used herein in conjunction with vaccination refers to how well any treatment utilizing a compound, substance, drug, composition, vaccine, or the like thereof actually (i.e., treats a subject), in clinical trials (e.g., research studies), or both, functions (e.g., the amount or degree).

[0035] The terms "efficacy" and "effectiveness" are used interchangeably herein.

[0036] Methods for determining the efficacy or effectiveness of vaccination are common and apparent to those skilled in the art. will be

[0037] In some embodiments, the increased vaccine efficacy, compared to a control, includes an increased concentration, titer, biological half-life, amount, or any combination thereof of antibodies in the plasma of the subject. In some embodiments, the increased vaccine efficacy includes increasing the production of antibodies in the subject, compared to a control. In some embodiments, the increased vaccine efficacy includes increased antibody diversity, compared to a control. In some embodiments, the increased vaccine efficacy includes increased antibody arsenal, compared to a control. In some embodiments, the increased vaccine efficacy includes an increased antibody repertoire that can target or respond to a broader range of antigens, compared to a control. In some embodiments, the increased vaccine efficacy, compared to a control, includes an increased concentration, titer, biological half-life, amount, or any combination thereof of a specific type of antibody in the plasma of the subject. In some embodiments, the increased vaccine efficacy includes increased production of a specific type of antibody in the subject, compared to a control. As used herein, a specific type of antibody is the class to which the antibody belongs (i.e., IgA, IgD, IgE, IgG, and IgM), or a subclass thereof (e.g., In some embodiments, the increased vaccine efficacy includes an increased concentration, titer, biological half-life, amount, or any combination thereof of a specific type of antibody in the plasma of the subject. In some embodiments, the increased vaccine efficacy includes increased production of a specific type of antibody in the subject, compared to a control. As used herein, a specific type of antibody is the class to which the antibody belongs (i.e., IgA, IgD, IgE, IgG, and IgM), or a subclass thereof (e.g., In some embodiments, the increased vaccine efficacy includes an increased antibody repertoire that can target or respond to a broader range of antigens, compared to a control.

[0038] As used herein, the term "antibody repertoire" refers to all of the specific types of antibodies produced or producible by a subject. In some embodiments, the increased vaccine efficacy, compared to a control,

[0039] includes an increased concentration, titer, biological half-life, amount, or any combination thereof of a specific type of antibody in the plasma of the subject. In some embodiments, the increased vaccine efficacy includes increased production of a specific type of antibody in the subject, compared to a control. As used herein, a specific type of antibody is the class to which the antibody belongs (i.e., IgA, IgD, IgE, IgG, and IgM), or a subclass thereof (e.g., In some embodiments, the increased vaccine efficacy, compared to a control, includes an increased concentration, titer, biological half-life, amount, or any combination thereof of a specific type of antibody in the plasma of the subject. In some embodiments, the increased vaccine efficacy includes increased production of a specific type of antibody in the subject, compared to a control. As used herein, a specific type of antibody is the class to which the antibody belongs (i.e., IgA, IgD, IgE, IgG, and IgM), or a subclass thereof (e.g., IgA, IgD, IgE, IgG, and IgM), or a subclass thereof (e.g., IgA1, IgG1, IgG2, etc.), specific molecules, antigens, or epitopes to which they react, or any combination thereof. It is defined based on the epitopes of these or any combination thereof.

[0040] As used herein, the term "increased production" includes increased production yield, increased production rate, increased production capacity, or any combination thereof.

[0041] In some embodiments, the increase is at least 5% or more, at least 20% or more, at least 50% or more, at least 75% or more, at least 1 00% or more, at least 250% or more, at least 500%, at least 750% or more, or at least 1000% or more, and any value and range therebetween. In some embodiments, the increase is more than 5 - 25%, more than 20 - 75%, more than 50 - 120%, more than 75 - 150%, 100 - 250 %, more than 200 - 550%, more than 500 - 750%, or more than 700 - 1 000% compared to the control. Each possibility represents a separate embodiment of the invention.

[0042] In some embodiments, an efficacy - increasing vaccine (e.g., resulting from the practice of the methods of the present invention) induces or promotes the production of more antibodies in a subject compared to a control. In some embodiments, an efficacy - increasing vaccine results in more antibodies in the plasma of a subject compared to a control. In some embodiments, an efficacy - increasing vaccine induces or promotes the production of antibodies with an increased biological half - life in the plasma compared to a control. In some embodiments, an efficacy - increasing vaccine is a specific antibody ​ result in an increase in the memory response, production or secretion of antibodies, antibody repertoires, or any combination thereof.

[0043] In one embodiment, the present invention is directed to a method for treating, comprising the step of inducing midbrain - limbic neurons. In another embodiment, cancers treatable by the methods of the present invention include solid tumors. In another embodiment, the methods of the present invention result in inhibiting tumor growth. In another embodiment, the methods of the present invention result in inhibiting metastasis.

[0044] In another embodiment, cancers treatable by the methods described herein include adrenocortical carcinoma, anal cancer, bladder cancer, brain tumor, brainstem glioma, brain tumor, cerebellar astrocytoma, cerebral astrocytoma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal, pineal tumor, hypothalamic glioma, breast cancer, carcinoid tumor, carcinoma, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, extrahepatic bile duct cancer, Ewing's tumor family (PNET), extracranial germ cell tumor, eye cancer, intraocular melanoma, cystadenocarcinoma, gastric cancer, germ cell tumor, extragonadal, gestational trophoblastic tumor, head and neck cancer, hypopharyngeal cancer, islet cell cancer, laryngeal cancer, leukemia, acute lymphoblastic, leukemia, oral cancer, liver cancer, lung cancer, small cell, lymphoma, AIDS - related, lymphoma, central nervous system (primary), lymphoma, cutaneous T - cell, lymphoma, Hodgkin's disease, non - Hodgkin's disease, malignant mesothelioma, melanoma, Merkel cell carcinoma, metastatic squamous cell carcinoma, multiple myeloma, plasma cell neoplasm, mycosis fungoides, myelodysplastic syndrome, myeloproliferative disorder, nasopharyngeal cancer, neuroblastoma, oropharyngeal cancer, osteosarcoma, ovarian epithelial cancer, ovarian germ cell tumor, low - grade ovarian tumor, pancreatic cancer, exocrine, pancreatic cancer, islet cell cancer, paranasal and nasal cancer, parathyroid cancer, penile cancer, pheochromocytoma, ​​​​​Cell carcinoma, pituitary carcinoma, plasmacytoma, prostate cancer, rhabdomyosarcoma, rectal cancer, renal cell carcinoma, salivary adenocarcinoma, Sézary syndrome, skin cancer, cutaneous T-cell lymphoma, skin cancer, Kaposi sarcoma, skin cancer, black tumor, small intestine cancer, soft tissue sarcoma, soft tissue sarcoma, testicular cancer, thymoma, malignant, thyroid cancer, urethral cancer, uterine cancer , sarcoma, abnormal childhood cancer, vaginal cancer, vulvar cancer, or Wilms tumor.

[0045] As used herein, the disease is an immune system disorder. In some embodiments, the immune system disorder is associated with abnormally low activity of the immune system. In another embodiment, the immune system disorder is an immunodeficiency disease. Non-limiting examples of immunodeficiency diseases are AIDS. In another embodiment the disease is an inflammatory disease. In another embodiment, the disease is a cell proliferation-related disease . In another embodiment, the disease is cancer. In some embodiments, the disease is an infectious disease. In some embodiments, the disease is a viral disease. The type of viral disease will be apparent to those skilled in the art. In one embodiment, the viral disease is influenza . In one embodiment, the viral disease is hepatitis B.

[0046] As used herein, the term "control" includes a subject, or a sample derived therefrom wherein the subject has not had a neurfeedback applied to neurons of the mesolimbic network. In some embodiments, the control subject has not been transcranially stimulated. In some embodiments, the control is a vaccinated subject, or a sample derived therefrom, where the control subject has had a neurfeedback applied to neurons of the mesolimbic network, or has had a neurfeedback applied thereto, ​It is not possible. In some embodiments, the control is a subject or a sample derived therefrom, where the control subject has or has not had neuronal feedback applied to neurons of the mesolimbic network.

[0047] In some embodiments, the control is a response (i.e., an immune response) regardless of the presence or absence of neuronal feedback application.

[0048] According to another embodiment, the method of the invention comprises inducing an immune response in a subject by co - activating mesolimbic neurons in the VTA and VS in the subject by applying neuronal feedback.

[0049] In some embodiments, activating the mesolimbic neurons comprises co - activating neurons located within the VTA and neurons located within

[0050] the VS. In some embodiments, mesolimbic co - activation (VTA and VS) results in an enhanced immune response compared to single activation (i.e., VTA or VS). In some embodiments, mesolimbic co - activation results in an equivalent improvement in the immune response compared to single activation (i.e., VTA or VS). In some embodiments, mesolimbic co - activation (VTA and VS) results in a synergistically

[0051] Neuronal feedback Generally, the invention utilizes real - time brain imaging or recording During a neurofeedback session, to modify his or her neuronal activity targets a method of training an individual subject. In some embodiments, the present method includes providing feedback to the subject to enable the subject to modify his or her neuronal activity within a selected brain region, area, or circuit. In some embodiments, the selected brain target being imaged is associated with a particular disease or disorder.

[0052] The subject can be treated, for example, using the following methods. In some cases, depending on the subject's condition, the subject may need to visit a clinic or research facility multiple times. rt -fMRI neurofeedback is provided to the subject based on images from specific regions or circuits of the brain. In some cases, the first rt-fMRI neurofeedback training is used to teach the subject how to use the system, and then the actual session is completed while the subject is required to complete a specific cognitive task during that time. In subsequent visits the subject receives substantially the same procedure as described for the first visit.

[0053] As used herein, "neurofeedback" makes available to the subject one or more recordings of the subject's neurological activity to which the subject typically does not have direct conscious access.

[0054] In one embodiment, the method of the invention is directed to fMRI-based neurofeedback. fMRI is an indirect method of visualizing neuronal activity in local brain regions and measures blood oxygenation level-dependent (BOLD) T2 weighted signal changes. The term "fM * ​ “RI feedback”, “fMRI neurofeedback”, etc. are interchangeable, In this specification, it refers to the use of an fMRI device to display or provide a display of the brain activity of a subject in a real-time or substantially simultaneous manner. As used herein, fMRI measures brain activity by detecting changes related to (BOLD) contrast for use in displaying or providing a display of the brain activity of a subject. In one embodiment, high BOLD values indicate highly active neural regions. In one embodiment,

[0055] active neurons have a greater BOLD level compared to inhibitory, suppressed, or inactivated neurons. In some embodiments, the use of fMRI neurofeedback can improve the correspondence between first-person experience and a specific brain activation pattern in a manner that has minimal impact on the experience itself. In some embodiments, the use of fMRI provides the mediator with the ability to enhance their control over their own brain activity. In some embodiments, the use of fMRI neurofeedback directly correlates subjective experience with neural activation. In some embodiments, as will be understood by those skilled in the art, fMRI neurofeedback data can be integrated and presented to the subject being measured via any type of visual, auditory, or other sensory mechanism. Non-limiting examples include visual displays, interactive visual displays (e.g., video games), auditory signals, or tactile signals. Optionally, the information can be further streamed to the subject. In some embodiments, the method In some embodiments, as will be understood by those skilled in the art, fMRI neurofeedback data can be integrated and presented to the subject being measured via any type of visual, auditory, or other sensory mechanism. Non-limiting examples include visual displays, interactive visual displays (e.g., video games), auditory signals, or tactile signals. Optionally, the information can be further streamed to the subject. In some embodiments, the method ​​It includes a step of measuring the activity of the mesolimbic network of the subject by fMRI, and simultaneously with the measurement a step of presenting a display of the mesolimbic activity of the subject to the subject, and a step of instructing the subject to change their meditation state such that, as a result, the change to the meditation state increases the mesolimbic activity. In some embodiments, the present invention is directed to a method for inducing an immune response, including a step of measuring the activity of the mesolimbic system of the subject by fMRI, a step of presenting a display of the activity of the mesolimbic system of the subject to the subject simultaneously with the measurement a step of instructing the subject to enter a meditation state, and a step of instructing to increase the activity of the mesolimbic system displayed by optimizing their current meditation state and .

[0056] In one embodiment, the neurofeedback is functional near-infrared spectroscopy (fNIRS). In some embodiments, the method using fNIRS measures brain activity through the hemodynamic response related to neuronal behavior.

[0057] In one embodiment, the neurofeedback is diffusion-weighted magnetic resonance imaging (DWI or DW-MRI). DWI is common and will be apparent to those skilled in the art as an MRI modality that utilizes the diffusion of water molecules to generate contrast in MR images. In one embodiment, DWI includes diffusion tensor imaging (DTI). In one embodiment, DWI includes perfusion and white matter diffusion MRI.

[0058] In one embodiment, the neurofeedback is functional magnetic resonance spectroscopy (fMRS). fMRS generates a resonance spectrum, and the area under the peak of the spectrum represents the relative concentration of metabolites. represents. In one embodiment, the method using fMRS provides multiple spectra and studies the metabolic metabolite concentration dynamics during brain function. In some embodiments, fMRS is dynamic MRS. In some embodiments, fMRS is event-related MRS. In some embodiments, fMRS is time-resolved MRS. In some embodiments fMRS is functional diffusion-weighted spectroscopy (fDWS). In some embodiments fDWS determines the diffusion characteristics of brain metabolites after brain activation.

[0059] In one embodiment, neurofeedback is EEG (electroencephalogram) neurofeedback As used herein, "EEG neurofeedback" refers to the EEG activity of a subject as a physiological system used for neurofeedback. In another embodiment, the EEG waveform changes at frequencies from 0.01 to 100 Hz. In another embodiment EEG is recorded from electrode sensors placed on or in the brain. In another embodiment EEG is recorded from electrode sensors placed on the scalp surface. In another embodiment in EEG neurofeedback, the electroencephalogram profile is presented to the subject and the subject receives a reward to change the profile. In another embodiment, the reward includes, but is not limited to, pleasant sounds, continuous sounds, dichotic sounds, visual displays, or others. In another embodiment, the neurofeedback according to the method of the present invention includes any combination of fMRI, fNIRS, DWI or DW-MRI, fMRS and EEG neurofeedback.

[0060] In one embodiment, the neurofeedback by the method of the present invention includes any combination of fMRI, fNIRS, DWI or DW-MRI, fMRS and EEG neurofeedback. combination of fMRI, fNIRS, DWI or DW-MRI, fMRS and EEG neurofeedback.

[0061] As long as the activation of neurons in the mesolimbic network is maintained / achieved, any neurofeedback modality is applicable.

[0062] One of ordinary skill in the art will understand to apply neurofeedback as described above as part of a medication or an improvement thereof.

[0063] As used herein, the term "subject" refers to any subject, particularly a mammalian subject, such as a human, for whom treatment is desired.

[0064] In the specification and claims of the present application, each of the verbs "comprise", "include" and "have" and their respective inflected forms are used to indicate that the subject or object of the verb is not necessarily a complete list of the components, elements or parts of the subject or object of the verb. are used.

[0065] Throughout the present application, various embodiments of the invention can be presented in range format. The description in range format is for convenience only and should not be construed as a rigid limitation on the scope of the invention. It should be understood, therefore, that a description of a range is considered to specifically disclose not only the individual numerical values within that range but also all possible subranges. For example, a description of a range such as 1-6 is considered to specifically disclose subranges such as 1-3, 1-4, 1-5, 2-4, 2-6, 3-6, etc., as well as the individual numbers within that range, e.g., 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range. This applies regardless of the breadth of the range.

[0066] Unless otherwise specified in the specification, the features or feature conditions of the embodiments of the present invention Adjectives such as "substantially" and "about" that modify a condition or relative characteristic of the embodiment are understood to mean that the condition or characteristic is defined within an acceptable range acceptable for the operation of the embodiment for its intended use. Unless otherwise specified, the term "or" in the specification and claims is to be regarded as inclusive rather than exclusive, indicating at least one of the items it combines or any combination thereof.

[0067] In the specification and claims of the present application, each of the verbs "comprise", "include" and "have" and their conjugations is used to indicate that the subject or object of the verb is not necessarily a complete list of the components, elements or parts of the subject or object of the verb.

[0068] Other terms used in this specification are defined by their known meanings in the relevant technical field.

[0069] Further objects, advantages and novel features of the present invention will become apparent to those skilled in the art by considering the following examples, which are not intended to be limiting. In addition, each of the various embodiments and aspects of the present invention described herein and recited in the claims below finds experimental support in the following examples.

[0070] For clarity, it is understood that specific features of the present invention described in the context of separate embodiments may also be provided in combination in a single embodiment. Conversely, the various features of the present invention briefly described in the context of a single embodiment may be​​ nation, or as appropriate in any other described embodiment of the invention, provided can also be. Specific features described in the context of various embodiments should be considered essential features of those embodiments only if the embodiments are inoperable without those elements should not.

Example

[0071] Materials and Methods fMRI-NF training session In each NF run consisting of 5 NF cycles, an intermittent feedback protocol is applied. Each NF practice session includes 3 NF runs, and each session is 15 cycles (about 25 minutes). In EEG-NF practice, multiple sessions are employed. In fMRI-NF, probably due to scan costs, and probably because fMRI provides more accurate measurements for specific functions, usually fewer sessions (between 1 session and 4 sessions) are applied. According to a pilot study of mesolimbic reward network modulation, it was found that the maximum mesolimbic reward network modulation was observed during the 4th session Therefore, 4 NF practice sessions are applied, resulting in 60 NF cycles. Immediately after the 4th session, which is expected to induce the strongest neuromodulation the subject receives a hepatitis B vaccination.

[0072] NF transfer task A transfer task is applied at the end of each NF practice session, during which the subject receives the same instructions as during the NF task and the feedback at the end of the adjustment phase ​​​Only without cued screens, i.e., the subjects apply those mental strategies without feedback guidance. Thus, the BOLD activation in this task indicates the applicability of our

[0073] Functional MRI resting scans To assess the neural correlates of cytokine concentrations before NF, after NF, before vaccination, and 3 days after vaccination (when cytokine concentrations are expected to reach their peak), functional resting scans are applied during these sessions. During the resting scans, the subjects

[0074] are instructed to fixate their gaze on a cross centered on a black screen and move as little as possible.

[0075] Blood is drawn from all participants at the Ichilov Medical

[0075] Center in Tel-Aviv. Plasma is separated from serum using centrifugation and then stored at -80°C, and whole blood samples are stored for later analysis. To effectively preserve whole blood samples and ensure proteomic The concentration is quantified using enzyme-linked immunosorbent assay (ELISA).

[0076] Example 1 Neuromodulation induces an immune response The inventors implemented new software for fMRI-NF, which enabled customization of fMRI-NF to specific needs, and an fMRI-NF session targeting the limbic region of the brain (VTA in the midbrain) was conducted on six participants -NF to specific needs, and an fMRI-NF session targeting the limbic region of the brain (VTA in the midbrain) was conducted on six participants The results reflect the inventors' analysis of fMRI modulation (NF vs. baseline) in the mesolimbic test region Based on the neurofeedback pilot, the inventors set several important research parameters such as task length Based on the neurofeedback pilot, the inventors set several important research parameters such as task length , means to individually select brain regions for regulation, and the rules of communication with the subject during the experiment -chins. Importantly, in addition to utilizing the neurofeedback paradigm, the inventors applied different mental strategies (as revealed by offline analysis) by the subject so that the mesolimbic activity dynamics changed significantly in such a way that the subject could regulate it within a single session -chins. Importantly, in addition to utilizing the neurofeedback paradigm, the inventors applied different mental strategies (as revealed by offline analysis) by the subject so that the mesolimbic activity dynamics changed significantly in such a way that the subject could regulate it within a single session (as revealed by offline analysis), and confirmed that the mesolimbic activity dynamics changed significantly in such a way that the subject could regulate it within a single session (as revealed by offline analysis), and confirmed that the mesolimbic activity dynamics changed significantly in such a way that the subject could regulate it within a single session .

[0077] Furthermore, the subjects were vaccinated against hepatitis B surface antigen (HB), and blood samples were collected for HB antibody (anti-HB) measurement The immunological results showed a positive correlation with the neuromodulatory effect (Figure 4). Therefore, neurofeedback regulation can induce an immune response The immunological results showed a positive correlation with the neuromodulatory effect (Figure 4). Therefore, neurofeedback regulation can induce an immune response .

[0078] Example 2 Upregulation of the mesolimbic pathway by co-activation of VTA and VS The inventors pursued a more accurate and effective mesolimbic modulation paradigm. In this regard Based on the Neurosynth.org meta-analysis results of the functional activation of the reward circuit Three additional pilot studies were conducted that upregulate the simultaneous activation of three major mesolimbic nodes that are anatomically defined and restricted, including the mesolimbic network NF This network is known to include the VTA and bilateral ventral striatum. As is clear from the results (Figure 5), the three regions are substantially correlated, indicating the functional relationship between them. Therefore, the co-activation of the VTA and VS by neurofeedback can upregulate the mesolimbic pathway and subsequently upregulate the induced immune response (Figure 5), the three regions are substantially correlated, indicating the functional relationship between them. Therefore, the co-activation of the VTA and VS by neurofeedback can upregulate the mesolimbic pathway and subsequently upregulate the induced immune response .

[0079] Example 3 Activation of the mesolimbic pathway by NF improves the effectiveness of vaccination Fifteen participants are randomly assigned to three groups: the mesolimbic network NF group, the control region of interest (ROI) NF group, and the untreated group (blood tests and vaccination only). Two active NF test groups are used to evaluate the correlation and causal relationship between the voluntary regulation of the mesolimbic system and the immunological effects . The "untreated" group is used to evaluate the consistency of the normal immunological response to hepatitis B vaccination and thus constitutes a comparison group for evaluating the magnitude of the immunological effect . Any correlation between mesolimbic activation and immunological effects, or a consistent measurable immunological response to hepatitis B vaccination is considered a satisfactory result and thus indicates an improvement in the effectiveness of vaccination . is considered a satisfactory result and thus indicates an improvement in the effectiveness of vaccination .

[0080] Example 4 Self-regulate the nodes located deep within the mesolimbic reward network via fMRI-NF The ability of the subject To clarify the causal relationship between mesolimbic reward network activity and immunological effects, the meso Substantial and accurate induction of the limbic reward network is required, which is considered difficult For that purpose, the inventors dissociated the feedback reward cue from the adjustment phase and thus By using an intermittent feedback protocol that allows for a cleaner measure of adjustment success that is not Contaminated by external reward cues, we customized the state-of-the-art fMRI-NF software ( OpenNFT) for the desired mesolimbic reward network regulation. Furthermore, the inventors hypothesized That by upregulating the mesolimbic reward circuit, i.e., the VTA along with its ascending dopaminergic Counterparts, i.e., the bilateral ventral striatum, to promote our desired dopaminergic activity and reward Related activity, this should further ensure the excitation of the desired neural mechanism. Finally, to Answer the question of whether the subject can self-induce substantial neural activation in the region Specified via the fMRI-NF protocol, the inventors conducted a pilot study Ten (10) healthy subjects participated in 2-4 fMRI-NF practice sessions on the mesolimbic reward network The data were analyzed using the above pipeline. The results are shown in FIGS. 6-8. 6 to 8.

[0081] The inventors found a significant difference in BOLD activation between NF task conditions in the desired Direction (regulation > wacht; FIG. 6), indicating that the subjects were able to upregulate mesolimbic Activity. Furthermore, from FIG. 7, the overall difference was due to the engagement and effort of general Rather than being the result of entanglement, it is shown to result from the progressive development of regulatory skills imparted to the subject by practice. As a result, these results suggest that a customized fMRI-NF protocol was designated to promote substantial neural activation in the mesolimbic reward network to examine its association with immunological outcome measures. To examine whether the subject learned to regulate mesolimbic activity without feedback and thus learned to gather evidence regarding the applicability of the intervention, the inventors applied a transfer task at the end of each NF practice session, during which the subject received instructions similar to those received during the NF task without feedback display. The results are shown in FIG. 8.

[0082]

[0083] Example 5 Evaluation of immunological outcome measures To test the effect of neuromodulation on the immune system, the inventors selected HBV as a defined immunological challenge with known kinetics and, as outcome measures, selected the developed antibodies in blood and cytokines, evaluated 3, 14, and 28 days after vaccination. However, the hepatitis B vaccine (HBV) is considered to be quite effective, and most adults have been vaccinated in infancy, raising two valid concerns. First, the baseline HB antibody levels may vary among subjects depending on their vaccination history, which may introduce noise into our data and prevent clear conclusions. Second, the vaccine may induce an immunological response that is too large to vary further due to neuromodulation (i.e., a possible ceiling effect). ​ To evaluate these limitations and obtain preliminary evidence regarding the immunological effects after HBV vaccination, 7 subjects participated in a pilot study. Four subjects completed the entire test protocol (Figure 6), and an additional 3 subjects completed a non-NF test protocol to evaluate the immunological impact at baseline. The results are shown in Figures 9-10. As shown in Figure 9, the baseline levels of HBV antibodies were high in 2 subjects before vaccination. Importantly, these 2 subjects reported receiving 1 out of 3 (NF_sub-02) or all 3 (noNF_sub-01) Hep.B shots approximately 10 years prior to the experiment. Therefore, the inventors verified the exclusion criteria regarding vaccination history, thereby minimizing the contamination of results with fluctuating baseline levels. Furthermore, the post-test immunological responses (both HBV and cytokines) varied among subjects in terms of both magnitude and temporal dynamics. Importantly, this addressed the concern of a potential ceiling effect: despite generally strong antibody expression after vaccination, there was significant variability among subjects in this outcome measurement dynamic. For example, most individuals showed an increase in antibody levels on day 14 after vaccination, but 1 subject showed an increase in levels at TP7 on day 28 after vaccination. Similarly, most individuals reached a plateau after this initial increase, while others showed further increases or decreases. Collectively, these results demonstrated the importance of the timing of immunological measurements for capturing critical periods.

[0084]

[0085] ​​​​​​​​​​​​​​​​The inventors further examined cytokine levels over all time points. Figure 1 0 shows a particularly clear pattern of change among individuals who received NF training before vaccination. There is.

[0086] The NF subjects showed an increase in levels 5 days after vaccination (TP5) and a stronger immune response to vaccination. Although these results should be interpreted with caution, they provide insightful evidence for possible outcomes of the current design. There is. Provide evidence for possible outcomes of the current design.

[0087] In this specification, specific features of the invention have been described, but many modifications, substitutions, changes, and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the scope of the claims is intended to protect all such modifications and changes as falling within the true spirit of the invention. There is. Please understand that you are trying to protect.

Claims

1. A method for inducing an immune response in a subject, comprising applying neurofeedback. thereby activating mesolimbic neurons in the subject, thereby The method comprises the step of inducing an immune response in a subject.

2. The mesolimbic neurons are located in the ventral tegmental area (VTA), the bilateral ventral striatum (VS), and is located at a combination thereof.

3. Activating the mesolimbic neurons interacts with neurons located within the VTA.

3. The method of claim 1 or 2, further comprising coactivating a neuron located in the VS with a neuron located in the VS. Method of posting.

4. Inducing the immune response comprises activating or increasing the immune response. The method according to any one of claims 1 to 3.

5. The immune response may be a vaccination response, a humoral response, a cytotoxic response, an innate immune response, The method according to any one of claims 1 to 4, wherein the method is selected from the group consisting of: Law.

6. The vaccination response can be measured by measuring plasma antibody concentration, ... The method of claim 5, wherein the concentration is determined based on the biological half-life, the concentration of the active ingredient ... biological half-life, or a combination thereof.

7. The neurofeedback may be performed using electroencephalography, functional magnetic resonance imaging, functional near-infrared spectroscopy, or the like. The claimed method includes a method for detecting a tumor, ... The method according to any one of claims 1 to 6.

8. The method of any one of claims 1 to 7, wherein the subject is suffering from an immunodeficiency disease.

9. The method of any one of claims 1 to 7, wherein the subject is suffering from an infectious disease.

10. The method of any one of claims 1 to 7, wherein the subject is suffering from cancer.

11. 10. The method of claim 9, wherein the infectious disease is a viral disease.

12. The method of any one of claims 1 to 11, wherein the subject is in need of a vaccination.

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