| For a long time,behavioral interventions for children with autism spectrum disorders(ASD)in China have mainly adopted intervention methods and courses from European and American countries.There is an urgent need for ASD treatment professionals to establish ASD theories and diagnostic intervention systems that have independent intellectual property rights in China and are in line with China’s national conditions.Since 2005,Professor Zou Xiaobing’s team from the Third Affiliated Hospital,Sun Yat-sen University has proposed the three principles of ASD education and the behavior-structure-relationship(BSR)based on child developmental psychology,domestic and foreign experience,and their own 20 years of clinical practice.There are few domestic reports on the efficacy of BSR in children with ASD.So far,only three studies in China have reported the short-term efficacy of BSR intervention in children with ASD after one month.Therefore,one of the main objectives of this study is to evaluate the therapeutic effect of the BSR on ASD core symptoms,parental stress,behavioral and emotional issues,developmental level,and eye movement fixation by comparing it with the Early Start Denver Model(ESDM).In clinical practice,differences in the efficacy of BSR intervention in children with ASD have been found.At present,most studies on the prognostic factors of ASD mainly focus on diagnostic and intervention time,early language development status,severity of the disease,intelligence level,concomitancy of the disease,family factors and social acceptance,etc.Few studies on the influence of genes and brain structure on the prognosis.Therefore,the second objective of this study is to investigate the differences in response of ASD children to BSR from the perspective of genes and brain structure.Most parents in clinical practice are eager to predict the prognosis of children with ASD.However,currently most studies both domestically and internationally focus on predictive models for ASD diagnosis,and there are few studies on prognostic models of ASD children’s response to treatment.Therefore,the third objective of this study is to establish an intervention prediction model for ASD children’s response to BSR,hoping to guide clinical decision-making by doctors,carry out individualized treatment,and help children’s functional recovery and effective communication between doctors and patients.Part 1 Difference between BSR and ESDM in the treatment of children with ASDObjective: To evaluate the effects of BSR on core symptoms,parental stress,behavioral and emotional problems,developmental level and eye movement fixation in children with ASD,compared with ESDM.Method: This study selected 683 children with ASD who first visited the Department of Pediatrics at the first Hospital of Jilin University from September 2021 to January 2023 as the study subjects.All of them met the diagnostic criteria for ASD in the Diagnostic and Statistical Manual of Mental Disorders(DSM-5).A total of 583 children are enrolled after inclusion and exclusion.According to parents’ wishes,they are divided into ESDM group(185 cases)and BSR group(398 cases),and are given ESDM mode and BSR mode intervention for 6 months,respectively.Before and after intervention,core symptoms of autism are evaluated by the Autism Behavior Checklist(ABC),Childhood Autism Rating Scale(CARS),and Autism Treatment Evaluation Checklist(ATEC),Parental stress is evaluated by the Parenting Stress Index Short Form(PSI-SF),Behavioral and emotional issues are evaluated by the Achenbach Child Behavior Checklist(CBCL),developmental levels are evaluated by the Griffiths Mental Development Scales Chinese(GDS-C),and eye movement fixation is evaluated by eye tracking system.Result: 1.Improvement in core symptoms,parental stress,behavioral and emotional issues,and developmental levels before and after intervention in both groups: After 6 months of treatment,the total scores of ABC(P<0.001),CARS(P<0.001),ATEC(P<0.001),PSI-SF(P=0.027,P<0.001)and CBCL(P<0.001)in ESDM and BSR groups are significantly reduced.The scores of each functional area of GDS-C are significantly increased(P<0.001).2.Comparison of core symptoms,parental stress,behavioral and emotional issues,and improvement in developmental level between the two groups: In <3 years old group,the ESDM subgroup showed better improvement in the CBCL subscale(physical litigation,attention problems)IX than the BSR subgroup(P=0.008,P=0.021).In ＜3 years old group,the BSR subgroup showed better improvement in total ABC scores and subscales(sensation,language,social)and CBCL subscales(social withdrawal,anxiety,attention problems,introversion)compared to the ESDM subgroup(P<0.001,P=0.038,P=0.004,P=0.005,P=0.003,P=0.004,P=0.021,P=0.014).3.Differences in eye movement fixation between ASD children and normal children: ASD children showed significantly lower eye viewing time when facing angry/sad/happy/afraid/neutral expressions in children,and angry/sad/happy/afraid/neutral expressions in women compared to the normal control(P=0.002,P=0.042,P<0.001,P=0.002,P=0.003,P<0.001,P<0.001,P<0.001,P<0.001,P<0.001).When dynamic geometric shapes are presented together with characters,the viewing time of ASD children for characters is significantly lower than that of the normal control group(P<0.001),while the viewing time for geometric shapes is significantly longer than that of the normal control group(P<0.001).There is a significant correlation(P<0.05)between the duration of eye viewing and the symptoms,behavioral emotions,and developmental level of ASD children when facing different facial expressions of characters.When dynamic geometric shapes are presented together with characters,children’s viewing time of characters is negatively correlated with CARS total scores,ATEC total scores,and ATEC subscales(social and physiological)(R=-0.228,P=0.006;R=-0.250,P=0.006;R=-0.178,P=0.004;R=-0.200,P=0.005),and positively correlated with the individual-social and language regions of GDS-C(R=0.170,P=0.004;R=0.206,P=0.005).4.Improvement of eye movement fixation in both groups before and after intervention: After 6 months of intervention,ASD children in the BSR group and ESDM group showed a significant increase in eye viewing time when facing angry/sad/happy/afraid/neutral expressions in children and angry/sad/happy/afraid/neutral expressions in women compared to before intervention(P<0.001).When dynamic geometric shapes are presented together with characters,the viewing time of the characters in the BSR group and ESDM group is significantly increased(P<0.001),while the viewing time of geometric shapes is significantly decreased(P=0.013,P<0.001).5.Comparison of improvement of eye movement fixation between two groups: In <3 years old group,the ESDM subgroup significantly improved the eye viewing time when faced with angry,happy,fearful and neutral expressions in children and angry expressions in female than BSR subgroup(P=0.027,P=0.018,P=0.037,P=0.010,P=0.006).There is no significant difference in the improvement of eye movement fixation between the ESDM subgroup and the BSR subgroup in ＜3 years old group(P>0.05).Conclusion: 1.After 6 months of intervention with ESDM and BSR modes,both can effectively improve core symptoms,parental stress,behavioral and emotional problems,developmental level,and eye tracking ability in children with ASD.2.In<3 years old ASD children,ESDM showed better improvement in behavioral emotions(physical litigation,attention problems)and eye tracking than BSR.3.In ＜3years old ASD children,the improvement of core symptoms(sensation,language,social)and behavioral emotions(social withdrawal,anxiety,attention problems,introversion)in BSR is better than that in ESDM.Part 2 The Relationship between the Efficacy of BSR Intervention in Children with ASD and Genes,Brain StructureObjective: To analyze the differences in treatment response to BSR in children with ASD from the perspectives of genes and brain structure,and to understand the relevant factors affecting treatment response.Method: Among 398 ASD children in the BSR group,64 ASD children and their parents underwent core family whole exome sequencing(Trio Whole Exome Sequencing,Trio WES),and the proband underwent whole genome sequencing(WGS).The differences in response to BSR intervention in children with ASD are analyzed from a genetic perspective.48 children with ASD underwent head MRI examination.Philips 3.0T Elition magnetic resonance(Amsterdam,The Netherlands)is used for brain tissue structural image scanning,and the structural phase data are analyzed using Voxel Based Morphometry(VBM)for image processing.The difference in response to BSR in ASD children is analyzed from the perspective of brain structure.Assessment of the core symptoms of autism,parental stress assessment,behavioral and emotional assessment,and developmental level assessment are included in the first part.Result:1.After 6 months of BSR intervention,the total scores of ABC scale,ABC subscale sociability,ATEC subscale speech/language expression,CBCL subscale body litigation,emotional response,and extroversion scores of ASD children in the gene negative group are significantly reduced(P=0.009,P=0.004,P=0.037,XI P=0.039).P=0.019,P=0.032),GDS-C language and performance scores are significantly increased(P=0.034,P=0.039).In gene positive group,only the total scores of ABC decreased(P=0.028),while the total scores of PSI-SF scale,parent-child interaction and difficult children increased(P=0.037,P=0.012,P=0.017).After 6 months of BSR intervention,the gene negative group improved better than the gene positive group in ABC subscale sociability,PSI-SF total scores,parental distress,parent-child interaction,difficult children scores,CBCL total scores and emotional response(P=0.030,P=0.002,P=0.012,P=0.017,P=0.037,P=0.021,P=0.038).2.The total brain volume(P=0.012)and total gray matter volume(P=0.012)of children with ASD in the group with significant symptom improvement are significantly larger than those in the group with poor symptom improvement,and there is no significant difference in total white matter volume(P=0.149).The gray matter volume of the bilateral para-hippocampal gyrus,bilateral superior marginal gyrus,and right inferior parietal angular gyrus in the group with significant symptom improvement is greater than that in the group with poor symptom improvement(P<0.05).3.The total white matter volume(P=0.009)and left superior temporal gyrus white matter volume(P<0.05)of children with ASD in the group with significant language improvement are significantly larger than those in the group with poor language improvement.There is no significant difference in total brain volume and gray matter volume between the two groups(P>0.05).Conclusion: 1.After 6 months of BSR intervention,the treatment response of ASD children in the gene negative group is better than that in the gene positive group in terms of social interaction,parental stress,and emotions.2.After 6 months of BSR intervention,the total brain volume,total gray matter volume,bilateral para-hippocampal gyrus,bilateral superior marginal gyrus,and right inferior parietal angular gyrus gray matter volume in ASD children with significant symptom improvement are larger than those in the group with poor symptom improvement.The total white matter volume and left superior temporal gyrus white matter volume of ASD children with significant language improvement are larger than those with poor language improvement.Part 3 To construct and verify a model for predicting the response of ASD children to BSRObjective: To investigate the factors influencing the response of children with ASD to BSR,establish Nomogram model of symptoms improvement and language improvement in children with ASD after BSR,and verify the predictive efficacy of this model.Method: 398 children with ASD who received BSR intervention in the Department of Pediatrics of the first Hospital of jilin University from September 2021 to January 2023 were selected as the training set.A total of 170 children with ASD who received BSR mode intervention in the pediatric department of the first Hospital of jilin University from February 2023 to August 2023 served as an external validation set.Age,gender,place of residence,whether the child was the only child,family economic status,marital status of parents,maternal pregnancy,paternity age,parental education,PSI-SF,ABC,CARS,ATEC,CBCL,temperament scale and GDS-C were included as independent variables.Stata15.0 software was used to construct Nomogram model of symptoms improvement and language improvement in children with ASD who received BSR,and to verify the predictive efficacy of the model.Result: 1.The intervention of the age,ABC total scores,ABC subscale language,ATEC total scores,physical injury in preschool anxiety,adaptability in temperament scale and attention problems in CBCL were independent factors affecting the effect of ASD children’s symptoms improved(P < 0.001,P < 0.001,P = 0.014,P = 0.019,P <0.001,P=0.046,P=0.014).According to these 7 independent risk factors and the corresponding regression coefficients of each factor,the prediction model of symptom improvement in children with ASD can be constructed.2.The place of residence,ABC subscale language,total scores of preschool anxiety,separation anxiety in preschool anxiety,activity level in temperament,GDS-C large motor and performance areas are independent influencing factors on the language improvement effect of ASD children.According to the 7 independent risk factors and the corresponding regression coefficients of each factor,the prediction model of language improvement in children with ASD can be constructed.Conclusion: 1.The Nomogram prediction model constructed based on intervention age,total ABC scores,ABC subscale language,total ATEC scores,physical injury in preschool anxiety,adaptability of temperament scale,and attention problems in CBCL has good discrimination and predictive power for the improvement of symptoms in ASD children after receiving the BSR.2.The Nomogram prediction model based on residence,ABC language,total scores of preschool anxiety,separation anxiety in preschool anxiety,activity level in temperament,GDS-C large motor and performance areas have good discrimination and predictive power for the language improvement effect of ASD children after receiving BSR. |
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