Brain function improving agent, use for manufacturing brain function improving agent, and method for improving brain function

Abstract

Provided are: a brain function-improving agent with which a brain function-improving effect can be obtained regardless of the state of acquisition of sleep; a use for producing a brain function-improving agent; and a method for improving brain function. The present invention relates to an agent for improving brain function, which comprises, as an active ingredient, at least one of a cell of Lactobacillus paracasei and a treated product of the cell of Lactobacillus paracasei. The present invention also relates to the use of at least one of a cell of Lactobacillus paracasei and a treated product of the cell of the Lactobacillus paracasei in the manufacture of an agent for improving brain function, and to the use of the cell of Lactobacillus paracasei and a treated product of the cell of the Lactobacillus paracasei in the manufacture of an agent for improving brain function. The present invention also relates to a method for improving brain function, wherein the brain function is continuously ingested orally for at least four weeks in an amount of 1010 cfu / day or more in terms of the viable count of Lactobacillus paracasei.

Description

[Technical Field]

[0002] This disclosure relates to agents that enhance brain function. [Background Technology]

[0004] The human brain is known to consist of the cerebrum, brainstem, and cerebellum, which work together to perform complex tasks, such as thinking, remembering, and making decisions based on stimuli transmitted from the extremities via the spinal cord. Furthermore, in everyday life, it is known that physical and mental fatigue, especially mental fatigue, can be relieved through rest or sleep.

[0005] On the other hand, in modern society with its 24-hour activity and widespread internet use, physical and mental fatigue caused by long working hours and shift work, resulting in symptoms such as drowsiness, fatigue, stiff shoulders, headaches, back pain, abdominal pain, constipation, dizziness, fever, hot flashes, anxiety, palpitations, eye strain, memory loss, decreased concentration or motivation, and irritability—all stemming from brain dysfunction—has been identified as a social problem. Such discomfort is not only a symptom of illness but also leads to decreased performance and an increased risk of errors and accidents. Consequently, economic losses due to decreased productivity also become a problem (Reference: https: / / www.meti.go.jp / policy / mono_info_service / healthcare / kenkokeiei-guidebook2804.pdf). For such brain dysfunction caused by rest or sleep alone, methods independent of sleep are proposed.

[0006] For example, Patent Document 1 discloses that docosahexaenoic acid (DHA) not only improves cognitive function impaired by aging, dementia, or brain disorders, but also improves cognitive response function in healthy individuals. Furthermore, Patent Document 2 discloses that arachidonic acid and / or compounds with arachidonic acid as a constituent fatty acid prevent, improve, or enhance the decline in normal cognitive responses. Moreover, Patent Document 3 discloses an effect on increased alertness of the brain before and after brushing teeth.

[0007] [Existing Technical Documents]

[0008] [Patent Documents]

[0009] Patent Document 1: Japanese Patent Application Publication No. 10-059844

[0010] Patent Document 2: Japanese Patent Publication No. 2006-502196

[0011] Patent Document 3: Japanese Patent Application Publication No. 2011-5056 [Summary of the Invention]

[0013] [The problem the invention aims to solve]

[0014] The aforementioned existing technologies do not provide brain function enhancers suitable for the lifestyles of modern people. The inventors conducted various studies to discover components that can improve brain function regardless of whether sufficient sleep is obtained. As a result, it was found that ingesting Lactobacillus (… Lacticaseibacillus Lactobacillus paracasei, in particular, is a member of the genus Lactobacillus. Lacticaseibacillus paracasei Bacterial cells or their processed products can improve brain function.

[0015] [Solutions for solving the problem]

[0016] To address the problems illustrated above, a brain function enhancer according to one embodiment of the present invention is characterized by containing *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei At least one of the bacterial cells and their processed products is used as the active ingredient.

[0017] Furthermore, one embodiment of the invention is characterized by the presence of *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei The use of at least one of the bacterial cells and their processed products in the manufacture of brain function enhancers.

[0018] Furthermore, a method for improving brain function according to one embodiment of the present invention is characterized by using *Lactobacillus paracasei* (… Lacticaseibacillus paracasei The number of viable bacteria was 10. 10 Continue oral intake of more than CFU / day for at least 4 weeks.

[0019] [The effects of the invention]

[0020] According to the brain function enhancer disclosed herein, brain function can be improved regardless of the sleep acquisition status. [Attached Image Description]

[0022]

【 Figure 1 The image above is an example of a questionnaire used in subjective evaluations (daytime mood indicators).

[0023]

【 Figure 2 The graph represents the results of subjective evaluation (daytime mood indicators).

[0024]

【 Figure 3 The image shown is a graph representing the results of an objective evaluation (spontaneous brainwaves).

[0025]

【 Figure 4 The image shown is a graph representing the results of an objective evaluation (spontaneous brainwaves).

[0026]

【 Figure 5The graph represents the results of the objective evaluation (P300 latency and button press response time).

[0027]

【 Figure 6 The graph shows the correlation between subjective evaluation (the change in concentration) and objective evaluation (the rate of change of theta waves).

Detailed Implementation Methods

[0029] <Brain Function Enhancer>

[0030] The brain function enhancement agent disclosed herein is characterized in that its active ingredient is *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei ( ) at least one of the bacterial cells and the bacterial cell treatment products.

[0031] In this disclosure, as long as it is Lactobacillus paracasei ( Lacticaseibacillus paracasei There are no particular restrictions on the strain, but as a preferred example, *Lactobacillus paracasei* can be listed. Lacticaseibacillus paracasei YIT 9018 (FERM BP-665), Lactobacillus paracasei ( Lacticaseibacillus paracasei YIT 9029 (FERM BP-1366), Lactobacillus paracasei ( Lacticaseibacillus paracasei YIT 10003 (FERM BP-7707). Among these, from the perspective of improving brain function, *Lactobacillus paracasei* (… Lacticaseibacillus paracasei YIT 9029 (FERM BP-1366) is a preferred choice.

[0032] The above-mentioned Lactobacillus paracasei ( Lacticaseibacillus paracasei YIT 9018 strain as Lactobacillus casei ( Lactobacillus casei YIT 9018 (FERM BP-665, deposit date: November 14, 1984), Lactobacillus paracasei ( Lacticaseibacillus paracasei YIT 9029 strain as Lactobacillus casei ( Lactobacillus casei YIT 9029 (FERM BP-1366, deposit date: May 1, 1981), Lactobacillus paracasei ( Lacticaseibacillus paracasei YIT 10003 (FERM BP-7707) is a Lactobacillus casei ( Lactobacillus casei YIT 10003 (FERM BP-7707, deposit date: August 14, 2001) is deposited at the Patent Biological Collection Center of the Technical Base for the Evaluation of Artifacts, an independent administrative agency and an international collection body under the Budapest Treaty (Room 120, 2-5-8 Kazusa-Kamazutari, Kisarazu City, Chiba Prefecture, Japan 292-0818). Also, *Lactobacillus paracasei* (… Lacticaseibacillus paracasei In previous classifications, it was recorded as Lactobacillus casei (Lactobacillus casei However, in recent years, lactobacillus ( Lactobacillus The genus *Lactobacillus paracasei* was reclassified as a subgenus of *Lactobacillus paracasei*. Lacticaseibacillus paracasei (Zheng et al., A taxonomic note on the genus Lactobacillus: Description of 23 novel genera, emended description of the genus Lactobacillus Beijerinck 1901, and union of Lactobacillaceae and Leuconostocaceae. Int. J. Syst. Evol. Microbiol. 2020 Apr; 70(4):2782-2858 DOI10.1099 / ijsem.0.004107). In this specification, the classification of lactic acid bacteria is marked with the new classification based on the above literature classification.

[0033] In this disclosure, the term "bacterial treatment material" refers to the treatment of bacteria (Lactobacillus paracasei) used in the treatment. Lacticaseibacillus paracasei The product of a certain treatment is not subject to any particular treatment.

[0034] As Lactobacillus paracasei ( Lacticaseibacillus paracasei The bacterial cell processing products of *Lactobacillus paracasei* can include bacterial cell decomposition products, etc. Specifically, *Lactobacillus paracasei* (…) can be listed as… Lacticaseibacillus paracasei The ultrasonic disruption fluid, etc., and Lactobacillus paracasei ( Lacticaseibacillus paracasei The enzyme treatment solution, the supernatant obtained by separating it through solid-liquid separation methods such as filtration or centrifugation, and the solid residue.

[0035] In addition, as disclosed in this paper, *Lactobacillus paracasei* ( Lacticaseibacillus paracasei The bacterial cell treatment products also include Lactobacillus paracasei ( Lacticaseibacillus paracasei Nucleic acid obtained by dissolving it with surfactants and then precipitating it with ethanol contains fractions.

[0036] Furthermore, as disclosed in this study, *Lactobacillus paracasei* (… Lacticaseibacillus paracasei The bacterial cell treatment product also includes the Lactobacillus paracasei ( Lacticaseibacillus paracasei The products were further separated and purified by various chromatographic methods, such as ultrasonic disruption fluid and cell enzyme treatment fluid.

[0037] Furthermore, as disclosed in this study, *Lactobacillus paracasei* (… Lacticaseibacillus paracaseiThe bacterial cell treatment products also include dead bacterial cells. These dead bacterial cells can be obtained, for example, through heat treatment, treatment with drugs such as antibiotics, treatment with chemicals such as formalin, treatment with ultraviolet light, or treatment with radiation such as gamma rays. Furthermore, among these treatments, ultrasonic treatment, enzyme treatment, or heat treatment are preferred, particularly from the viewpoints of cost, ease of manufacture, or stability of the resulting brain function enhancer.

[0038] On the other hand, in this disclosure, as Lactobacillus paracasei ( Lacticaseibacillus paracasei From the perspective of improving brain function, live bacteria are particularly preferred for the use of bacterial cells and their processed products.

[0039] In this disclosure, as Lactobacillus paracasei ( Lacticaseibacillus paracasei From the perspectives of ease of intake, sustained intake, and improvement in brain function, Lactobacillus paracasei (Lactobacillus paracasei) and its processed products are more preferably preferred. Lacticaseibacillus paracasei The form of fermented products. Examples of fermented products include not only milk fermented products, but also plant-based liquid fermented products such as soy milk fermented products, grain juice fermented products, and fruit juice fermented products, with milk fermented products being more preferred.

[0040] Contains Lactobacillus paracasei ( Lacticaseibacillus paracasei The fermentation product of Lactobacillus paracasei is obtained, for example, by the following method: Lactobacillus paracasei ( Lacticaseibacillus paracasei In animal milk such as cow's milk, milk powder, fatty milk powder, skim milk powder, etc., it is cultured at 30-40°C for 4 hours to 10 days. Cultivation methods include standing, stirring, shaking, and aeration. More preferably, *Lactobacillus paracasei* is inoculated into sterilized milk culture medium, either alone or together with other microorganisms. Lacticaseibacillus paracasei The mixture is homogenized to obtain a fermented milk base. Next, a separately prepared syrup solution is added and homogenized using a homogenizer, and then flavorings are added to produce the final product.

[0041] In this disclosure, fermented products refer to beverages such as fermented milk, dairy products with lactic acid bacteria, hard yogurt, soft yogurt, and plain yogurt, as defined by the Ministry of Milk and Food Ordinance. Furthermore, the fermented products in this disclosure include those utilizing *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei Foods and beverages, such as original flavor, flavored flavor, fruit flavor, sweet flavor, soft, beverage, solid (hard), and frozen fermented milk and lactic acid bacteria beverages.

[0042] In this disclosure, these fermented products, as needed, can be combined with various other food ingredients, in addition to sweeteners such as syrups, such as various sugars, thickeners, emulsifiers, various vitamins, antioxidants, stabilizers, and other optional components. Specific examples of these food ingredients include sugars such as sucrose, glucose, fructose, isomaltulose, trehalose, lactose, xylose, and maltose; sugar alcohols such as sorbitol, xylitol, erythritol, lactitol, isomaltulose, reduced maltose syrup, and reduced maltose syrup; high-sweetness sweeteners such as aspartame, sematrandole, sucralose, acesulfame potassium, and stevia; various thickeners (stabilizers) such as agar, gelatin, carrageenan, guar gum, xanthan gum, pectin, locust bean gum, gellan gum, carboxymethyl cellulose, soybean polysaccharides, and propylene glycol alginate; and sucrose fatty acid esters and glycerol fatty acids. Emulsifiers such as esters, polyglycerol fatty acid esters, sorbitan fatty acid esters, and lecithin; milk fats such as cream, butter, and sour cream; acidulants such as citric acid, lactic acid, acetic acid, malic acid, tartaric acid, and gluconic acid; various vitamins such as vitamin A, B vitamins, vitamin C, and vitamin E; minerals such as calcium, magnesium, zinc, iron, and manganese; flavorings such as yogurt, berry, orange, pear, perilla, citrus, apple, mint, grape, apricot, pear, custard, peach, melon, banana, tropical fruits, herbal flavorings, black tea, and coffee.

[0043] In the production of fermented products, *Lactobacillus paracasei* can also be used. Lactobacillus cheese Other known microorganisms besides Bifidobacterium breve. Examples of such microorganisms include, for instance, Bifidobacterium breve (Bifidobacterium breve). Bifidobacterium breve Bifidobacterium longum ( Bifidobacterium longum Bifidobacterium bifidum ( Bifidobacterium bifidum Bifidobacterium animalis ( Bifidobacterium animalum ), Bifidobacterium suis ( Bifidobacterium suis ), Bifidobacterium infantis ( Bifidobacterium infantis Bifidobacterium adolescentis ( ) Bifidobacterium adolescentis ), Bifidobacterium chain ( Bifidobacterium catenulatum ), Bifidobacterium pseudochain ( Bifidobacterium pseudocatenulatum ), Bifidobacterium lactis ( Bifidobacterium milk ), Bifidobacterium coccidioides ( Bifidobacterium globosum Bifidobacteria (such as) Bifidobacterium ) genus of bacteria, Lactobacillus paracasei ( Lactobacillus paracasei Lactobacillus casei ( Lactobacillus casei Lactobacillus (etc.) Lactobacillus ) genus of bacteria, Lactobacillus gasseri ( Lactobacillus gasseri ), Lactobacillus acidophilus ( Lactobacillus acidophilus Lactobacillus helveticus ( Lactobacillus helveticus Lactobacillus delbrueckii subsp. bulgaricus ( Lactobacillus delbrueckii subsp. bulgaricus Lactobacillus delbrueckii subsp. delbrueckii ( Lactobacillus delbrueckii subsp. delbrueckii Lactobacillus johnsonii ( Lactobacillus johnsonii Lactobacillus (etc.) Lactobacillus ) genus of bacteria, Lactobacillus salivarii ( Ligilactobacillus salivarius Lactobacillus and others ( ) Ligilactobacillus ) belongs to bacteria, fermenting lactobacillus ( LimosiLactobacillus fermentum Lactobacillus mucinus (etc.) Limosilactobacillus ) genus of bacteria, Lactobacillus apple fibrillaria ( Liquorilactobacillus mali Lactobacillus alcoholicus (Lactobacillus) and other spirits Liquorilactobacillus ) genus of bacteria, Lactobacillus plantarum ( Lactiplantibacillus plants Lactobacillus (e.g., Lactobacillus) Lactiplantibacillus ) genus of bacteria, thermophilic streptococci ( Streptococcus thermophilic Streptococci (etc.) Streptococcus ) genus of bacteria, Lactococcus lactis subsp. lactis ( Lactococcus lactis subsp. lactis Lactococcus lactis subsp. milk fat ( Lactococcus lactis subsp. cremoris Lactococcus plantarum ( Lactococcus plants ), Lactococcus raffinis ( Lactococcus raffinolactis ), Lactococcus fatii ( Lactococcus creameri Lactococcus ( ) etc. Lactococcus ) genus of bacteria, Enterococcus faecalis ( Enterococcus faecalis ), Enterococcus faecalis ( Enterococcus faecium Enterococci such as ) Enterococcus These are bacteria belonging to the genus Lactobacillus. One or more of these lactic acid bacteria can be used. Because high palatability and easy consumption can be obtained by using multiple types to make ferments, they are preferred.

[0044] In this disclosure, as Lactobacillus paracasei ( Lacticaseibacillus paracasei At least one of the bacterial cells and their processed products can be used as a component of Lactobacillus paracasei ( Lacticaseibacillus paracasei Commercially available products can be obtained from the fermentation of *Lactobacillus paracasei*. As an example, products containing *Lactobacillus paracasei* manufactured by Yakult Corporation are preferred. Lacticaseibacillus paracasei Fermented milk beverages containing live bacteria (such as *Lactobacillus paracasei*). Specific examples include Yakult-type beverages such as "Yakult," "NewYakult," "Yakult400," "Yakult1000," and "Y1000," as well as "Joie," "Soful," and "Pretio," especially those containing large amounts of *Lactobacillus paracasei*. Lacticaseibacillus paracasei Since it contains live bacteria, Yakult is the preferred choice.

[0045] In this disclosure, as Lactobacillus paracasei ( Lacticaseibacillus paracasei At least one of the bacterial cells and their processed forms can be used from commercially available products as pharmaceutical preparations. As an example, a product containing *Lactobacillus paracasei* (manufactured by Yakult Corporation) can be preferably used. Lacticaseibacillus paracasei Pharmaceutical preparations containing live bacteria. A specific example is "YakultBL intestinal medicine".

[0046] The daily intake of the brain function enhancer disclosed herein is based on Lactobacillus paracasei (Lactobacillus paracasei). Lacticaseibacillus paracasei The viable count is preferably 10. 5 CFU or higher, preferably 10. 8 CFU or higher, preferably 10. 10 CFU or higher, with 10 being the most preferred. 11 CFU or higher. Furthermore, the duration of intake is preferably 5 days or more, more preferably 2 weeks or more, further preferably 4 weeks or more, and particularly preferably 8 weeks or more.

[0047] Furthermore, the brain function enhancer disclosed herein is preferably a product containing *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei The density of a single intake of *Lactobacillus paracasei* is above a specified value. Specifically, the density of a single intake is based on *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei The viable count is preferably 10. 5 CFU / 100mL or higher, preferably 10. 8 CFU / 100mL or higher, more preferably 10 10 CFU / 100mL or higher, preferably 10. 11 CFU / 100mL or higher. Furthermore, the inventors considered the following specifications for *Lactobacillus paracasei* (…). Lacticaseibacillus paracasei The effect of density in a single intake of Lactobacillus paracasei. Although the details are unclear, it is speculated that the reason for the improved brain function based on density is that, according to the inventors' research, it is believed that Lactobacillus paracasei (… Lacticaseibacillus paracasei When the intake density of [a substance] exceeds a specified value, the stimulation of specific gastric endocrine cells increases. It is believed that substances secreted by stimulated gastric endocrine cells stimulate the centripetal vagus nerve, thereby exerting an effect on brain function.

[0048] Furthermore, the brain function enhancer of this disclosure is preferably taken continuously over the number of days between said intakes, at the density of said single intake.

[0049] The brain function enhancing agent disclosed herein can be used either orally or non-orally, preferably orally. When administered, the composition containing the active ingredient can be mixed with a solid or liquid non-toxic pharmaceutical carrier suitable for oral, rectal, or injection administration, and administered in the form of a conventional pharmaceutical preparation. Examples of such preparations include solid dosage forms such as tablets, granules, powders, and capsules; liquid dosage forms such as solutions, suspensions, and emulsions; and freeze-dried preparations. These preparations can be prepared using common pharmaceutical methods. Examples of non-toxic pharmaceutical carriers include glucose, lactose, sucrose, starch, mannitol, dextrin, fatty acid glycerides, polyethylene glycol, hydroxyethyl starch, ethylene glycol, polyoxyethylene sorbitol fatty acid esters, amino acids, gelatin, albumin, water, and physiological saline. Furthermore, commonly used additives such as stabilizers, wetting agents, emulsifiers, binders, isointense agents, and excipients can be added as needed.

[0050] Through repeated experiments and dedicated research, the inventors discovered that ingesting *Lactobacillus paracasei* (… Lacticaseibacillus paracasei In the case of at least one of the bacterial cells and their processed products, excellent effects on improving brain function are observed. Specific examples of these effects include improved attention, increased alertness, and enhanced stimulus response. More specifically, effects include maintaining focus and responding quickly to stimuli.

[0051] The effectiveness of the brain function enhancer disclosed herein can be confirmed through at least one of subjective and objective evaluations.

[0052] As a subjective evaluation, specific examples include questionnaires of the subjects. More specifically, by collecting questionnaires on items such as fatigue, alertness, motivation, concentration, optimism, and anxiety under both ingestion and non-ingestion of the brain function enhancer disclosed herein, and comparing the results, the aforementioned effects can be confirmed.

[0053] As an objective evaluation, specific examples include the measurement of spontaneous brain waves and the measurement of event-related potentials.

[0054] Regarding spontaneous brainwaves, spontaneous brainwaves are constantly observed, and the intensity of alpha, beta, theta, and delta waves, classified according to frequency, affects the level of arousal. Delta waves are 0.5–4 Hz, theta waves are 4–8 Hz, alpha waves are 8–13 Hz, and beta waves are above 13 Hz. Beta waves dominate when the brain is in an activated state, but alpha waves appear in a relaxed state. Furthermore, theta waves increase during meditation or falling asleep, while delta waves dominate during deep sleep. By measuring delta waves, theta waves, alpha waves, and beta waves, the brain function enhancement effect of this disclosure can be confirmed. For example, outside of sleep, a decrease in the intensity of theta waves indicates an improvement in brain function, more specifically, an increase in brain arousal. Specifically, if the intensity of theta waves during the administration of the brain function enhancer of this disclosure is lower than the intensity of theta waves when not administered, it can be said that brain function is enhanced (arousal is increased). Furthermore, the ratio of beta waves to alpha waves (β / α) in spontaneous brainwaves can also serve as an indicator of improved brain function, specifically attention. More specifically, when the aforementioned ratio (β / α) is higher during the intake of the brain function enhancer disclosed in this invention compared to the ratio when not ingested, it can be said that brain function is improved (attention is improved).

[0055] Furthermore, event-related potentials (ERPs) are potential changes induced in a person's brainwaves by mental activity. They are potential changes following stimulation known as mental tasks, and therefore reflect human mental function, contributing to its objective evaluation. The effects of the brain function enhancer disclosed herein can be confirmed by measuring ERPs such as P300 and N400. In particular, in this disclosure, ERP P300 is preferably used. ERP P300 is an event-related potential that appears as a peak in a positive direction approximately 300 milliseconds (ms) after stimulation, targeting sensory stimuli that appear irregularly among various stimuli, based on an Oddball exercise that draws the subject's attention. Specifically, the effects of the brain function enhancer disclosed herein can be confirmed by shortening the P300 latency (the time from stimulation to its peak). Generally, it is known that the P300 latency prolongs with age, depression, dementia, and other conditions that indicate a decline in brain function. Therefore, since the shortening of the peak latency is confirmed by ingesting the brain function enhancer disclosed herein, it can be said that the brain's processing speed is faster, and alertness and concentration are improved. Furthermore, in the inventors' previous continuous experiments, it was generally found that since the event-related potential (P300) is composed of multiple components, it is rarely detected as a single peak. However, in the experiments of this disclosure, it was observed that the detection rate of the P300 peak is increased by ingesting the brain function enhancer disclosed herein. The increased detection rate of the P300 peak by ingesting the brain function enhancer disclosed herein can be said to aid in obtaining P300 latency data.

[0056] The brain function enhancer disclosed herein can improve brain function regardless of sleep duration or quality. In other words, even when sleep is insufficient or the subject is dissatisfied with their sleep (e.g., difficulty falling asleep, waking up in the middle of the night, inability to wake up refreshed, daytime drowsiness), improvement in brain function can be expected by taking the brain function enhancer disclosed herein, which is excellent.

[0057] <Manufacturing Method of Brain Function Enhancer>

[0058] The following describes a method for manufacturing the brain function enhancer of this disclosure. In the method for manufacturing the brain function enhancer of this disclosure, *Lactobacillus paracasei* (… Lacticaseibacillus paracasei At least one of the bacterial cells and their processed products, preferably Lactobacillus paracasei ( Lacticaseibacillus paracasei ) YIT 9029 (FERM BP-1366).

[0059] <Methods to Improve Brain Function>

[0060] The following describes a method for improving brain function according to this disclosure. The method for improving brain function according to this disclosure includes: using *Lactobacillus paracasei* (… Lacticaseibacillus paracasei The number of viable bacteria was 10. 10 The process involves continuous oral ingestion of more than CFU / day for at least 4 weeks.

[0061] Furthermore, in the method for improving brain function disclosed herein, it is preferable to include: using Lactobacillus paracasei (… Lacticaseibacillus paracasei The density of a single intake of 10 (based on the number of live bacteria) is 10. 10 The process involves oral ingestion of amounts of CFU / 100mL or higher.

[0062] More specifically, methods to improve brain function, such as reducing the intensity of theta waves or shortening the latency of event-related potentials (P300), are preferred. Furthermore, methods for measuring spontaneous brain waves and event-related potentials are as described above, and therefore will not be explained here.

[0063]

Example

[0064] Next, embodiments will be listed to illustrate the present invention in more detail, but the present invention is not limited to the following embodiments.

[0065] Example 1 (Preparation of the test beverage)

[0066] Inoculated with Lactobacillus paracasei ( Lacticaseibacillus paracaseiYIT 9029 strain (LcS), along with other materials shown in Table 1, was added to a skim milk powder solution fermented at 37°C, homogenized, and filled into containers to obtain the test beverage. The *Lactobacillus paracasei* (LcS) was present in 100 mL of this test beverage. Lacticaseibacillus paracasei The bacterial count was 10. 11 CFU. Store refrigerated (below 10°C) until used.

[0067] [Reference Example 1 (Preparation of a placebo beverage)]

[0068] Except for not containing Lactobacillus paracasei ( Lacticaseibacillus paracasei Apart from the test beverage, a placebo beverage was prepared using the same manufacturing method as the test beverage. Materials were as shown in Table 1. Furthermore, considering the production of lactic acid from sugar metabolism during the manufacturing process of the test beverage, lactic acid was used instead of glucose-fructose syrup in the ingredients of the placebo beverage.

[0069] Table 1

[0070]

[0071] Twelve healthy individuals (5 men, 7 women, aged 40–59 years) with sleep dissatisfaction were given the test beverage prepared in Example 1 and the placebo beverage prepared in Reference Example 1, respectively. Examples of sleep dissatisfaction experienced by these subjects included difficulty falling asleep, waking up in the middle of the night, inability to wake up refreshed, and strong daytime drowsiness.

[0072] The human trials disclosed herein were conducted in accordance with the spirit of the Declaration of Helsinki and with full care. After an explanation of the trial content, 12 healthy individuals who agreed to participate in the trial were randomly assigned to Group I (placebo beverage leading group) and Group II (test beverage leading group) (Group I: n=6, Group II: n=6). As shown in Table 2 below, Group I consumed 100 mL of the placebo beverage prepared according to Example 1 daily after dinner for 4 weeks, while Group II consumed the test beverage in the same manner (Phase 1). During the final week of Phase 1, daytime mood indicators were assessed, and spontaneous brain waves and event-related potentials were measured. Subjects in both Groups I and II then discontinued beverage consumption for 4 weeks (washout period). After the washout period, Group I consumed the test beverage, and Group II consumed the placebo beverage for 4 weeks (Phase 2), during which daytime mood indicators and spontaneous brain waves and event-related potentials were measured in the final week (double-blind crossover trial).

[0073] Table 2

[0074]

[0075] [Subjective evaluation (daytime mood indicators)]

[0076] Daytime fatigue, motivation, focus, and optimism were evaluated using a questionnaire employing the Visual Analog Scale (VAS). Regarding the specific methodology, focusing on attention is used as an example... Figure 1 As shown, the left end of a 100mm long black line is designated as "completely unable to concentrate (poor)" and the right end as "very able to concentrate (good)". Subjects mark an × at the position that corresponds to their own state. The distance (mm) from the left end to the × mark is set as the variable (VASmm) for this item.

[0077] [Objective evaluation (spontaneous EEG and event-related potentials)]

[0078] Spontaneous EEG measurements were performed in a sealed room on the morning and afternoon of any day during the final week of Phase 1 and Phase 2. A biosignal recording device (Polymate, Mikko G.K. Co., Ltd.) was used for the measurements. Silver disk electrodes were installed at three points on the head: Fz (frontal lobe), Cz (central lobe), and Pz (parietal lobe), following the international 10-20 electrode configuration. In addition, reference electrodes were installed at both ears, and ground and reference electrodes were installed at two points on the forehead, respectively. The electrode impedance was set to 10 kΩ or less. With the subject seated in a chair and focusing on a point on a monitor, EEG was recorded for 2 minutes in a quiet, open-eye state, followed by 5 minutes of EEG recording during the auditory Oddball exercise. This was performed in three groups as shown in Table 3 below, with a final 2 minutes of EEG recording in a quiet, closed-eye state.

[0079] Table 3

[0080]

[0081] In the auditory Oddball study, two short tones of 2000Hz and 1000Hz (presentation time 100msec) were used as auditory stimuli, presented 150 times at intervals of 2.0 seconds, with occurrence probabilities of 20% and 80%, respectively. Subjects were instructed to press a button when they heard the 2000Hz auditory stimulus (target stimulus), and the reaction time from the presentation of the target stimulus to the pressing of the button was also measured.

[0082] For the frequency analysis of spontaneous EEG, a bandpass filter of 0.5–30 Hz was used to remove artifacts such as eye movements. Fourier transforms were performed on 120,000 points in the quiet state (2 minutes) and 300,000 points during the Oddball project (5 minutes). Power spectrum analysis (quiet state: μV) was then performed in each frequency band (θ wave: 4–8 Hz, α wave: 8–13 Hz, β wave: 13–30 Hz). 2 / 2min, Oddball topic: μV2 ( / 5min). Mathematical analysis software (MATLAB) was used in the analysis. Regarding the acquisition and analysis of event-related potentials (P300), the weighted average of the waveforms observed during 30 presentations of the target stimulus was calculated using analysis software (EP Travel Light, nolpro Light Systems Co., Ltd.) in accordance with the guidelines of the Japan Society for Clinical Neurophysiology. P300 consists of more than two components; when P300a and P300b were observed, P300b, which appeared relative to the target stimulus, was selected instead of P300a, which appeared relative to the deviating stimulus.

[0083] [An examination of daytime mood indicators]

[0084] The results are shown in Figure 2 The daytime mood indicators (fatigue, motivation, focus, and optimism) were independent of the time of day (morning or afternoon), showing a trend towards improved performance when the test beverage was ingested compared to when the placebo was ingested. In particular, afternoon focus was significantly improved when the test beverage was ingested. Comparing morning and afternoon, the daytime mood indicators generally trended towards decreased performance, but afternoon scores when the test beverage was ingested improved to the same level as morning scores when the placebo was ingested. That is, it was confirmed that the intake of the test beverage suppressed the afternoon performance decline, maintaining it at a level equivalent to that of the morning.

[0085] [An investigation into spontaneous brainwaves]

[0086] The results are shown in Figure 3 During the intake of the test beverage, the intensity of theta waves was lower compared to the placebo beverage, a phenomenon particularly pronounced in the afternoon. The same tendency was confirmed in both subjects during quiet, open-eyed states and during the Oddball exercise. Figure 4 The figure shows the ratio of beta waves to alpha waves (β / α). This ratio was higher during the Oddball exercise and in a quiet, open-eye state compared to the placebo beverage intake. This confirms that the intake of the test beverage improves alertness and attention. Furthermore, some subjects showed no change in alpha waves, but their ratio increased due to increased beta waves.

[0087] [Examination of event-related potential (P300 latency) and button press response time]

[0088] The results are shown in Figure 5At any of the central lobe (Cz), frontal lobe (Fz), and parietal lobe (Pz), a shorter P300 latency was confirmed during test beverage intake compared to placebo intake. Furthermore, regarding button press reaction time in the auditory Oddball exercise, a tendency for shorter button press reaction time was confirmed during test beverage intake compared to placebo intake. This confirms that test beverage intake enhances response to stimuli. Moreover, button press reaction time was 365.9 msec in the morning and 381.6 msec in the afternoon during placebo intake, and 349.2 msec in the morning and 356.0 msec in the afternoon during test beverage intake, with smaller variations during test beverage intake compared to placebo intake. This confirms that test beverage intake suppressed afternoon performance decline, maintaining a level similar to that of the morning.

[0089] It should be noted that, Figure 5 The P300 latency shown was measured in the morning. The event-related potential P300 consists of multiple components; therefore, in afternoon measurements, the peak may sometimes be unidentifiable, or the amplitude may be too shallow to confirm the peak itself. In this embodiment, measurements were performed in both the morning and afternoon, and the detection frequency and detection rate of the peak corresponding to the event-related potential P300 were analyzed. The analysis results are shown in Table 4.

[0090] Table 4

[0091]

[0092] As shown in Table 4 above, the peak detection rate in afternoon measurements tended to be lower compared to morning measurements. On the other hand, the peak detection rate when the test beverage was ingested tended to be higher compared to when the placebo beverage was ingested. In other words, it was confirmed that ingestion of the test beverage helped in obtaining P300 latency data. Furthermore, in Table 4, P represents the significance probability in Fisher's exact test, and the cumulative number of detections represents the proportion of times a peak corresponding to the event-related potential P300 was detected in a total of 36 measurements performed on 12 subjects in 3 separate tests.

[0093] The Correlation Between Subjective and Objective Evaluation

[0094] The study investigated the interaction between subjective evaluation methods (daytime mood indicators) and objective evaluation methods (spontaneous brainwaves). A graph showing the relationship between the two variables for 12 subjects is presented, showing the change in afternoon concentration (horizontal axis, VAS mm) during the intake of the test beverage relative to the placebo beverage, and the rate of change in theta wave intensity (vertical axis, ratio) under quiet, closed-eye conditions. Figure 6As shown, a negative correlation can be observed between the two, indicating that the subjective and objective indicators change in tandem with the intake of the tested beverage. Furthermore, in Figure 6 Figure 6 The study only exemplifies the results related to concentration among daytime mood indicators; for other mood indicators, a correlation with spontaneous brainwaves was also confirmed.

[0095] The preferred embodiments of this disclosure have been described in detail above, but this disclosure is not limited to such examples. It will be apparent to those skilled in the art that various modifications or variations can be conceived within the scope of the technical ideas described in the patent claims, and these naturally fall within the technical scope of this disclosure.

Claims

1. A brain function improver which uses at least one of a cell of Paracasei LMG S-26427 (P. casei) and a cell-treated product thereof as an effective ingredient. Lacticaseibacillus paracasei 1. A brain function improver which uses at least one of a cell of Paracasei LMG S-26427 (P. casei) and a cell-treated product thereof 2. The brain function improving agent according to claim 1, wherein the Paracasei (P. Lacticaseibacillus paracasei ) is Paracasei (P. Lacticaseibacillus paracasei ) YIT 9029 (FERM BP-1366).

3. The brain function enhancing agent according to claim 1 or 2, wherein, 1 day intake is 10 Lacticaseibacillus paracasei cfu or more of viable bacteria of the said 10 Paracasei.

4. The brain function improving agent according to claim 1 or 2, wherein the density of 1 intake of the B. paraplastici (B. paraplastici Lacticaseibacillus paracasei ) is 10 10 cfu / 100 mL or more in terms of viable cell count.

5. The brain function enhancer according to claim 1 or 2, wherein the brain function enhancer is at least one of attention function enhancer, arousal enhancer, stimulus response enhancer, and performance maintenance agent.

6. Lactobacillus paracasei ( Lacticaseibacillus paracasei The use of at least one of the bacterial cells and their processed products in the manufacture of brain function enhancers.

7. The use according to claim 6, wherein the Paracaseicetus casei (P. casei) Lacticaseibacillus paracasei ) is Paracaseicetus casei (P. casei) Lacticaseibacillus paracasei ) YIT 9029 (FERM BP-1366).

8. Methods to improve brain function, among which, Lactobacillus paracasei ( Lacticaseibacillus paracasei The number of viable bacteria was 10. 10 Continue oral intake of more than CFU / day for at least 4 weeks.

9. The method for improving brain function according to claim 8, wherein, with the density of one intake of the said Lacticaseibacillus paracasei ) is 10 10 cfu / 100mL or more.

10. The method for improving brain function according to claim 8 or 9, wherein the improvement in brain function is a reduction in the intensity of theta waves.

11. The method for improving brain function according to claim 8 or 9, wherein the improvement of brain function is a shortening of the latency of event-related potentials (P300).

12. Lactobacillus paracasei ( Lacticaseibacillus paracasei The use of at least one of the bacterial cells and the bacterial cell treatments in assisting in obtaining the latency of the event-related potential P300.

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