Treatment Of Attention Deficit Hyperactivity Disorder With The Combination Of Repetitive Transcranial Magnetic Stimulation And Atomoxetine And Its MicroRNA Expression

Objectives: 1.To investigate and compare the threpeutic efficacy of repetitive transcranial magnetic stimulation(r TMS),atomoxetine(ATX),as well as the combination of r TMS and ATX on attention deficit hyperactivity disorder(ADHD).2.To evaluate the improvement of cold and hot executive functions in ADHD patients after receiving systematic treatment.3.To compare the difference in the expression levels of serum miRNA let-7d and miRNA-107 between ADHD patients and healthy children,as well as the difference in the expression levels of the two miRNAs before and after treatment.Methods: 1.Clinical treatment: seventy patients with ADHD were randomly divided into three groups: the r TMS group(n=23)treated with r TMS+placebo,the ATX group(n=23)taking ATX+sham r TMS,and the combination of r TMS+ATX group(n=24)treated with r TMS using the same parameters and taking ATX with the same dose.2.Efficacy evaluation of three treatments: The improvement of clinical symptoms of ADHD patients was assessed by using Conners Parent Symptom Questionnaire(PSQ)and SNAP-IV Rating Scale before treatment and six weeks after treatment,and compared among three treatments.3.The difference in executive functions of ADHD patients before and after the treatments: the continuous performance test(CPT)and three subtests(Arithmetic,Digit Span,and Coding)of the Wechsler Intelligence Scale for Children(WISC)were used to assess impairment and improvement of cold executive functions of ADHD patients before treatment and six weeks after treatment;Meanwhile,Iowa Gambling Task(IGT)was used to assess impairment and improvement of heat executive functions of ADHD patients.4.The difference in serum miRNAs level between ADHD patients and healthy children: after blood samples from the ADHD group(n=75)and the healthy control group(n=18)was collected,the serum expression level of miRNA let-7d and miRNA-107 was examined by using fluorescence quantitative PCR and compared the difference between two groups.5.The difference in the serum level of two miRNAs in ADHD patients before and after treatment: seventy-five ADHD patients were divided into two groups: the drug group(n=32)and the non-drug group(n=43),then each group was randomly divided into the two subgroups,respectively: the ATX group(n=16)and the placebo group(n=16),the real r TMS group(n=22)and the sham r TMS group(n=21),after blood samples from the ADHD group before and after six week of treatment was collected,the serum expression level of miRNA let-7d and miRNA-107 was examine,and compared the difference before and after the treatment.Results: 1.Conners Parent Symptom Questionnaire(PSQ): After six weeks of treatment,ADHD patients in the ATX group and the combination group showed a decreased score in all six factors: conduct problems,learning problems,psychosomatic disorder,impulsivity/hyperactivity,anxiety,and hyperactive index(p<0.05).Except for the score of psychosomatic disorder in the r TMS group,the difference in other five scores was statistically significant(p<0.05).2.SNAP-IV Rating Scale: After 6 weeks of treatment,ADHD patients in the three groups all showed a decreased score in attention deficit,hyperactivity/impulsivity,and oppositional defiant disorder(p<0.05).3.Arithmetic,Digit Span,and Coding: After 6 weeks of treatment,ADHD patients of the three groups all showed an increased score in Arithmetic,Digit Span(forward and back number),and Coding subtests.(p<0.05).4.Continuous performance test(CPT): After 6 weeks of treatment,ADHD patients in the r TMS group,the ATX group,and the combination group showed increased use error warning(DEPRIME)(p<0.05).5.Iowa Gambling Task(IGT): After 6 weeks of treatment,ADHD patients in the r TMS group,the ATX group,and the combination group showed increased IGT scores(the difference in choosing times between advantageous and disadvantageous decks)(p<0.05).6.Therapeutical effects of the combination treatment relative to the single treatment: Compared with the two single treatments,the combination treatment showed a better improvement in conduct problem and hyperactive index from PSQ(p< 0.05),attention deficits and hyperactivity impulse from the SNAP-IV questionnaire(p <0.05),as well as cold and hot executive functions such as arithmetic,forward numbers,coding,and IGT(p< 0.05).In addition,the ATX group performed better than the r TMS group in coding and IGT..7.Compared with healthy children,ADHD patients showed an increased level of serum miRNA let-7d(p<0.05).The two groups showed no significant difference in the expression level of serum miRNA-107(p>0.05).8.After six weeks of ATX or r TMS treatment,there were significant differences in the expression level of serum miRNA let-7d in ADHD patients(p<0.05).The expressions level of serum miRNA-107 showed no significant difference before and after the treatment(p>0.05).Conclusions: 1.The treatment with r TMS,ATX,or the combination of r TMS and ATX effectively improves attention deficit,hyperactivity/ impulsivity,cool executive function and hot executive function in ADHD patients.The combined treatment has significant therapeutic advantages over the single treatment groups.Compared with r TMS,the drug therapy has a better improvement in coding and IGT.2.The serum miRNA let-7d may serve as one potential biomarker of ADHD in clinical diagnosis and efficacy evaluation.