TWI770487B - Method for reducing behavioral abnormalities - Google Patents

Abstract

Provided is a method of reducing a behavioral abnormality associated with a neurodevelopmental disorder in a subject, including administering to the subject an effective amount of Lactobacillus plantarum subsp. plantarum PS128. Also provided is a composition for preventing or treating a behavioral abnormality associated with a neurodevelopmental disorder in a subject in need thereof.

Description

Ways to reduce abnormal behavior

The present disclosure relates to methods of reducing abnormal behavior in individuals. In particular, the present disclosure relates to the use of Lactobacillus plantarum subsp. planta PS128 for improving the behavior of individuals suffering from conditions or diseases associated with neurodevelopmental disorders.

Both abnormal behaviors and psychiatric conditions are characteristic of individuals with neurodevelopmental disorders, such as restricted, repetitive or stereotyped behaviors, interests or activities, attention deficits, oppositional and defiant behaviors, and communication and social interaction deficits. Such neurodevelopmental disorders include, for example, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), oppositional defiant disorder (ODD), and Tourette's Symptoms (Tourette syndrome, TS).

To treat these neurodevelopmental disorders, the US FDA has approved antipsychotics such as risperidone and aripiprazole for the treatment of autism-related disorders in patients aged 5 to 16 and 6 to 17, respectively ADHD symptoms and irritability. However, these drugs are not effective in treating other abnormal behaviors, and thus have not been approved by the FDA for indications related to core ASD symptoms, such as persistent deficits in communication and social interaction, and the accompanying limitations and Repeated patterns of behaviors, interests, and activities. While not all individuals respond to the drug, there are side effects, such as increased appetite, drowsiness, and hormonal changes, make the drug appear undesirable and inappropriate.

In addition to the use of antipsychotics, mainstream interventions for the relief of ASD symptoms involve psychosocial strategies, such as educational interventions, speech therapy, behavioral interventions, developmental therapy, and parenting skills training programs, which have different effects on improving communication and social behavior. influences. Dietary and nutritional supplements, such as the ketogenic diet, vitamins, fatty acids, and gluten-free, have been reported to play a role in a variety of ASD symptoms. However, insufficient evidence was found to support efficacy in ASD.

Therefore, there remains a need for a safe and effective method to reduce and improve behavioral abnormalities associated with neurodevelopmental disorders. Reducing behavioral abnormalities in individuals with neurodevelopmental disorders is important and would greatly benefit treatment, training, and education with less distraction, so individuals can better assimilate and adapt, thereby improving their quality of life.

In view of the foregoing, the present disclosure provides a method for reducing one or more behavioral abnormalities in an individual with a neurodevelopmental disorder, the method comprising administering a composition comprising an effective amount of Lactobacillus plantarum subsp. planta PS128. In a specific embodiment, the effective amount of PS128 is as follows, but not limited thereto: at least 1×10 ⁹ CFU (colony-forming unit), at least 1×10 ¹⁰ CFU or at least 1×10 ¹¹ CFU, including 2× 10 ⁹ CFU, 3×10 ⁹ CFU, 4×10 ⁹ CFU, 5×10 ⁹ CFU, 6×10 ⁹ CFU, 7×10 ⁹ CFU, 8×10 ⁹ CFU, 9×10 ⁹ CFU, 2×10 ¹⁰ CFU, 3×10 ¹⁰ CFU, 4×10 ¹⁰ CFU, 5×10 ¹⁰ CFU, 6×10 ¹⁰ CFU, 7×10 ¹⁰ CFU, 8×10 ¹⁰ CFU, 9×10 ¹⁰ , 2×10 ¹¹ CFU, 3 ×10 ¹¹ CFU, 4×10 ¹¹ CFU, 5×10 ¹¹ CFU, 6×10 ¹¹ CFU, 7×10 ¹¹ CFU, 8×10 ¹¹ CFU, and 9×10 ¹¹ CFU.

In a specific embodiment of the present disclosure, an individual is between the ages of 7 and 15 and has a neurodevelopmental disorder. In another specific embodiment of the present disclosure, an individual with a neurodevelopmental disorder Body age is between 7 and 12 years old. In another specific embodiment, the individual with a neurodevelopmental disorder is 7, 8, 9, 10, 11, 12, 13, 14 or 15 years old. In yet another specific embodiment, the individual suffering from the neurodevelopmental disorder is 7, 8, 9, 10, 11 and 12 years old.

In a specific embodiment of the present disclosure, the composition is administered to the individual for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, or 6 weeks. In another specific embodiment, the composition is administered to the individual for at least 1 month, 2 months, or 3 months.

In a specific embodiment of the present disclosure, the neurodevelopmental disorder is anxiety, autism, autism spectrum disorder (ASD), psychiatric conditions with some ASD symptoms, Tourette's syndrome, obsessive-compulsive disorder, attention deficit hyperactivity disorder Disorder, Resistant Defiance Disorder, Asperger's Syndrome, Childhood Disintegration Disorder or Rett Syndrome. In another embodiment of the present disclosure, the neurodevelopmental disorder is autism or autism spectrum disorder (ASD).

In a specific embodiment of the present disclosure, the one or more behavioral abnormalities include withdrawn behavior, stereotyped behavior, repetitive behavior, compulsive behavior, aggressive behavior, rule-breaking behavior, lack of social interaction, lack of communication, lack of attention, adaptability, and Insufficient self-care, social awareness, socioemotional deficits, abnormal sensations and perceptions, abnormal behavior in relation to and bonding, abnormal body and object use, hyperactive or impulsive behavior, oppositional or defiant behavior, or anxious behavior.

In one embodiment of the present disclosure, one or more behavioral anomalies are assessed by standard behaviors. In another specific embodiment of the present disclosure, the standard behavioral assessment includes the Taiwan version of the Autism Behavior Checklist (Autism Behavior Checklist-Taiwan version, ABC-T), the Child Behavior Checklist (CBCL), the clinical overall Impression Improvement (Clinical Global Impression-Improvement, CGI-I), Clinical Global Impression-Severity (CGI-S), Swanson, Nolan and Pelham (SNAP)-IV-Taiwan Version (SNAP-IV), Social Responsiveness Scale (SRS), and combinations thereof.

In a specific embodiment of the present disclosure, reducing one or more behavioral abnormalities includes reducing anxiety levels, reducing abnormal body and object use behaviors, reducing rule-violating behaviors, reducing hyperactive or impulsive behaviors, reducing oppositional or defiant behaviors, reducing Insufficient concentration or a combination thereof. In another embodiment of the present disclosure, reducing one or more behavioral abnormalities includes reducing oppositional or defiant behavior, reducing anxiety levels, reducing rule-violating behavior, reducing attention deficit, reducing hyperactive or impulsive behavior, or a combination thereof. In another embodiment of the present disclosure, reducing one or more behavioral abnormalities results in an improvement in mental age. In another specific embodiment, reducing one or more behavioral abnormalities comprises reducing dystonia.

In one aspect of the present disclosure, there is provided a method for treating a neurodevelopmental disorder in an individual in need thereof, the method comprising administering a composition comprising an effective amount of Lactobacillus plantarum subsp. planta PS128, the Lactobacillus plantarum The plant subspecies PS128 is used as the sole active ingredient for reducing one or more behavioral abnormalities associated with neurodevelopmental disorders. In an embodiment of the present disclosure, the composition is administered orally to the individual. In another specific embodiment, the method further comprises administering to the individual an antipsychotic drug in combination with the composition. In another specific embodiment, the antipsychotic is selected from the group consisting of risperidone, aripiprazole and atomoxetine hydrochloride. In another specific embodiment, the antipsychotic drug and composition are administered to the individual at different time intervals.

In an embodiment of the present disclosure, the method further comprises administering an additional therapy to the individual. In another specific embodiment, the additional therapy is selected from the group consisting of applied behavior analysis (ABA), developmental, individual differences, relationship-based approach (DIR), autism Children with Symptoms and Related Communication Disorders treatment and education of autistic and related communication-handicapped children (TEACCH), picture exchange communication system (PECS), sensory integration therapy, Floortime method and combinations thereof.

In a specific embodiment of the present disclosure, the composition is a pharmaceutical composition further comprising a pharmaceutically acceptable carrier. In another specific embodiment of the present disclosure, the pharmaceutically acceptable carrier can be a physiologically acceptable excipient or diluent. In another specific embodiment of the present disclosure, examples of physiologically acceptable excipients or diluents include, but are not limited to, lactose, starch, dextrin, cyclodextrin, sodium carboxymethyl starch, carboxylated starch Propionate, microcrystalline cellulose, carboxymethyl cellulose, maltodextrin and magnesium stearate.

The following examples serve to illustrate the present disclosure. Other advantages of the present disclosure will come to mind to those skilled in the art based on the description of the present disclosure. The present disclosure may also be implemented or applied as described in the various embodiments. For different aspects and applications, the embodiments for carrying out the present disclosure may be modified and/or changed without departing from the spirit and scope of the present disclosure.

All terms used herein, including descriptive or technical terms, should be construed as having the meanings obvious to those of ordinary skill in the art. However, these terms may have different meanings according to the intentions of those with ordinary knowledge in the art, case precedents, or the appearance of new technologies. In addition, the applicant may arbitrarily select some terms, and in this case, the meanings of the selected terms will be described in detail in the embodiments of the present disclosure. Therefore, the terms used herein must be defined based on their meanings and descriptions throughout the specification.

In addition, when parts "include" or "comprise" parts or steps, unless specifically described to the contrary, this section may further include other components or other steps, but does not exclude other components or steps.

It should also be noted that the singular forms "a (a)", "an (an)" and "the (the)" as used in this specification include the plural unless it is obvious and expressly limited to one referent. an indicator. The term "or" is used interchangeably with the term "and/or" unless the context clearly dictates otherwise.

The phrase "effective amount" refers to the amount of active ingredient required to result in the reduction, inhibition or prevention of a behavioral disorder, abnormality or symptom in a subject. The effective amount will vary depending on the route of administration, the use of excipients, and the possibility of co-use with other methods of treatment, as recognized by those of ordinary skill in the art.

As used herein, the term "individual" includes a single organism that may develop a neurodevelopmental disorder, including but not limited to animals, especially vertebrates, such as mammals, especially humans.

As used herein, the terms "condition", "disorder", "symptom" or "behavioral disorder" refer to symptoms exhibited by individuals with psychiatric disorders such as, but not limited to, anxiety, autism , Autism Spectrum Disorder, Rett Syndrome, Tourette Syndrome, Obsessive Compulsive Disorder, Attention Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, Asperger's Syndrome, or Childhood Disintegrative Disorder.

The term "individual in need of such treatment" refers to a person who exhibits or suffers from one or more of the above behavioral disorders or symptoms. An appropriately qualified person can use standard behavioral testing protocols or guidelines to identify such individuals in need of treatment. The same behavioral testing protocols or guidelines can also be used to determine whether an individual's disease or symptoms have improved, or to determine the most effective dose of PS128 to administer to an individual in need of such treatment.

As used herein, the term "improvement in behavioral performance" refers to preventing or reducing to some extent the severity or frequency of one or more of the above-mentioned behavioral disorders, symptoms or abnormalities exhibited by an individual. This improvement is observed by the individual being treated or by another person.

The present disclosure is illustrated using different embodiments. The following examples should not be construed as limiting the scope of the present disclosure.

Example

The present disclosure examines the effect of Lactobacillus plantarum PS128 in the treatment of neurodevelopmental disorders.

A randomized, double-blind, placebo-controlled trial was conducted in Taiwan, in which 80 individuals were recruited. Eligible individuals were randomly assigned in a 1:1 ratio to the two arms of this study using a treatment code, according to a randomized cohort of the probiotic group (PS128) and the placebo group. Randomization was performed by a research assistant who had no contact with the participants. This assignment order is not available to any member of the study team, physician or participant. The primary outcome of this study was changes in the Taiwanese version of the Autism Behavior Checklist (ABC-T) questionnaire, Social Responsiveness Scale (SRS) score, and Child Behavior Checklist (CBCL) questionnaire, and secondary outcomes were responses to the Chinese version of the Swanson , Nolan and Pelham-IV (SNAP-IV) assessment and improvement in Clinical Global Impression Improvement (CGI-I). During participation in the trial, trained testers further confirmed the diagnosis of ASD in all individuals according to the Autism Diagnostic Interview-Revised (ADI-R).

participant

Study participants were screened according to inclusion and exclusion criteria. The selection criteria are based on the spirit of Boys aged 7 to 15 years diagnosed with ASD according to the Diagnostic and Statistical Manual of Diseases, 5th edition (DSM-V) criteria. Primary caregivers were required to provide proof of disability from the Taiwanese government, and the researchers in this study checked the ICD-9 (International Classification of Diseases, Ninth Revision) code as 299.00. Considering that the prevalence of ASD in boys is four times higher than in girls, only boys with ASD were recruited for this study. Exclusion criteria included consumption of designated antibiotics and yogurt or probiotic products two weeks prior to the start of recruitment. With the exception of antibiotics, participants were allowed to continue their usual medications, treatments and regimens, and participants were instructed not to consume yogurt or probiotic products during the study. Written informed consent was obtained from all individuals and the individual's parents or caregivers prior to the start of the study.

PS128 and placebo products

The isolated strain of Lactobacillus plantarum PS128 used in this study was deposited in DSMZ with accession number DSM28632, and has also been deposited with the Food Industry Development Research Institute, and obtained accession number BCRC 910622. The participant's PS128 was provided in capsule form containing a milky white powder. The probiotic capsules weighed 425 ± 25 mg and contained 3 x 10 ¹⁰ CFU of PS128 per capsule with microcrystalline cellulose as a carrier, while the placebo capsules contained only microcrystalline cellulose. All capsules were identical in taste and appearance and were stored at refrigerated temperatures (4 to 8°C).

Evaluate

Clinical Global Impression Severity (CGI-S) and Clinical Global Impression Improvement (CGI-1) forms were completed by medical professionals at baseline (Week 0) and after completion of the intervention (Week 4), respectively. Follow-up scores for parents or caregivers to complete ABC-T, CBCL, SRS, and SNAP-IV questionnaires. The study consisted of two visits, where the baseline visit involved recruitment, randomization prior to study initiation, and assessment using a questionnaire, while the second visit (week 4) involved a review of individual medical histories and adverse event reporting .

The ABC-T is a 47-item questionnaire used to assess behavioral problems in children with intellectual and developmental disabilities, obtained from the Autism Behavior Checklist for Autism Screening Tools for Educational Programs (Third Edition). modified. The validated tool is divided into five subscales and includes questions related to sensory (feeling and perception; 8 items), association (relationship and connection; 11 items), body and object use (physical activity and strictness) Object use; 12 items), language (communication and interaction; 8 items), and socialization and self-help (adaptation and self-care; 8 items). During the assessment, each question on the ABC-T item was rated as "yes" (1, symptomatic) or "no" (0, asymptomatic).

The SRS is a validated 65-item assessment tool designed to assess social communication and interaction as well as restricted interests and repetitive behaviors. These assessments are divided into social awareness, social communication, social-emotional, and autistic ritual behavior.

The CBCL is a 113-item questionnaire used to assess eight experience-based symptom scales, including aggressive behavior, anxiety, attention problems, rule-breaking behavior, complaints of physical discomfort, social problems, thought problems, and withdrawal problems .

The CGI-S and CGI-I questionnaires each contained items measured on a seven-point scale that were assessed by clinicians to determine symptom severity and improvement, respectively.

SNAP-IV is used to assess ADHD and ODD in children aged 6 to 15 years, which is useful for interpreting the impact of interventions on patients in clinical studies. The Taiwan version of SNAP-IV consists of 26 items that reflect DSM-IV symptoms of attention deficit hyperactivity disorder (ADHD) (18 items) and oppositional and defiance problems (8 items).

data analysis

Using GraphPad Prism (version 7; GraphPad Software, California, USA San Diego, Asia) to analyze the data.

Two-tailed t-tests were performed to compare demographics (parametric tests), clinical characteristics (ADI-R scores, CGI-S, and CGI-I), and outcome measures between the PS128 and placebo groups at baseline and week 4 Score.

For age-stratified exploratory analyses, individuals were divided into age groups 7 to 12 and 13 to 15 years to compare the differences in questionnaires between PS128 and placebo groups using independent t-tests (week 4 scores and baseline scores), and the baseline scores and week 4 scores were then analyzed within groups by paired t-test. A two-tailed significance level of P<0.05 was considered statistically significant.

result

A total of 80 subjects were recruited and randomly assigned to treatment: 39 subjects to PS128 and 41 subjects to placebo. An individual diagnosis of ASD was confirmed by experienced investigators by ADI-R assessment. Of the 80 eligible subjects aged 7 to 15 years, 3 and 6 subjects dropped out of the PS128 and placebo groups, respectively, resulting in 71 subjects at the end of the study period (PS128, n=36; placebo, n=35). No adverse events were reported in this study, and no individuals or their parents reported any gastrointestinal intolerance or allergic reactions during participation.

As shown in Table 1 below, demographic data such as age, height, weight, and clinical characteristics were similar between the PS128 and placebo groups (p>0.05). Both groups of individuals met criteria for autism with similar scores above thresholds in four domains, two-way social interaction, language and communication (verbal and non-verbal), stereotyped repetitive behaviors or interests, and age of onset (P>0.05). CGI-S scores were also similar at baseline in the PS128 and placebo groups (P=0.26).

Table 1. Demographic and clinical characteristics of individuals at baseline

Results are presented as mean (standard deviation).

The evaluation results of CGI-1, ABC-T, SRS, CBCL and SNAP-IV are shown in Table 2 below. The results showed that the CGI-I score was equivalent to "least improvement" in both groups (3.64 and 3.66 in PS128 and placebo groups, respectively; P=0.94). There were no differences between PS128 and placebo groups in total and subscale scores for ABC-T, SRS, CBCL, and SNAP-IV at baseline and week 4.

Table 2. Evaluation of CGI-I, ABC-T, SRS, CBCL, and SNAP-IV after 4 weeks of PS128 treatment

Results are presented as mean (standard deviation).

ABC-T: Taiwan version of the Autism Behavior Checklist;

CBCL: Child Behavior Checklist;

CGI-I: improvement in clinical global impression;

SNAP-IV: Swanson, Nolan and Pelham (SNAP)-IV-Taiwan version;

SRS: Social Responsiveness Scale.

However, when the assessment results were further stratified by age analysis (7 to 12 years in primary school; 13 to 15 years in middle school), the PS128 group showed significant improvement, as shown in Table 3 below.

Among elementary school students aged 7 to 12, the placebo group had lower social awareness scores than the PS128 group at both baseline (P=0.02) and week 4 (P=0.04). By comparing changes over time (week 4 scores and baseline scores), the PS128 group showed an improvement in SNAP-IV opposition/rebellion (P=0.03) and total score (P=0.02) compared to the placebo group. improve.

Table 3. Age-stratified outcome analysis for individuals aged 7 to 12 years

Results are presented as mean (standard deviation). * P < 0.05.

ABC-T: Taiwan version of the Autism Behavior Checklist;

CBCL: Child Behavior Checklist;

CGI-I: improvement in clinical global impression;

CGI-S: Clinical Global Impression Severity;

SNAP-IV: Swanson, Nolan and Pelham (SNAP)-IV-Taiwan version;

SRS: Social Responsiveness Scale.

Further exploratory analyses were performed in PS128-treated and placebo groups at different ages (see Table 4).

In the age group 7 to 15 years (7-15), four weeks of PS128 administration showed a tendency to improve body and object use (P=0.04), slightly lower total SRS score (P=0.04), and reduce anxiety (P=0.02) ) and rule-violating behavior (P=0.02), reduced hyperactivity and impulsivity (P=0.04), reduced opposition and defiance (ODD; P=0.045, 0.05 shown in Table 4, rounded to two decimal places) ), and reduced the total SNAP-IV score (P=0.018, shown in Table 4 as 0.02 due to rounding to the nearest decimal point).

In the age group 7 to 12 years (7-12 years), four weeks of PS128 administration showed CBCL anxiety (P=0.01), CBCL rule violations (P=0.01), SNAP-IV-inattention (P=0.01) 0.03), SNAP-IV hyperactivity/impulsivity (P=0.02), SNAP-IV opposition/rebellion (P=0.02), and SNAP-IV total scores (P=0.004) were further reduced. In the age group 7 to 12 years (7-12), the reduction in abnormal behavior was more pronounced and the p-value was smaller than in the age group 7-15 years (7-15).

Table 4. Exploratory Analysis by Age Group to Compare Difference Between Baseline and Week 4 of Treatment

Data are presented as P-values.

NC: The difference is equal to 0, the p-value is not computable. ^* P < 0.05.

ABC-T: Taiwan version of the Autism Behavior Checklist;

CBCL: Child Behavior Checklist;

SNAP-IV: Swanson, Nolan and Pelham (SNAP)-IV-Taiwan version;

SRS: Social Responsiveness Scale.

In fact, 31 of the PS128-treated groups who completed all assessments at baseline and after 4 weeks of treatment Of the 14 individuals, 14 of them showed a reduction in anxiety, expressed as a reduction in the CBCL anxiety score, with a maximum score from 12 to 4. Among the other syndromes assessed by the CBCL score, 15 individuals showed a decrease in withdrawal problems, 10 individuals reported a decrease in complaints of physical discomfort, 14 individuals experienced a decrease in social problem scores, 12 individuals experienced a decrease in thought problems, and 11 individuals had fewer attention problems, 17 individuals had fewer rule-breaking behaviors, and 11 individuals had fewer aggressive behaviors. A total of 14 individuals showed a reduction in the total CBCL score, with the largest reduction in score being 57 (from 113 to 56).

Total ABC-T scores, which indicate behavioral problems in children with intellectual and developmental disabilities, also decreased in 14 of 31 individuals. Of the five subscales measured by the ABC-T, 8 individuals showed a decrease in problems related to sensation and perception; 9 individuals showed a decrease in association problems such as building relationships and connections; 14 individuals exhibited abnormal physical and Reduced object use behaviors, such as strict object use; improved communication and interaction in 10 individuals; improved adaptation and self-care in 12 individuals.

On assessments of social communication and interaction, restricted interests, and repetitive behaviors, 14 of 31 individuals had a decrease in the total SRS score, with a maximum decrease of 25 (from 139 to 114). Across the four dimensions of social communication and interaction assessed by the SRS, 16 individuals demonstrated better social communication; 16 individuals exhibited reduced autistic ritual behavior; 12 individuals exhibited increased social awareness; 15 individuals social-emotional improvement.

Using the SNAP-IV to measure attention deficit, hyperactivity or impulsivity, and oppositional or defiant behavior, 18 of 31 individuals were found to have lower overall scores. 17 of the individuals had improved attention deficit; 14 showed less hyperactivity or impulsivity; and 14 showed less oppositional and defiant behavior.

In fact, only one of the 31 individuals treated with PS128 for 4 weeks did not show any improvement or decrease in abnormal behavior. This means that among the 31 individuals treated with PS128 for 4 weeks, Thirty subjects showed improvement in one or more conditions or reduction in abnormal behaviors associated with neurodevelopmental disorders as assessed by CBCL, ABC-T, SRS, or SNAP-IV.

A total of 4 individuals (individual ID: 1017, 7 years old; individual ID: 1028, 7 years old; individual ID: 1069, 8 years old; individual ID: 1076, 7 years old) showed CBCL, ABC-T after 4 weeks of PS128 treatment , SRS, and SNAP-IV assessments decreased in all total scores. This means that all four assessments showed a reduction in abnormal behaviors associated with neurodevelopmental disorders in these 4 individuals.

As an example, Individual ID: 1064 (age 12) showed a significant decrease in the score related to anxious behavior as assessed by CBCL from 21 to 14, less feelings of worthlessness or inferiority, and less anxiety, anxiety , fear, and guilt; after 4 weeks of treatment with PS128, there was a reduction in the frequency of mentioning suicide, and a reduction in self-consciousness and embarrassment. In addition, the individual's aggressive behavior improved significantly, and the CBCL's aggressive behavior score decreased from 26 to 8. Individuals argue and taunt less often, do not threaten, fight and attack others more often, less frequently destroy things that belong to themselves or others, demand less attention, and scream less. Individuals were found to be more emotionally stable, less tantrums, less sudden changes in mood or feeling, less suspicious, stubborn, or irritable.

Additionally, Individual ID: 1064 was also thought to significantly improve social communication, showing less autistic ritualistic behaviors, such as stereotyped behaviors or interests. For example, individuals exhibit less unusual ways of playing with toys or other odd repetitive behaviors, such as clapping or shaking hands, less talking or thinking about the same thing repeatedly, less stupid or odd behavior, less unusual tones or not Appropriate laughter, better relationships with peers and play together appropriately, and care more about being "out of tune" with others. The subject was also found to show a greater range of interest and was less sensitive to sounds, textures or smells, and was less ridiculed by others for being eccentric or weird.

As another example, individual ID: 1017 shows some improvement, such as individual enjoyment More fun, less complaining about loneliness, less crying, less demanding attention, guilt rather than jealousy after misbehaving, less fear of certain animals, situations or outside of school, less fear or Nervousness, less fearful movements or twitches, more liked by other children, less constipation, less fear or anxiety, less overeating, less physical discomfort of unknown medical cause, such as headaches, less physical aggression, less prefer to be with older children, sleep no more during the day and/or night than most children, have fewer stubborn, sullen, or irritable emotions, fewer moods or sudden changes in emotions, fewer withdrawn emotions, and Interact with others more.

In another assessment, Individual ID: 1017 also showed increased attention to social/environmental stimuli, better hearing, less suspicion of hearing loss, less intense responses to routine/environmental changes, less attention to other people's more responsive facial expressions and/or sensations, more responsiveness to painful stimuli such as bruises, cuts, and injections, less harming others by biting, hitting, kicking, etc., less repetition of phrases over and over, More imitating other children's play, less waving, spinning and hitting objects, less repeating sounds or words over and over, less showing "ignorance" of people, less disruptive.

In the third assessment, Individual ID: 1017 exhibited less "auto-pilot patterns" under stress, such as displaying odd-looking rigid or rigid behavior patterns; / When she is cheap, he is more able to recognize; less strange or bizarre-looking behavior, more understanding of the meaning of older children or adults talking, less avoidance of eye contact or less abnormal eye contact, easier to change him / Her daily habits are more concerned with being "out of sync" with others or not being "on the same frequency", less perceived by other children as strange or weird, less annoying when a lot of things are happening, "connected" with adults less difficulty, more appropriate responses to mood changes, less aimless wandering from one activity to another, less inappropriate or silly laughter, barriers to directly answering questions and ultimately having a conversation around the subject less, less sound like a robot Talking to a person in a loud or unusual voice, or as if he/she is speaking, less emotional distance and showing more of his/her emotions, less contact with others in unusual ways, and in social situations less tension.

In the fourth assessment, Subject ID: 1017 showed less frequency of losing things necessary for activities, less distraction from external stimuli, less forgetfulness in daily activities, and less wriggling of hands or feet in the Seating restlessness, fewer obstacles to playing quietly or engaging in leisure activities, less excessive talking, less impulsive behavior such as blurting out before a problem is completed, less tantrums, less quarrels with adults, less Or her mistakes or misconduct to blame others, less sensitive or annoyed by others, and less anger, resentment, and malice.

To give another example, Individual ID: 1028 is more capable of freeing him/her from certain thoughts, less confusion, less crying, less daydreaming or less immersion in his own world, less self-harm, less damage to things belonging to his/her family or others, eat better, get along better with other children, more guilt after misbehavior, less frequent injuries, less chance of accidents, More liked by other children, less fear or anxiety, less overeating, more regular and normal sleep, less bed-wetting, less playing with one's own sexuality, less repetition of certain behaviors, less refusal to speak, more Less screaming, less speech problems, less stubbornness, sulking or irritability, less sudden changes in mood or feeling, less tantrums, less thumb sucking, more active, less unhappy, sad or depressed, more Active, less unusually loud and less vandal.

In another assessment, "Individual ID: 1028" showed improvement in hearing others, less injury to bites, punches, and kicks in others, more responsiveness to others' facial expressions and sensations, less tantrums or less Less frequent tantrums, less repetitive vocalizations or speeches over and over, less disruptive.

In the third assessment, Individual ID: 1028 was more able to understand and understand the conversation of an older child or adult, was less dependent on adults, was less embarrassed in interactions with peers, had Better coordination, facial expressions more in line with his/her speech, less perceived by other children as weird or weird, less socially awkward, better at making friends, less seen as weird or weird by other kids , less socially awkward, more 'connected' to peers and adults, more aware of the causes and consequences of events, less overly serious facial expressions, less stupid or inappropriate smiles, more direct Answers questions and ends up talking less about topics, is more resilient and easy to change your mind, and less stares or stares.

In the fourth assessment, Individual ID: 1028 was found to be better at organizing tasks and activities, more able to complete tasks that require sustained effort, more able to play quietly or engage in leisure activities, and less likely to show "non-stop" or "engine-like" driven behavior”, less tantrums, less sensitivity or annoyance to others, less anger and resentment, and less malice or grudge.

As another example, Individual ID: 1033 showed some improvements, including less defecation outside the toilet, less boasting or bragging, less reliance on adults or less reliance on people, less intentional harm to self, less Disobedience at home and at school, getting along better with other children, less breaking rules at home, school or elsewhere, less fear of certain animals, environments or places outside of school, less fearful, high tension or nervousness, less fear or anxiety, less physical discomfort of unknown medical cause, such as rashes or other skin problems, less sex with oneself, better schoolwork, less refusal to speak, less repetition of certain less running away, less screaming, less secrets, less odd behavior, less anger, less sexual thoughts, less unusual loud talk, less daytime wetting, less complaining and less flinch.

In another assessment, Subject ID: 1033 showed less robustness to daily/environmental changes Violent reactions, less jabs and throws, better ability to follow simple commands about prepositions, less tantrums and/or less frequent tantrums, better imitation of other children at play, less visible "Ignore" people, manipulate and possess less inanimate objects, and engage in less complex "rituals" such as lining up objects.

In the third assessment, Individual ID: 1033 showed less strange-looking or bizarre behavior, better communication with others about one's feelings, better coordination in physical activity, and more active participation in group activities , more willing to offer comfort to others when they are sad, less avoidance of social interaction with peers or adults, better personal hygiene, less wandering aimlessly from one activity to another, better understanding of events Relationship with children of other ages, less overly serious facial expressions, more noticing that he/she speaks too loudly or makes too much noise, less robotic-like or unusual pitch to people, or as if he/she In speaking, treat people less like objects, give unusual or illogical reasons for doing things, and touch people in unusual ways.

On the fourth assessment, Individual ID: 1033 was more able to follow directions and complete homework, chores or duties, less avoid engaging in tasks that require sustained effort, less lose things necessary for activities, less forgetful in daily activities, Fewer self-eating out of seats, less excessive running or climbing in inappropriate situations, fewer obstacles to quiet play or engaging in leisure activities, fewer obstacles to waiting in line, less distractions or interruptions to others, less His or her wrongdoing or misconduct blames others, is less angry and resentful, and is less malicious or vengeful.

To give another example, "Individual ID: 1069" showed improvements in many dimensions, including being able to focus more and for longer periods of time, easier to free his/her mind from certain thoughts; less confusion, and better getting along with other children. Well, less fear of certain animals, environments, or places other than school, less fear that s/he might think or do bad things, less that he/she has to be perfect, less others Grab his/her feelings, feel less worthless or inferior, be ridiculed less, dislike someone less than when they are with others, lie or cheat less, be less afraid, highly tense or nervous, More liked by other kids, less fear or anxiety, less guilt, less playing with their sex in public, less playing with their sex, less screaming, less coy or embarrassed, less shy or timidity, less glazed eyes, less hoarding of many things he/she doesn't need, less odd thoughts, less over-talking, less teasing, less unusually loud talking, less whining, less withdrawal and more involved others.

In another assessment, Individual ID: 1069 was more able to listen to others, pay more attention to their surroundings, had more visual responses to "new" people, and was less involved in complex "rituals" such as lining up objects.

In the third assessment, Individual ID: 1069 performed less in social situations than alone, and had fewer "autopilot patterns", such as appearing inflexible or rigid behavioral patterns that seemed odd under stress, and less likely to be involved in getting along with people. More interest, less strange or bizarre-looking behavior, less dependence on adults, better self-confidence, less frustration trying to get ideas in conversations, less unusual sensory interest, better personal hygiene , less social awkwardness, less avoidance of those who want to be emotionally close to him/her, better "connection" with adults, more imaginative, better at pretending without losing connection to reality, easier Separation from caregiver, better sense of humor and better understanding of jokes, better understanding of when he/she is too close to someone or invading someone's space, less unusual or illogical reasons for doing things, more Less contact with others in unusual ways, less nervousness, staring or staring into the void in social situations.

On the fourth assessment, Individual ID: 1069 was more able to maintain focus during tasks or game activities, listened more to others when speaking directly to them, and was less able to avoid execution requiring ongoing mental effort tasks, less distraction from external stimuli, less forgetfulness in daily activities, less fidgeting with hands or feet wriggling in the seat, less inappropriate overrunning or climbing, more ability to play or participate more quietly Leisure activities that avoid blurting out until the problem is done, are more likely to wait in line, are less disruptive or intrusive to others, such as having conversations/games, and are less intentionally annoying.

As another example, Individual ID: 1076 showed improvements in many dimensions, including being more able to sit still, less restless, less hyperactive, able to eat better, less thinking he/she must be perfect, less other How the person grasps him/her, less worthlessness or inferiority complex, less ridicule, less time with people in trouble, fewer nightmares, less fear or anxiety, better able to do schoolwork, no Prefer to be with older children, less stubbornness, sulking or irritability, less sudden changes in mood or feeling, less sulking, less sleep-talking or sleepwalking, less excessive talking, less tantrums or tantrums, more Less unhappy, sad or depressed, less complaining and worrying. In another assessment, Subject ID: 1076 showed less intense reactions to routine/environmental changes, less frequent tantrums and/or less frequent tantrums, greater ability to wait for time to be fulfilled, greater awareness of surroundings Greater knowledge of the environment and hazardous situations, less participation in complex "rituals" such as lining up objects, and less disruption. In the third assessment, Individual ID: 1076 showed less behavior that looked strange or bizarre, was better able to understand the meaning of conversations with older children or adults, was better able to communicate one's own feelings to others, was better at interacting with peers Less embarrassed, more able to imitate others' behavior, less seen as strange or weird by other children, more easily absorbed once he/she starts thinking, less avoidant of those who want to be emotionally close to him/her, able to Focus more on where others are looking or listening, show less overly serious facial expressions, answer questions more directly instead of ending up on topics, be ridiculed less, less rigid, easier to change ideas, less unusual or illogical reasons for doing things, and less nervousness in social situations.

In another assessment, Individual ID: 1076 Listens better when talking directly to others, avoids tasks that require sustained mental effort, is less distracted by external stimuli, has less forgetfulness in daily activities, and has fewer hands Or fidgeting with feet wriggling in the seat, less inappropriate overruns or climbs, less 'non-stop' or 'engine-like behavior', less talking too much, less blurring out before the problem is done , more ability to wait in line, less distraction or intrusion with others, less tantrums, less quarrels with adults, less active resistance or rejection of adults’ requests or rules, less intentionally annoying behavior, less Blame others for his or her mistakes or misconduct, be less irritable or annoyed by others, less angry, less resentful, and less malicious or vengeful.

The foregoing detailed descriptions of the embodiments are only used to illustrate the principles and functions of the present disclosure, and are not intended to limit the scope of the present disclosure. Those skilled in the art should understand that, according to the spirit and principles of the present disclosure, all modifications and changes should fall within the scope of the appended patent application. The specification and examples are intended to be considered by way of example only, the true scope of the disclosure being indicated by the appended claims.

【Biological Material Deposit】

Domestic deposit information: Lactobacillus plantarum plant subsp. PS128 was deposited in the Food Industry Development Research Institute on April 17, 103, and obtained the registration number BCRC 910622.

Foreign deposit information: Lactobacillus plantarum plant subsp. PS128 was deposited in the German Microbiology and Cell Culture Collection Center on March 31, 2014, and obtained the DSMZ accession number DSM 28632.

Claims (13)

A composition comprising an effective dose of Lactobacillus plantarum plant subspecies PS128 and its carrier is used for preparing the purposes of the medicine that reduces one or more abnormal behaviors to an individual in need, wherein, the deposit number of this Lactobacillus plantarum plant subspecies PS128 is BCRC 910622, wherein the system is an individual aged 7 to 15 years with a neurodevelopmental disorder, wherein the one or more behavioral abnormalities include withdrawn behavior, stereotyped behavior, repetitive behavior, obsessive-compulsive behavior, aggressive behavior, rule-breaking behavior , Inadequate social interaction, Insufficient communication, Insufficient attention, Inadequate adaptation and self-care, Inadequate social awareness, Inadequate socio-emotional, Abnormal sensations and perceptions, Abnormal behavior in relationship and bonding, Abnormal physical and object use behavior, Hyperactive or impulsive behavior, oppositional or defiant behavior, or anxious behavior, and where the neurodevelopmental disorder is anxiety, autism, autism spectrum disorder, mental conditions with symptoms of autism spectrum disorder, Tourette's syndrome , Obsessive-Compulsive Disorder, Attention Deficit Hyperactivity Disorder, Oppositional Defiant Disorder, Asperger's Syndrome, Childhood Disintegration Disorder, or Rett Syndrome. The use according to claim 1, wherein the neurodevelopmental disorder is autism or autism spectrum disorder. The use of claim 1, wherein the reducing one or more abnormal behaviors comprises reducing anxiety levels, reducing abnormal body and object use behaviors, reducing rule-violating behaviors, reducing hyperactive or impulsive behaviors, reducing oppositional or defiant behaviors , reducing attention deficit, or a combination thereof. The use of claim 1, wherein the individual is between 7 and 12 years old. The use of claim 4, wherein the reducing one or more behavioral abnormalities comprises reducing oppositional or defiant behavior, reducing anxiety levels, reducing rule-violating behavior, reducing attention deficit, reducing hyperactive or impulsive behavior, or a combination thereof. The use of claim 1, wherein the reduction in one or more behavioral abnormalities in the individual is determined by a standard behavioral assessment selected from the group consisting of: Taiwan Version of Autism Behavior Checklist, Child Behavior Checklist, Clinical Global Impression Improvement, Clinical Global Impression Severity, Swanson, Nolan, and Pelham-IV-Taiwan Version, Social Responsiveness Scale, and combinations thereof. The use according to claim 1, wherein the Lactobacillus plantarum subsp. planta PS128 is the only active ingredient in the composition for reducing one or more abnormal behaviors. The use of claim 1, which is administered orally to the individual. The use according to claim 1, which is a pharmaceutical composition for administration to the individual in combination with an antipsychotic. The use according to claim 9, wherein the antipsychotic is selected from the group consisting of risperidone, aripiprazole and atomoxetine hydrochloride. The use of claim 9, which is administered to the individual at different time intervals in combination with an antipsychotic. The use of claim 1, which is administered to the individual in combination with additional therapy selected from the group consisting of: applied behavioral analysis; developmental, individual differences, relationship-based methods; autistic children and related Treatment and education of children with communication disorders; picture-for-communication systems; sensory integration therapy; Floortime methods; and combinations thereof. The use of claim 1 , wherein the Lactobacillus plantarum subsp. planta PS128 line is administered to the individual for at least 2 weeks in an amount of at least 3×10 ⁹ CFU.