Accelerated theta-burst stimulation over the motor cortex improves social communication impairment in children with autism spectrum disorder: An open-label trial

Accelerated theta-burst stimulation over the motor cortex improves social communication impairment in children with autism spectrum disorder: An open-label trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Accelerated theta-burst stimulation over the motor cortex improves social communication impairment in children with autism spectrum disorder: An open-label trial Hangyu Tan, Mingyu Xu, Lin Deng, Lingli Zhang, Shaowen Wang, Miao Cao, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4140990/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Social communication impairment (SCI) is a defining feature in autism spectrum disorder (ASD) but remains difficult to treat. Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) is a potential method for treating this aspect of ASD, but the stimulation protocols used vary widely, and limited effects of these protocols on SCI have been reported, particularly in younger children with ASD. Thus, we developed an accelerated rTMS protocol and investigated its feasibility, efficacy and potential neural mechanism for the treatment of SCI in ASD children. Methods In the open-label study, thirty children aged 4–10 with ASD received accelerated theta-burst stimulation (a-cTBS) over the motor cortex for 5 consecutive days. Before and after the intervention, all participants underwent a battery of clinical assessments regarding SCI, and 26 of them cooperated and participated in the collection of electroencephalogram (EEG) data. The primary clinical efficacy outcome was the Social Responsiveness Scale (SRS) score. Results All participants completed the trial and the adverse effects were low-incidence and mild. Repeat measurement analysis showed a significant improvement in the Social Responsiveness Scale (SRS) score with a mean decrease of 12.77 (95% CI 7.58 to 17.95; P < .001) between pre-intervention and post-intervention, and 16.60 (95% CI 11.47 to 21.73; P < .001) between pre-intervention and one-month follow-up, respectively, and the improvement was associated with the observed EEG signal changes of right temporoparietal region. Paired tests showed significant increases in language-related indicators scores from baseline to the one-month follow-up (all P < 0.05). Conclusions This study indicated that a-cTBS over the motor cortex is a safe, feasible and efficient protocol for treating SCI in children with ASD, and provided further evidence for the association of the motor cortex with the social/language network. Trial registration The trial was registered at ClinicalTrials.gov (NCT05472870) on 22th July, 2022. Autism spectrum disorder Repetitive transcranial magnetic stimulation Clinical trial Social communication Language Children Figures Figure 1 Figure 2 Figure 3 Figure 4 1. Introduction Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by a specific combination of impairments in social communication and restricted repetitive patterns of behavior, interests, or activities. This disorder typically begins early in life and affects approximately 1 in 100 children worldwide, and its incidence is increasing annually[ 1 – 6 ]. Social communication impairment (SCI) is the core symptom of ASD and manifests as deficits in social-emotional reciprocity, nonverbal communication and relationship development. These deficits can severely impact children’s daily lives and psychological development. However, there are currently no US Food and Drug Administration (FDA)-approved drugs or therapies for treating ASD, nor for specifically treating SCI [ 2 , 7 ]. To date, behavioral intervention, which is individualized, developmentally appropriate and intensive, requires full-time engagement with professional therapists for several years and starts as early as possible, is the most widely recommended treatment for children with ASD. However, many families of ASD patients do not have access to or cannot afford these interventions. Additionally, even among children receiving timely intensive interventions, the efficacy of these interventions is often limited to small-to-medium improvements [ 2 , 7 – 9 ]. In this sense, it is imperative to find new treatments, especially targeting SCI, that are safe, tolerable, rapid acting and efficient for children with ASD. In the past decade, a noninvasive neurostimulation technique, repetitive transcranial magnetic stimulation (rTMS), has been proposed as a potential therapeutic option for the modification of the pathological neuroplasticity involved in neuropsychiatric disorders, including ASD [ 8 , 10 – 12 ]. It is hypothesized that rTMS may stabilize aberrant neural connectivity and remedy dysfunction in GABAergic and other neurochemical transmission in ASD [ 12 – 14 ]. Recent studies have suggested that rTMS could effectively treat restricted repetitive behaviors (RRBs), cognitive inflexibility and executive functioning (EF) deficits in individuals with ASD [ 11 , 15 , 16 ]; however, the effects of rTMS on SCI symptoms have yielded inconsistent results, and the underlying mechanisms of treating SCI have not been fully investigated [ 17 – 20 ]. Multiple factors, including stimulation target, frequency, intensity, mode and treatment course, are involved in rTMS. All of these factors can influence the effectiveness of neuromodulation intervention; of these, the most basic and critical aspect is the stimulus target. Previous studies have shown considerable variation in stimulation targets, most of which were selected based on their association with ASD pathogenesis; common targets include the dorsolateral prefrontal cortical areas (DLPFC) and the posterior superior temporal sulcus (pSTS)[ 11 , 15 , 16 ]. The primary motor cortex (M1) might serve as a viable target for the treatment of SCI in ASD patients, as it is potentially involved in aspects of action execution [ 21 – 25 ], emotion evaluation [ 26 , 27 ], and language comprehension [ 28 , 29 ], all of which are essential in social communication. Several studies have investigated the underlying neuropathological mechanisms of ASD through stimulation of M1 and found atypical neuroplasticity in ASD patients compared to that in neurotypical controls through the use of neurophysiological bioindicators (e.g., motor-evoked potential (MEP), long-term potentiation (LTP) and long-term depression (LTD) [ 30 – 32 ]. Regrettably, no clinical rTMS trial targeting M1 has been conducted yet to examine its effects on ASD symptoms. Furthermore, the recommended stimulation parameters, particularly for pediatric patients with low cognitive levels and poor cooperation, are still lacking. Continuous theta-burst stimulation (cTBS) [ 33 ], an efficient form of rTMS that can deliver pulses in bursts of three at a higher frequency, requires less stimulation time and functions at a lower overall intensity than traditional rTMS and has promising applications in pediatric patients gives the safety and efficiency benefits of the technique [ 34 ]. Additionally, several studies have shown that neuromodulatory effects can be enhanced and maintained by accelerated, spaced delivery of stimulation sessions and increased overall pulses [ 35 – 38 ], which suggests that the stimulus protocol could be optimized. Overall, we conducted an open-label trial to investigate the feasibility, safety and efficacy of accelerated cTBS (a-cTBS) targeting the left M1 for children with ASD. Additionally, we employed electroencephalography (EEG) to probe the underlying neurological effects of M1 stimulation in individuals with ASD. 2. Materials and methods 2.1 Design In this open-label pilot trial, thirty eligible children received a-cTBS (18,000 pulses/day) targeting the left M1 for 5 consecutive days. All of them underwent clinical assessments three times: pre-intervention (within 2 weeks before the cTBS intervention), post-intervention (within 3 days after the completion of the cTBS course), and 1-month follow-up (1 month following the last cTBS session). Participants were also invited to complete EEG recordings before and after the intervention. Twenty-six participants completed the EEG collection, but four participants failed to collect the data due to poor cooperation. The study was conducted in accordance with the guidelines for Good Clinical Practic e and the principles of the Declaration of Helsinki and approved by the Xinhua Hospital Ethics Committee (XHEC-C-2022-008-4). The procedures and purposes of the study were explained face-to-face to all participants’ legal guardians, who subsequently provided written informed consent. The trial was registered with ClinicalTrials.gov (NCT05472870). 2.2 Participants Participating children were recruited from outpatient clinics in the Department of Developmental and Behavioral & Child Primary Care of Xinhua Hospital affiliated with the Shanghai Jiaotong University School of Medicine. An eligibility visit was subsequently scheduled with the research clinicians. Children were considered eligible if they were aged 4–10 years, were diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5) and were confirmed by the Autism Diagnostic Observation Schedule (ADOS). We excluded patients if they had metal in the head or neck, a history of epilepsy or other neurological diseases, structural brain abnormalities requiring surgical treatment, as indicated by magnetic resonance imaging (MRI), confirmation of genetic or chromosomal abnormalities, a diagnosis of psychiatric disorders other than ASD (e.g., very early-onset schizophrenia), or severe heart disease and/or hearing impairment. Patients who received other interventions or treatments within 4 weeks prior to enrollment or who were currently participating in other clinical trials were also excluded. Notably, participants with cooccurring attention-deficit hyperactivity disorder (ADHD) were included because ADHD is the most common cooccurring condition of ASD; moreover, it might have a similar neurodevelopmental nature and share some etiologies with ASD. All psychotropic medications were continued without change during the trial. 2.3 A-cTBS procedure Two pulsed magnetic stimulation devices (M-100 Ultimate, Shenzhen Yingchi Technology Co., Ltd., Shenzhen, China) were used. Before the intervention, each participant’s stimulation target position and resting motor threshold (RMT) were determined by a physician who was professionally trained according to standard methods [ 39 ]. The RMT was defined as the lowest TMS intensity needed to elicit a MEP of more than 50 µV in at least 5 out of 10 stimuli recorded in the right abductor pollicis brevis (APB) muscle. The optimum position for the left M1 (‘motor hot spot’) was subsequently determined as the site at which stimuli of slight suprathreshold intensity consistently produced the largest MEP in the right APB muscle. During stimulation, the children were instructed to sit on a chair and keep their heads still (and their parents could assist as needed). The TMS coil was held tangentially over the left M1, and the handle of the coil was pointed backward at 45° from the mid-sagittal line. The stimulus intensity was set to 80% of the RMT. The detailed a-cTBS protocol was as follows: 60 cycles of 10 bursts of 3 pulses at 50 Hz were delivered in 2-second trains (5 Hz) with no intertrain interval (i.e., triplet standard cTBS, 1800 pulses, 120 seconds). Stimulation sessions were delivered hourly, and 10 sessions were performed per day (18,000 pulses/day) for 5 consecutive days (90,000 pulses in total) (see Fig. 1 ). 2.4 Clinical behavioral measurements The primary outcome measure of clinical behavior was the Social Responsiveness Scale (SRS) [ 40 ], which provides a multidimensional measure of social interaction allowing for the rating of social impairment in ASD patients. The SRS generates a total score and five subscale scores (social awareness, social cognition, social communication, social motivation, and autistic mannerisms); higher scores indicate greater social impairment. Parents were requested to complete the SRS at three time points (pre-intervention, post-intervention and 1 month follow-up) to monitor the children’s responses in the social domain to the rTMS intervention over time. Three indicators were employed to evaluate children’s language improvements from baseline to the 1-month follow-up: the Chinese Communicative Development Inventory (CCDI, a powerful tool for assessing early vocabulary development and the language skills of older children with developmental disorders) [ 41 ], the Peabody Picture Vocabulary Test (PPVT, a standard test for measuring single-word comprehension) [ 42 ] and the Multilingual Assessment Instrument for Narratives (MAIN, a test for assessing narrative comprehension and production skills) [ 43 ]. In the MAIN test, children were asked to tell and retell several stories and answer some questions, which is applicable only to a subset of ASD children with adequate expressive ability (those able to at least use phrases). Other clinical behavioral measurements included the Behavior Rating Inventory of Executive Function (BRIEF) [ 44 ] and the Conners Parent Rating Scale (CPRS) [ 45 ], which provided a quantitative picture of children's executive function, emotion and behavioral problems. Additionally, we used the Clinical Global Impression of Improvement (CGI-I) [ 46 ] to rate how much the patient’s illness improved or worsened relative to a baseline measurement before the intervention (a seven-point scale: 1 = ‘‘very much improved” to 7 = ‘‘very much worse”). 2.5 EEG acquisition and preprocessing Before and after the 5-day intervention, resting-state EEG signals were collected from all participants while they were watching a simple 4-minute cartoon video. EEG data were recorded using a 128-channel high-density EEG system from Electrical Geodesics, Inc. (EGI), Eugene, OR, USA, with the reference electrode positioned at the vertex (channel Cz). Impedances were maintained below 100 kΩ. Prior to formal preprocessing, the raw EEG data in NetStation format were exported to MATLAB [ 47 ]. Subsequently, offline data processing was conducted in a consistent manner using the EEGLab toolbox [ 48 ]. Continuous EEG data were subjected to bandpass filtering (0.5–45 Hz) and a notch filter at 50 Hz. We excluded data from 46 'skirt channels' from all the collected EEG data as these channels are particularly sensitive to noise and muscle artifacts[ 49 ]. Data from the remaining 82 channels were included in analysis, with those from noisy electrodes removed and interpolated. The preprocessed EEG data were then segmented into 1-second epochs. After experienced EEG researchers visually confirmed the exclusion of artifacts, fast independent component analysis (fast ICA) was employed to identify and eliminate artifacts caused by eye blinks, movements, and muscle activities [ 48 ]. Finally, the data were rereferenced to the average reference. 2.6 EEG analysis After the above preprocessing, the power spectral density (PSD) within the alpha frequency band (8–13 Hz) was calculated for each of the 82 EEG channels. This computation was performed by employing the Fast Fourier Transform (FFT) algorithm [ 50 ], after which the resultant frequency components were squared to derive the amplitude spectrum. Subsequently, the bilateral spectrum was converted into a unilateral spectrum, and the values were normalized by dividing them by the frequency resolution to obtain the final PSD estimates [ 51 ]. For standardization, each subject’s alpha PSD value for each channel was divided by their own mean value of the whole-brain PSD. 2.7 Assessment of adverse events A semistructured interview was administered following each treatment session and followed up by the rTMS technician. The standardized interview included an open-ended query for any adverse events or physical discomfort experienced. If any adverse events or physical discomfort were reported, detailed descriptions were recorded and the severity was graded as mild (no impairment, no need to stop the trial), moderate (some impairment, need to stop the trial but no need for intervention), or severe (evidence of impairment, need to stop the trial and intervention is needed). 2.8 Sample size The minimum total sample size was estimated using G*Power, which is powered (80% power and two-sided 5% significance) to detect a moderate-to-large standardized effect of treatment. The estimated effect size was guided by existing results on social behavior deficits (Ni HC, et al ., 2021; Barahona-Correa et al ., 2018) [ 15 , 19 ]. Considering the 10% dropout rate, the final sample size of this study was estimated to be at least 30. 2.9 Statistical analysis All clinical outcome analyses were conducted using SPSS version 25.0, and the statistical significance level was set at 0.05. To compare the changes in SRS, BRIEF and CPRS scores across three time points (pre-intervention, post-intervention, and 1 month follow-up), we used the one-way analysis of variance (ANOVA) with repeated measures or the Friedman test, followed by post hoc analyses incorporating Bonferroni correction to adjust for multiple comparisons. The Mann‒Whitney Wilcoxon test or paired-samples t test was used for the CCDI, PPVT and MAIN measurements at only two time points (pre-intervention vs. 1 month follow-up). To explore whether high/low-functioning (full-scale intelligence quotient (FSIQ) ≥ 70 as the cutoff point) moderated stimulation effects, a two-way repeated-measures ANOVA was performed to examine the effects of time, group and time-by-group interaction on our primary variables (i.e., SRS). Linear regression was also performed, with FSIQ score or age as the independent variable and SRS score change as the dependent variable. For the EEG data, we first compared the PSD within the alpha band between baseline and post-intervention across all the remaining channels using a paired t test. Subsequently, we stratified participants into two groups, a significantly effective (SE) group and a nonsignificantly effective (NE) group, based on the median reduction in SRS total score after the 5-day intervention. Then, we compared the alpha PSD values between the groups before and after the intervention. Furthermore, a Pearson correlation analysis was conducted to explore the relationship between neurophysiological effects of rTMS and clinical improvement by analyzing alpha PSD values and changes in SRS scores. 3. Results 3.1 Feasibility and acceptability From July 2022 to December 2022, of the 36 patients who were assessed for eligibility, thirty children with ASD were enrolled and completed the full intervention course and follow-up assessments (Fig. 2). The average age of these 30 patients was 7.06 years (standard deviation, SD 1.55), and 80% were male (Table 1). Among them, EEG data were successfully collected from twenty-six children at pre-intervention and post-intervention. Table 1. Demographic and clinical characteristics of the participants at the baseline. Total Sample (n=30) Age (years) 7.06±1.55 Gender (male/female) 24/6 FSIQ 74.97±24.70 CARS 33.48±2.59 ADOS Communication 4.70±1.24 Social Interaction 9.03±1.81 SA_Total score 13.73±2.74 Abbreviations: FSIQ = full-scale IQ, CARS = Childhood Autism Rating Scale, ADOS = Autism Diagnostic Observation Schedule, SA_Total score = ADOS_Communication score + ADOS_Social Interaction score. Adverse events were reported in a subset of participants. Six children showed agitation during the intervention period, three children complained of scalp pain during the first few stimulation treatments, and one child experienced transient nausea during the follow-up period after completing the treatment. All adverse events were rated as mild and disappeared without any specific therapy, and no patient withdrew from the trial due to side effects. 3.2 Clinical behavioral outcomes There was a significant reduction in the SRS total score after the a-cTBS intervention, with a mean decrease of 12.77 (95% CI 7.58 to 17.95; P <.001) between the pre-intervention and post-intervention assessments and 16.60 (95% CI 11.47 to 21.73; P <.001) between the pre-intervention and one-month follow-up assessments (Table 2, Fig. 3A). Additionally, significant decreases were noted in the five subscales of the SRS (Table 2). Table 2. Changes in clinical outcomes from baseline (pre-intervention) to follow-up (post-intervention and one-month follow-up). Outcome measures N Mean (SD)/Median (interquartile range) a P value b Pre Post 1mth Pre* Post Pre* 1mth Post* 1mth SRS 30 Total scores 94.27 (20.26) 81.50 (21.27) 77.67 (20.13) <.001 <.001 .25 Social awareness 12.13 (2.76) 11.50 (2.74) 10.87 (2.27) .18 .003 .32 Social cognition 20.03 (3.84) 17.40 (4.45) 16.40 (4.34) .001 <.001 .12 Social communication 32.73 (7.42) 28.07 (7.31) 26.63 (7.31) <.001 .99 Autistic mannerisms 15.90 (5.73) 13.07 (5.85) 12.30 (6.01) .001 <.001 .68 CCDI 22 Words produced 733.00 (615.25, 789.50) NA 771.50 (657.00, 793.25) NA .001 NA Sentence complexity 69.00 (42.00, 76.00) NA 71.00 (54.00, 79.00) NA .07 NA PPVT 27 Raw score 67.78 (27.23) NA 76.11 (26.89) NA <.001 NA IQ 100.63 (28.74) NA 111.00 (30.89) NA .001 NA MAIN_ Telling 14 Story Structure 7.57 (2.34) NA 8.96 (2.43) NA .02 NA Structural Complexity 2.11 (0.59) NA 2.50 (0.55) NA .05 NA Internal States Terms 3.68 (2.00) NA 5.21 (3.20) NA .02 NA Comprehension Questions 6.50 (1.79) NA 8.32 (1.56) NA <.001 NA MAIN_ Retelling 14 Story Structure 9.07 (2.18) NA 12.21 (2.28) NA <.001 NA Structural Complexity 2.32 (0.58) NA 2.75 (0.38) NA .04 NA Internal States Terms 5.07 (2.13) NA 6.14 (1.56) NA .05 NA Comprehension Questions 6.46 (1.96) NA 8.21 (1.66) NA .002 NA Abbreviations: SRS, Social Responsiveness Scale; CARS, Childhood Autism Rating Scale; CCDI, Chinese Communicative Development Inventory; PPVT, Peabody Picture Vocabulary Test; MAIN, Multilingual Assessment Instrument for Narratives. a. Quantitative outcomes (CCDI) that were not normally distributed were expressed as medians (interquartile ranges); b. Multiple comparisons were performed using Bonferroni correction; c. Repeated measures ANOVA: SRS; Mann‒Whitney Wilcoxon test: CCDI, MAIN-SC, and MAIN-IST; paired-samples t test: PPVT, MAIN-SS, and MAIN-CQ. We also observed significant improvements in language-related indicator scores, such as the raw scores for CCDI words produced ( P =.001) and raw PPVT scores ( P <.001) (Table 2 and Fig. 3B). Among the 14 children who had sufficient expressive ability and who completed the MAIN test at baseline and at the one-month follow-up, the “story structure”, “structural complexity” and “comprehension questions” scores were found to significantly increase (Table 2). The CPRS and BRIEF scores showed no noticeable changes after the intervention, except for the emotional control score of the BRIEF (preschool version), which reached statistical significance but did not pass correction for multiple comparisons (sTable 1). The improvements in autistic symptoms were supported by the CGI-I at the one-month follow-up assessment (5 participants reached ‘‘improved’, 22 participants reached ‘‘slightly improved”) and by caregiver reports (sTable 2). Most caregivers reported that their children showed improvements in the social and/or language domains (e.g., social motivation, vocabulary size and sentence complexity) after the intervention. A summary of these improvements can be found in sTable 2. 3.3 High-functioning and low-functioning subgroup analyses At baseline, no differences were found in demographic characteristics or clinical severity of autistic symptoms between the high-functioning and low-functioning groups, except for FSIQ score (sTable 3). The SRS scores decreased significantly from baseline to follow-up in both groups (except for the social awareness score in the low-functioning group, the autistic mannerisms score in the high-functioning group and the social motivation score in both groups) (sTable 4 and sFig. 1). Two-way repeated-measures ANOVA revealed a significant time effect ( P <.001), no significant group effect ( P =.194), and no significant interaction effect ( P =.332) on SRS scores (sTable 5). The linear regression model also indicated that there was no significant effect of IQ or age ( P >.05) on SRS score change. The above results showed that the decrease in SRS score was not different between the two subgroups. 3.4 PSD values in the alpha band We successfully collected EEG data from 26 children before and after the intervention, and one patient was excluded after a quality control procedure. Using the 25 children’s median decrease in SRS total score after the 5-day intervention (10 points) as a threshold for treatment response, we categorized all the children into either the SE group (n = 13) or the NE group (n = 12). No statistically significant differences in age, sex, or FSIQ score were found between the two groups at baseline. We compared the PSD within the alpha frequency band across the whole brain before and after the intervention in 25 participants and found no significant difference ( P > .05). There was also no statistically significant difference in the alpha PSD across any of the remaining channels between the SE and NE groups before intervention ( P > .05), whereas the PSD in the alpha band of the right temporoparietal region at post-intervention was greater in the SE group (P< .05; Fig. 4A). Furthermore, a noteworthy positive correlation was detected between the PSD in the right temporoparietal region postintervention and the decrease in SRS score, particularly in relation to the social communication subscale score (Fig. 4B-C, sTable 6). 4. Discussion To our knowledge, this was the first clinical trial in which a-cTBS was applied to the left M1 of children with ASD. We provided preliminary evidence for the safety and feasibility of the a-cTBS protocol and were delighted to find that the 5-day exploratory intervention yielded positive results in improving not only social communication but also language function, as measured by clinical behavioral outcomes, in these patients. Through the combination of EEG analysis, we found a positive correlation between improvements in social function scores and alpha power in the right temporoparietal region postintervention, revealing the potential neurophysiological effect of this rTMS intervention. Our work revealed that 5-day a-cTBS to the left M1 could significantly improve social communication and language function in children with ASD. To reliably evaluate changes in SCI symptoms in ASD patients, several specific and sensitive behavioral outcome measurements were carefully selected. Our primary outcome measure was SRS, which not only quantifies the severity of social impairment associated with ASD but is also sensitive enough to detect even subtle changes in symptoms [40]. The results showed that the SRS total score decreased by an average of 12.77 points immediately after the 5-day intervention and 16.60 points at the one-month follow-up. The scores of five subscales of the SRS also decreased significantly. Compared with previous clinical research that used the SRS as an indicator of social impairment [19, 52, 53], our study revealed greater improvement in this short intervention period. The subgroup analysis showed that the SRS scores significantly decreased from baseline to follow-up in both the high-functioning and low-functioning groups, and there was no significant effect of IQ on the change in SRS score, indicating that a-cTBS targeting the left M1 could contribute to similar improvements in clinical measurements in children with ASD at different functional levels. This finding suggested that our protocol might be broadly applicable among children with ASD. Notably, we found considerable improvements in language comprehension and expression among participants after 5 days of a-cTBS targeting the left M1; such improvement has not been reported in previous rTMS intervention studies of ASD. Language impairment is a common occurrence in children with ASD and can limit social development in these individuals [54], making this impairment important and necessary to treat. However, significantly improving language capacity in a short period through drugs or behavioral interventions is very challenging. Although some therapies are effective, the effect sizes are relatively small and not robust [55-58]. The clinical behavioral results mentioned above are encouraging but limited by the use of an open-label single-arm design; the efficacy of this rTMS protocol needs to be confirmed by future large-scale randomized controlled trials (RCTs). The TMS procedure employed in this work was scientifically designed to be well tolerated and suitable for children with ASD. According to previous physiological experiments in humans, high-frequency rTMS (>1 Hz) and low-frequency rTMS (≤1 Hz) can evoke LTP and LTD of synaptic transmission, respectively; moreover, it can subsequently alter cortical excitability, which is most likely modulated by GABAergic activities [59-61]. These changes are not only restricted to the site of stimulation but also widely observed in the entire brain network [62]. The evidence above suggests that rTMS treatment may benefit ASD patients, as the excitation/inhibition ratio (E/I) imbalance might underlie the pathogenesis of ASD [63, 64], particularly in children with rapid neural development. However, most previous clinical trials of rTMS in ASD patients have been limited to intellectually capable youth or adults due to the traditional rTMS requirement of patient cooperation for at least 20 minutes [11, 15, 16, 19]. Our study focused on individuals of early developmental age (4-10 years), which have greater neuroplasticity and a desire for functional improvement; however, given their poor cooperation, the acceptability and feasibility of the rTMS protocol were major challenges. The emergence of TBS solved this challenge, as it is a rapid form of rTMS cortical conditioning that produces a more controllable, long-lasting and powerful effect on cortex physiology and behavior after very short periods of overall low-intensity stimulation [33]. Notably, our protocol had a short-term accelerated stimulation design. The multisession requirement has long been established, and many studies have shown that repeated short training sessions are more effective than a single prolonged session [37, 65, 66]. Therefore, our a-cTBS intervention course consisted of 50 sessions within 5 days to provide sufficient stimulation to the target. The one-hour spacing used in the protocol was based on the evidence from basic neuroscience research and human physiology or behavioral data [33, 67-69]. We expected this multiple, daily a-cTBS protocol to have an enhanced effect, and our results proved this to be the case. Another advantage of the current rTMS protocol is the targeted stimulation of M1, which is a crucial factor in determining treatment efficacy. M1 is easy to localize (it can be found by the MEPs recorded on the APB muscle of the contralateral hand, instead of requiring neurological navigation that is difficult for children with ASD to cooperate with). Although numerous previous studies have investigated the neuropathological mechanisms of ASD through stimulation of the left M1 region and found atypical neural plasticity [31, 32], no relevant rTMS intervention study targeting the left M1 region in ASD patients has been conducted. This work highlighted the therapeutic potential of M1 as a viable target for treating ASD, and we speculated that the underlying mechanisms may be attributed to its modulation of related networks. Pertinently, the human brain exhibits a distinct spatiotemporal organization that supports brain function and can be manipulated via local brain stimulation [70, 71]. There is growing evidence that M1 is not simply a static motor control region; it also plays a dynamic role in learning and cognition [72]. Interestingly, M1 has been demonstrated to be closely linked to the processing of social information and social-related networks. For instance, some studies have reported that M1 excitability increases during emotion-related tasks [24], and M1 is densely connected to some core regions of the network involved in emotion evaluation (e.g., occipitotemporal regions, the amygdala, the pulvinar cortex, the orbitofrontal cortex and the cingulate cortex) [24, 73, 74]. In a system critical for social cognition and interaction, which contains mirror neurons (MNs), M1 is an essential region that allows humans to coordinate emotional actions and social behaviors [21]. A recent study revealed that a somato-cognitive action network (SCAN) for whole-body action planning was intertwined with M1 [22], and a newly discovered major hub, the retrosplenial cortex (RSC), which is highly selective and specific for social behavior regulation, is inextricably linked to sensorimotor networks [25], both of which support the importance of M1 in social function. Additionally, some evidence has demonstrated that the motor system plays a core role in semantic processing [28, 29], which is an important part of language function and has a strong impact on social interaction. The clinical behavioral improvements in social and language functions in our study provided further evidence for the involvement of M1 in social language networks; EEG analysis also supported this finding. Through EEG analysis, we revealed the potential mechanism underlying the use of M1 stimulation as a treatment for ASD. In the present study, we found that participants with a greater decrease in SRS score had a significantly greater alpha PSD in the right temporoparietal region after 5 days of intervention than did those with a smaller decrease. Moreover, there was a significant positive correlation between the PSD in the right temporoparietal region postintervention and the reduction in SRS scores, suggesting that a greater alpha power in the right temporoparietal region after 5 days of a-cTBS may be associated with greater improvement in autistic social deficits, particularly in those related to social communication. Oscillations in the alpha band are thought to indirectly reflect cortical excitability in brain regions, and higher alpha power at rest is considered to be correlated with lower neuronal excitability [75-77]. However, another conception is that high resting alpha power may reflect active preparation for information processing or task performance [77-79], and some research has shown that greater resting alpha power is associated with positive behavioral outcomes, such as enhanced performance in cognitive tasks [80, 81] and good response inhibition [82]. Some evidence of an association between an increase in alpha power after treatment and the improvement in ASD symptom indicators has also been found [83-85], which is consistent with our present findings. The EEG data also indicated individual differences in the responsiveness of rTMS among children with ASD, which prompted further exploration of which individuals are likely to benefit from this rTMS protocol in future work. Notably, the positive results of the alpha PSD analysis were concentrated in the right temporoparietal region. The right temporal lobe and parietal lobe have been extensively investigated in neuroimaging studies and animal experiments; these regions are important for regulating social behaviors or language processes, and they exhibit atypical morphological and functional alterations in individuals with ASD [86-88]. After combining the findings of previous studies with the findings of our study, we can reasonably speculate that a-cTBS over the left M1 may impact patients’ social responsiveness and language ability by indirectly modulating the “social/language brain network” (e.g., the right temporoparietal junction [rTPJ] [89] and STS) [90]. However, due to the limitations of the low spatial resolution of EEG signals and the use of image analysis methods, these inferences need to be interpreted with caution. In the future, more advanced methods of image analysis (i.e., EEG source analysis) or imaging methods with higher spatial resolution, such as MRI, may need to be included in patient assessments to better explore the underlying neurological mechanism of the effects of cTBS over the left M1 in ASD children. In summary, our study showed that a-cTBS over the left M1 for 5 consecutive days is safe and effective at improving SCI and language deficits in children with ASD. This work suggested that the M1 may be a new therapeutic target for ASD, and the underlying mechanisms for the therapeutic affect may be attributed to the modulation of associated networks, providing further evidence for the association of M1 with the social/language network. Future large RCTs incorporating advanced neuroimaging analysis (e.g., EEG and MRI) methods are needed to validate the clinical efficacy of a-cTBS over the left M1and investigate the exact extent of brain network remodeling after M1 stimulation. Abbreviations a-cTBS Accelerated theta-burst stimulation ADOS Autism Diagnostic Observation Schedule ADHD Attention-deficit hyperactivity disorder ANOVA Analysis of variance APB Abductor pollicis brevis ASD Autism spectrum disorder BRIEF Behavior Rating Inventory of Executive Function CCDI Chinese Communicative Development Inventory CGI-I Clinical Global Impression of Improvement CPRS Conners Parent Rating Scale cTBS Continuous theta-burst stimulation DLPFC Dorsolateral prefrontal cortical areas DSM-5 Diagnostic and Statistical Manual of Mental Disorders, Edition 5 EEG Electroencephalogram EF Executive functioning EGI Electrical Geodesics, Inc FDA Food and Drug Administration FFT Fast Fourier Transform FSIQ Full-scale intelligence quotient ICA Independent component analysis LTD Long-term depression LTP Long-term potentiation M1 Primary motor cortex MAIN Multilingual Assessment Instrument for Narratives MEP Motor-evoked potential MNs Mirror neurons MRI Magnetic resonance imaging NE Nonsignificantly effective PPVT Peabody Picture Vocabulary Test PSD power spectral density pSTS Posterior superior temporal sulcus RCTs Randomized controlled trials RMT Resting motor threshold RRBs Restricted repetitive behaviors RSC Retrosplenial cortex rTMS Repetitive transcranial magnetic stimulation rTPJ right temporoparietal junction SCAN Somato-cognitive action network SCI Social communication impairment SE Significantly effective SRS Social Responsiveness Scale Declarations Acknowledgments We acknowledge the other students, teachers, and assistants on our research team who provided valuable assistance during this trial. We also thank the children and families for their participation and support in this study. Funding This study was supported by grants from the National Natural Science Foundation of China (82125032, 81930095 and 81761128035), the Science and Technology Commission of Shanghai Municipality (19410713500 and 2018SHZDZX01), the Foundation of Shanghai Municipal Commission of Health and Family Planning (GWV-10.1-XK07, 2020CXJQ01 and 2018YJRC03), the Shanghai Clinical Key Subject Construction Project (shslczdzk02902), the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20211100), and the Guangdong Key Project (2018B030335001). Ethics approval and consent to participate The authors assert that all procedures were conducted in accordance with the guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki and approved by the Xinhua Hospital Ethics Committee (XHEC-C-2022-008-4). Consent for publication Not applicable. Competing interests The authors declare that there are any competing financial interests in relation to the work described. Authors and Affiliations Department of Developmental and Behavioural Pediatric & Child Primary Care, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Hangyu Tan, Mingyu Xu, Lin Deng, Lingli Zhang & Fei Li Brain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children’s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Hangyu Tan, Mingyu Xu, Lin Deng, Lingli Zhang & Fei Li Department of Developmental and Behavioural Pediatric & Child Primary Care, Zhengzhou Children’s Hospital, Henan, China. Shaowen Wang Institute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China. Miao Cao Key Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Fudan University, Shanghai, China. Miao Cao Shanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Ti-Fei Yuan Contributions FL and TY supervised the design and protocol of the study and contributed to the interpretation and discussion of the results. HT, MX, LD and SW contributed to the study design, trial implementation, and collected the data. HT, MX, LD, SW and MC contributed to the data processing and statistical analysis. HT, MX, LD, LZ, MC and TY contributed to the writing of the manuscript. All authors reviewed and approved the final version of the manuscript. Corresponding authors Correspondence to Miao Cao, Ti-fei Yuan or Fei Li. Availability of data and materials The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request. References Lord C, Brugha TS, Charman T, Cusack J, Dumas G, Frazier T, et al. Autism spectrum disorder. Nat Rev Dis Primers. 2020;6:5. Hyman SL, Levy SE, Myers SM. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020, 145. Zeidan J, Fombonne E, Scorah J, Ibrahim A, Durkin MS, Saxena S, et al. Global prevalence of autism: A systematic review update. Autism Res. 2022;15:778–90. Maenner MJ, Shaw KA, Bakian AV, Bilder DA, Durkin MS, Esler A, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018. MMWR Surveill Summ. 2021;70:1–16. Maenner MJ, Warren Z, Williams AR, Amoakohene E, Bakian AV, Bilder DA, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ. 2023;72:1–14. Zhou H, Xu X, Yan W, Zou X, Wu L, Luo X, et al. Prevalence of Autism Spectrum Disorder in China: A Nationwide Multi-center Population-based Study Among Children Aged 6 to 12 Years. Neurosci Bull. 2020;36:961–71. Frye RE. Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents. CNS Drugs. 2018;32:713–34. Baribeau D, Vorstman J, Anagnostou E. Novel treatments in autism spectrum disorder. Curr Opin Psychiatry. 2022;35:101–10. Sharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacol Ther. 2018;190:91–104. Lefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014–2018). Clin Neurophysiol. 2020;131:474–528. Zhang J, Zhang H. Effects of non-invasive neurostimulation on autism spectrum disorder: A systematic review. Front Psychiatry. 2022;13:989905. Fitzsimmons SMDD, Oostra E, Postma TS, van der Werf YD, van den Heuvel OA. Repetitive transcranial magnetic stimulation-induced neuroplasticity and the treatment of psychiatric disorders: state of the evidence and future opportunities. Biol Psychiatry 2023. Casanova MF, Sokhadze EM, Casanova EL, Opris I, Abujadi C, Marcolin MA, et al. Translational Neuroscience in Autism: From Neuropathology to Transcranial Magnetic Stimulation Therapies. Psychiatr Clin North Am. 2020;43:229–48. Masuda F, Nakajima S, Miyazaki T, Yoshida K, Tsugawa S, Wada M, et al. Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review. Transl Psychiatry. 2019;9:110. Barahona-Correa JB, Velosa A, Chainho A, Lopes R, Oliveira-Maia AJ. Repetitive Transcranial Magnetic Stimulation for Treatment of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Front Integr Neurosci. 2018;12:27. Smith JR, DiSalvo M, Green A, Ceranoglu TA, Anteraper SA, Croarkin P et al. Treatment Response of Transcranial Magnetic Stimulation in Intellectually Capable Youth and Young Adults with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Neuropsychol Rev 2022. Baruth JM, Casanova MF, El-Baz A, Horrell T, Mathai G, Sears L, et al. Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Evoked-Gamma Frequency Oscillations in Autism Spectrum Disorder (ASD). J Neurother. 2010;14:179–94. Ni HC, Hung J, Wu CT, Wu YY, Chang CJ, Chen RS, et al. The Impact of Single Session Intermittent Theta-Burst Stimulation over the Dorsolateral Prefrontal Cortex and Posterior Superior Temporal Sulcus on Adults with Autism Spectrum Disorder. Front Neurosci. 2017;11:255. Ni HC, Chen YL, Chao YP, Wu CT, Wu YY, Liang SH, et al. Intermittent theta burst stimulation over the posterior superior temporal sulcus for children with autism spectrum disorder: A 4-week randomized blinded controlled trial followed by another 4-week open-label intervention. Autism. 2021;25:1279–94. Enticott PG, Fitzgibbon BM, Kennedy HA, Arnold SL, Elliot D, Peachey A, et al. A double-blind, randomized trial of deep repetitive transcranial magnetic stimulation (rTMS) for autism spectrum disorder. Brain Stimul. 2014;7:206–11. Bonini L, Rotunno C, Arcuri E, Gallese V. Mirror neurons 30 years later: implications and applications. Trends Cogn Sci. 2022;26:767–81. Gordon EM, Chauvin RJ, Van AN, Rajesh A, Nielsen A, Newbold DJ et al. A somato-cognitive action network alternates with effector regions in motor cortex. Nature 2023. Fini C, Fischer M, Bardi L, Brass M, Moors A. Support from a TMS/MEP study for a direct link between positive/negative stimuli and approach/avoidance tendencies. Neuropsychologia. 2020;143:107496. Xia X, Wang D, Song Y, Zhu M, Li Y, Chen R, et al. Involvement of the primary motor cortex in the early processing stage of the affective stimulus-response compatibility effect in a manikin task. NeuroImage. 2021;225:117485. Alexander AS, Place R, Starrett MJ, Chrastil ER, Nitz DA. Rethinking retrosplenial cortex: Perspectives and predictions. Neuron. 2023;111:150–75. Borgomaneri S, Gazzola V, Avenanti A. Temporal dynamics of motor cortex excitability during perception of natural emotional scenes. Soc Cogn Affect Neurosci. 2014;9:1451–7. Loi N, Ginatempo F, Carta M, Melis F, Manca A, Deriu F. Face emotional expressions influence interhemispheric inhibition. Psychophysiology 2022: e14234. Solana P, Santiago J. Does the involvement of motor cortex in embodied language comprehension stand on solid ground? A p-curve analysis and test for excess significance of the TMS and tDCS evidence. Neurosci Biobehav Rev. 2022;141:104834. Wang X, Krieger-Redwood K, Zhang M, Cui Z, Wang X, Karapanagiotidis T, et al. Physical distance to sensory-motor landmarks predicts language function. Cereb Cortex. 2023;33:4305–18. Jannati A, Block G, Ryan MA, Kaye HL, Kayarian FB, Bashir S, et al. Continuous Theta-Burst Stimulation in Children With High-Functioning Autism Spectrum Disorder and Typically Developing Children. Front Integr Neurosci. 2020;14:13. Desarkar P, Rajji TK, Ameis SH, Blumberger DM, Lai MC, Lunsky Y, et al. Assessing and stabilizing atypical plasticity in autism spectrum disorder using rTMS: Results from a proof-of-principle study. Clin Neurophysiol. 2022;141:109–18. Jannati A, Ryan MA, Block G, Kayarian FB, Oberman LM, Rotenberg A, et al. Modulation of motor cortical excitability by continuous theta-burst stimulation in adults with autism spectrum disorder. Clin Neurophysiol. 2021;132:1647–62. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45:201–6. Elmaghraby R, Sun Q, Ozger C, Shekunov J, Romanowicz M, Croarkin PE. A Systematic Review of the Safety and Tolerability of Theta Burst Stimulation in Children and Adolescents. Neuromodulation. 2022;25:494–503. Cole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Psychiatry. 2020;177:716–26. Perera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9:336–46. Smolen P, Zhang Y, Byrne JH. The right time to learn: mechanisms and optimization of spaced learning. Nat Rev Neurosci. 2016;17:77–88. Goldsworthy MR, Pitcher JB, Ridding MC. Spaced Noninvasive Brain Stimulation: Prospects for Inducing Long-Lasting Human Cortical Plasticity. Neurorehabil Neural Repair. 2015;29:714–21. Rossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015;126:1071–107. Cen CQ, Liang YY, Chen QR, Chen KY, Deng HZ, Chen BY, et al. Investigating the validation of the Chinese Mandarin version of the Social Responsiveness Scale in a Mainland China child population. BMC Psychiatry. 2017;17:51. Tardif T, Fletcher P, Liang W, Kaciroti N. Early vocabulary development in Mandarin (Putonghua) and Cantonese. J Child Lang. 2009;36:1115–44. Krasileva KE, Sanders SJ, Bal VH. Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder. J Autism Dev Disord. 2017;47:1073–85. Kan RTY, Chan A, Gagarina N. Investigating Children's Narrative Abilities in a Chinese and Multilingual Context: Cantonese, Mandarin, Kam and Urdu Adaptations of the Multilingual Assessment Instrument for Narratives (MAIN). Front Psychol. 2020;11:573780. Rosenthal M, Wallace GL, Lawson R, Wills MC, Dixon E, Yerys BE, et al. Impairments in real-world executive function increase from childhood to adolescence in autism spectrum disorders. Neuropsychology. 2013;27:13–8. Goyette CH, Conners CK, Ulrich RF. Normative data on revised Conners Parent and Teacher Rating Scales. J Abnorm Child Psychol. 1978;6:221–36. de Beurs E, Carlier IVE, van Hemert AM. Approaches to denote treatment outcome: Clinical significance and clinical global impression compared. Int J Methods Psychiatr Res. 2019;28:e1797. Arns M, Bruder G, Hegerl U, Spooner C, Palmer DM, Etkin A, et al. EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study. Clin Neurophysiol. 2016;127:509–19. Delorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134:9–21. Frohlich J, Reiter LT, Saravanapandian V, DiStefano C, Huberty S, Hyde C, et al. Mechanisms underlying the EEG biomarker in Dup15q syndrome. Mol Autism. 2019;10:29. Gabard-Durnam LJ, Wilkinson C, Kapur K, Tager-Flusberg H, Levin AR, Nelson CA. Longitudinal EEG power in the first postnatal year differentiates autism outcomes. Nat Commun. 2019;10:4188. Angulo-Ruiz BY, Ruiz-Martínez FJ, Rodríguez-Martínez EI, Ionescu A, Saldaña D, Gómez CM. Linear and Non-linear Analyses of EEG in a Group of ASD Children During Resting State Condition. Brain Topogr; 2023. Dai Y, Zhang L, Yu J, Zhou X, He H, Ji Y, et al. Improved symptoms following bumetanide treatment in children aged 3 – 6 years with autism spectrum disorder: a randomized, double-blind, placebo-controlled trial. Sci Bull. 2021;66:1591–8. Li F, Wu D, Ren F, Shen L, Xue M, Yu J, et al. Effectiveness of Online-Delivered Project ImPACT for Children With ASD and Their Parents: A Pilot Study During the COVID-19 Pandemic. Front Psychiatry. 2022;13:806149. Hyman SL, Levy SE, Myers SM, Council On Children With Disabilities SOD, Behavioral P. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020, 145. Virués-Ortega J. Applied behavior analytic intervention for autism in early childhood: meta-analysis, meta-regression and dose-response meta-analysis of multiple outcomes. Clin Psychol Rev. 2010;30:387–99. Sandbank M, Bottema-Beutel K, Crowley S, Cassidy M, Feldman JI, Canihuante M, et al. Intervention Effects on Language in Children With Autism: A Project AIM Meta-Analysis. J Speech Lang Hear Res. 2020;63:1537–60. Brignell A, Chenausky KV, Song H, Zhu J, Suo C, Morgan AT. Communication interventions for autism spectrum disorder in minimally verbal children. Cochrane Database Syst Rev. 2018;11:Cd012324. Rossignol DA, Frye RE. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. J Pers Med 2021, 11. Hoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry. 2002;159:1093–102. Pascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117(Pt 4):847–58. Cardenas-Morales L, Nowak DA, Kammer T, Wolf RC, Schonfeldt-Lecuona C. Mechanisms and applications of theta-burst rTMS on the human motor cortex. Brain Topogr. 2010;22:294–306. Fox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). NeuroImage. 2012;62:2232–43. Casanova MF, Buxhoeveden D, Gomez J. Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist. 2003;9:496–507. Chao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010;468:263–9. Carew TJ, Pinsker HM, Kandel ER. Long-term habituation of a defensive withdrawal reflex in aplysia. Science. 1972;175:451–4. Lisanby SH. Transcranial Magnetic Stimulation in Psychiatry: Historical Reflections and Future Directions. Biol Psychiatry; 2023. Kramar EA, Babayan AH, Gavin CF, Cox CD, Jafari M, Gall CM, et al. Synaptic evidence for the efficacy of spaced learning. Proc Natl Acad Sci U S A. 2012;109:5121–6. Goldsworthy MR, Pitcher JB, Ridding MC. The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex. Eur J Neurosci. 2012;35:125–34. Nyffeler T, Cazzoli D, Hess CW, Muri RM. One session of repeated parietal theta burst stimulation trains induces long-lasting improvement of visual neglect. Stroke. 2009;40:2791–6. Gollo LL, Roberts JA, Cocchi L. Mapping how local perturbations influence systems-level brain dynamics. NeuroImage. 2017;160:97–112. Beynel L, Powers JP, Appelbaum LG. Effects of repetitive transcranial magnetic stimulation on resting-state connectivity: A systematic review. NeuroImage. 2020;211:116596. Sanes JN, Donoghue JP. Plasticity and primary motor cortex. Annu Rev Neurosci. 2000;23:393–415. Pessoa L, Adolphs R. Emotion processing and the amygdala: from a 'low road' to 'many roads' of evaluating biological significance. Nat Rev Neurosci. 2010;11:773–83. Livneh U, Resnik J, Shohat Y, Paz R. Self-monitoring of social facial expressions in the primate amygdala and cingulate cortex. Proc Natl Acad Sci U S A. 2012;109:18956–61. Pfurtscheller G. Event-related synchronization (ERS): an electrophysiological correlate of cortical areas at rest. Electroencephalogr Clin Neurophysiol. 1992;83:62–9. Neuper C, Wortz M, Pfurtscheller G. ERD/ERS patterns reflecting sensorimotor activation and deactivation. Prog Brain Res. 2006;159:211–22. Mathewson KJ, Jetha MK, Drmic IE, Bryson SE, Goldberg JO, Schmidt LA. Regional EEG alpha power, coherence, and behavioral symptomatology in autism spectrum disorder. Clin Neurophysiol. 2012;123:1798–809. Klimesch W. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Brain Res Brain Res Rev. 1999;29:169–95. Knyazev GG, Savostyanov AN, Levin EA. Alpha synchronization and anxiety: implications for inhibition vs. alertness hypotheses. Int J Psychophysiol. 2006;59:151–8. Mathewson KE, Gratton G, Fabiani M, Beck DM, Ro T. To see or not to see: prestimulus alpha phase predicts visual awareness. J Neurosci. 2009;29:2725–32. Marceglia S, Mrakic-Sposta S, Rosa M, Ferrucci R, Mameli F, Vergari M, et al. Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease. Front Neurosci. 2016;10:134. Klimesch W, Sauseng P, Hanslmayr S. EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev. 2007;53:63–88. Juarez-Martinez EL, Sprengers JJ, Cristian G, Oranje B, van Andel DM, Avramiea AE, et al. Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2023;8:251–61. Amatachaya A, Jensen MP, Patjanasoontorn N, Auvichayapat N, Suphakunpinyo C, Janjarasjitt S et al., The short-term effects of transcranial direct current stimulation on electroencephalography in children with autism: a randomized crossover controlled trial. Behav Neurol. 2015, 2015: 928631. Susam BT, Riek NT, Beck K, Eldeeb S, Hudac CM, Gable PA, et al. Quantitative EEG Changes in Youth With ASD Following Brief Mindfulness Meditation Exercise. IEEE Trans Neural Syst Rehabil Eng. 2022;30:2395–405. Wallace GL, Dankner N, Kenworthy L, Giedd JN, Martin A. Age-related temporal and parietal cortical thinning in autism spectrum disorders. Brain. 2010;133:3745–54. Gendry Meresse I, Zilbovicius M, Boddaert N, Robel L, Philippe A, Sfaello I, et al. Autism severity and temporal lobe functional abnormalities. Ann Neurol. 2005;58:466–9. Marin JC, Moura PJ, Cysneiros RM, Colugnati DB, Cavalheiro EA, Scorza FA, et al. Temporal lobe epilepsy and social behavior: an animal model for autism? Epilepsy Behav. 2008;13:43–6. Lombardo MV, Chakrabarti B, Bullmore ET, Baron-Cohen S. Specialization of right temporo-parietal junction for mentalizing and its relation to social impairments in autism. NeuroImage. 2011;56:1832–8. Zilbovicius M, Meresse I, Chabane N, Brunelle F, Samson Y, Boddaert N. Autism, the superior temporal sulcus and social perception. Trends Neurosci. 2006;29:359–66. Additional Declarations No competing interests reported. Supplementary Files 0cTBSSupplementcapmh.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzElEQVRIiWNgGAWjYBAC9gbGxgMJFQwJEC4bEVp4DjA2HEg4Q5oWBoYDjG0kaWFvbjjwcF5dnvy0MwYMH8oOM/DPbiCghedgw4HEbYeLDW7nGDDOOHeYQeLOAfxa7CUSQVoOJG6QzjFg5m07zGAgkUDAFvmHQC1z6hLnzwZq+UuUFglgiCU2MCc2AB3GzEiUFh6gwxKOHU7ccDut4GDPuXQeiRuEtLAff/jwRw3IYckbH/wos5bjn0FACwo4ADKDBPWjYBSMglEwCnABANnhSWZaxkLMAAAAAElFTkSuQmCC","orcid":"","institution":"Department of Developmental and Behavioural Pediatric \u0026 Child Primary Care, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Fei","middleName":"","lastName":"Li","suffix":""}],"badges":[],"createdAt":"2024-03-21 05:59:37","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4140990/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4140990/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":53874226,"identity":"316ccc3a-edbf-4d01-9e6c-40e8157ab528","added_by":"auto","created_at":"2024-04-01 16:18:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":69397,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ea-cTBS protocol.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: ISI, intersession interval\u003c/p\u003e\n\u003cp\u003ea. 10 sessions per day of 1,800 pulses per session for a total of 18,000 pulses per day;\u003c/p\u003e","description":"","filename":"Fig1.acTBSprotocol1.png","url":"https://assets-eu.researchsquare.com/files/rs-4140990/v1/f34180523d50378d88dd2980.png"},{"id":53874828,"identity":"0acadeda-7f6a-46ba-9878-de6e79367258","added_by":"auto","created_at":"2024-04-01 16:26:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":184135,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow chart of the current study.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Fig2.CONSORTflowdiagram.png","url":"https://assets-eu.researchsquare.com/files/rs-4140990/v1/d31535dffe1de57d14239309.png"},{"id":53874227,"identity":"2b72645d-5a3a-4a4c-b625-7bd33f1cb100","added_by":"auto","created_at":"2024-04-01 16:18:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":24884,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eChanges in social or language-related scores before and after the intervention.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Changes in social-related scores\u003c/p\u003e\n\u003cp\u003eAbbreviations: SRS, Social Responsiveness Scale.\u003c/p\u003e\n\u003cp\u003ea. This individual plot shows the change in SRS total score across pre-cTBS (pre), post-rTMS(post) and one-month follow-up (1mth) time-points. The horizontal lines between the upper and lower whisker marks indicate the mean, while the top and bottom whisker marks represent the standard error of the mean (SEM).\u003c/p\u003e\n\u003cp\u003eb. *** P \u0026lt; .001, repeated-measures ANOVA with multiple comparisons using Bonferroni correction.\u003c/p\u003e","description":"","filename":"Fig3AB.RelativeChangesinSocialorLanguagerelatedScores1.png","url":"https://assets-eu.researchsquare.com/files/rs-4140990/v1/a8899d2c08c5677cefaf224e.png"},{"id":53874228,"identity":"1fd4e3e0-22c3-4afa-8f50-f264d86c44d3","added_by":"auto","created_at":"2024-04-01 16:18:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":313650,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eThe analysis of the PSD in the alpha band of the right temporoparietal region.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA. Standardized alpha PSD values of the right temporoparietal region in the two groups at baseline and after the 5-day a-cTBS intervention (the difference between the two groups after the intervention remained significant when controlling for verbal IQ at baseline).\u003c/p\u003e\n\u003cp\u003eB-C. A significant positive correlation was shown between the PSD in the alpha band of the right temporoparietal region and the reduction in the SRS total score and social communication subscale score after the 5-day intervention.\u003c/p\u003e","description":"","filename":"Fig4.EEGresults.png","url":"https://assets-eu.researchsquare.com/files/rs-4140990/v1/12b63cdb7ceadfe340117013.png"},{"id":55696456,"identity":"3b025a58-c5ad-46e0-8013-867ea7e88e13","added_by":"auto","created_at":"2024-05-02 01:41:26","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1366492,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4140990/v1/5f61c5b9-6fdd-49bd-95f1-d305a215c9e3.pdf"},{"id":53874230,"identity":"3c14192a-3d3a-4359-b2d7-f5f6582b0ad9","added_by":"auto","created_at":"2024-04-01 16:18:02","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":291296,"visible":true,"origin":"","legend":"","description":"","filename":"0cTBSSupplementcapmh.docx","url":"https://assets-eu.researchsquare.com/files/rs-4140990/v1/9ea9cc2dbbd1f679ac0eee29.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Accelerated theta-burst stimulation over the motor cortex improves social communication impairment in children with autism spectrum disorder: An open-label trial","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAutism spectrum disorder (ASD) is a neurodevelopmental condition characterized by a specific combination of impairments in social communication and restricted repetitive patterns of behavior, interests, or activities. This disorder typically begins early in life and affects approximately 1 in 100 children worldwide, and its incidence is increasing annually[\u003cspan additionalcitationids=\"CR2 CR3 CR4 CR5\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Social communication impairment (SCI) is the core symptom of ASD and manifests as deficits in social-emotional reciprocity, nonverbal communication and relationship development. These deficits can severely impact children\u0026rsquo;s daily lives and psychological development. However, there are currently no US Food and Drug Administration (FDA)-approved drugs or therapies for treating ASD, nor for specifically treating SCI [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. To date, behavioral intervention, which is individualized, developmentally appropriate and intensive, requires full-time engagement with professional therapists for several years and starts as early as possible, is the most widely recommended treatment for children with ASD. However, many families of ASD patients do not have access to or cannot afford these interventions. Additionally, even among children receiving timely intensive interventions, the efficacy of these interventions is often limited to small-to-medium improvements [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. In this sense, it is imperative to find new treatments, especially targeting SCI, that are safe, tolerable, rapid acting and efficient for children with ASD.\u003c/p\u003e \u003cp\u003eIn the past decade, a noninvasive neurostimulation technique, repetitive transcranial magnetic stimulation (rTMS), has been proposed as a potential therapeutic option for the modification of the pathological neuroplasticity involved in neuropsychiatric disorders, including ASD [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. It is hypothesized that rTMS may stabilize aberrant neural connectivity and remedy dysfunction in GABAergic and other neurochemical transmission in ASD [\u003cspan additionalcitationids=\"CR13\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Recent studies have suggested that rTMS could effectively treat restricted repetitive behaviors (RRBs), cognitive inflexibility and executive functioning (EF) deficits in individuals with ASD [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]; however, the effects of rTMS on SCI symptoms have yielded inconsistent results, and the underlying mechanisms of treating SCI have not been fully investigated [\u003cspan additionalcitationids=\"CR18 CR19\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMultiple factors, including stimulation target, frequency, intensity, mode and treatment course, are involved in rTMS. All of these factors can influence the effectiveness of neuromodulation intervention; of these, the most basic and critical aspect is the stimulus target. Previous studies have shown considerable variation in stimulation targets, most of which were selected based on their association with ASD pathogenesis; common targets include the dorsolateral prefrontal cortical areas (DLPFC) and the posterior superior temporal sulcus (pSTS)[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The primary motor cortex (M1) might serve as a viable target for the treatment of SCI in ASD patients, as it is potentially involved in aspects of action execution [\u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], emotion evaluation [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e], and language comprehension [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e], all of which are essential in social communication. Several studies have investigated the underlying neuropathological mechanisms of ASD through stimulation of M1 and found atypical neuroplasticity in ASD patients compared to that in neurotypical controls through the use of neurophysiological bioindicators (e.g., motor-evoked potential (MEP), long-term potentiation (LTP) and long-term depression (LTD) [\u003cspan additionalcitationids=\"CR31\" citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Regrettably, no clinical rTMS trial targeting M1 has been conducted yet to examine its effects on ASD symptoms. Furthermore, the recommended stimulation parameters, particularly for pediatric patients with low cognitive levels and poor cooperation, are still lacking. Continuous theta-burst stimulation (cTBS) [\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e], an efficient form of rTMS that can deliver pulses in bursts of three at a higher frequency, requires less stimulation time and functions at a lower overall intensity than traditional rTMS and has promising applications in pediatric patients gives the safety and efficiency benefits of the technique [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Additionally, several studies have shown that neuromodulatory effects can be enhanced and maintained by accelerated, spaced delivery of stimulation sessions and increased overall pulses [\u003cspan additionalcitationids=\"CR36 CR37\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e], which suggests that the stimulus protocol could be optimized.\u003c/p\u003e \u003cp\u003eOverall, we conducted an open-label trial to investigate the feasibility, safety and efficacy of accelerated cTBS (a-cTBS) targeting the left M1 for children with ASD. Additionally, we employed electroencephalography (EEG) to probe the underlying neurological effects of M1 stimulation in individuals with ASD.\u003c/p\u003e"},{"header":"2. Materials and methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1 Design\u003c/h2\u003e \u003cp\u003eIn this open-label pilot trial, thirty eligible children received a-cTBS (18,000 pulses/day) targeting the left M1 for 5 consecutive days. All of them underwent clinical assessments three times: pre-intervention (within 2 weeks before the cTBS intervention), post-intervention (within 3 days after the completion of the cTBS course), and 1-month follow-up (1 month following the last cTBS session). Participants were also invited to complete EEG recordings before and after the intervention. Twenty-six participants completed the EEG collection, but four participants failed to collect the data due to poor cooperation.\u003c/p\u003e \u003cp\u003eThe study was conducted in accordance with the guidelines for \u003cem\u003eGood Clinical Practic\u003c/em\u003ee and the principles of the \u003cem\u003eDeclaration of Helsinki\u003c/em\u003e and approved by the Xinhua Hospital Ethics Committee (XHEC-C-2022-008-4). The procedures and purposes of the study were explained face-to-face to all participants\u0026rsquo; legal guardians, who subsequently provided written informed consent. The trial was registered with ClinicalTrials.gov (NCT05472870).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2 Participants\u003c/h2\u003e \u003cp\u003eParticipating children were recruited from outpatient clinics in the Department of Developmental and Behavioral \u0026amp; Child Primary Care of Xinhua Hospital affiliated with the Shanghai Jiaotong University School of Medicine. An eligibility visit was subsequently scheduled with the research clinicians. Children were considered eligible if they were aged 4\u0026ndash;10 years, were diagnosed with ASD according to the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5) and were confirmed by the Autism Diagnostic Observation Schedule (ADOS). We excluded patients if they had metal in the head or neck, a history of epilepsy or other neurological diseases, structural brain abnormalities requiring surgical treatment, as indicated by magnetic resonance imaging (MRI), confirmation of genetic or chromosomal abnormalities, a diagnosis of psychiatric disorders other than ASD (e.g., very early-onset schizophrenia), or severe heart disease and/or hearing impairment. Patients who received other interventions or treatments within 4 weeks prior to enrollment or who were currently participating in other clinical trials were also excluded. Notably, participants with cooccurring attention-deficit hyperactivity disorder (ADHD) were included because ADHD is the most common cooccurring condition of ASD; moreover, it might have a similar neurodevelopmental nature and share some etiologies with ASD. All psychotropic medications were continued without change during the trial.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3 A-cTBS procedure\u003c/h2\u003e \u003cp\u003eTwo pulsed magnetic stimulation devices (M-100 Ultimate, Shenzhen Yingchi Technology Co., Ltd., Shenzhen, China) were used. Before the intervention, each participant\u0026rsquo;s stimulation target position and resting motor threshold (RMT) were determined by a physician who was professionally trained according to standard methods [\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. The RMT was defined as the lowest TMS intensity needed to elicit a MEP of more than 50 \u0026micro;V in at least 5 out of 10 stimuli recorded in the right abductor pollicis brevis (APB) muscle. The optimum position for the left M1 (\u0026lsquo;motor hot spot\u0026rsquo;) was subsequently determined as the site at which stimuli of slight suprathreshold intensity consistently produced the largest MEP in the right APB muscle.\u003c/p\u003e \u003cp\u003eDuring stimulation, the children were instructed to sit on a chair and keep their heads still (and their parents could assist as needed). The TMS coil was held tangentially over the left M1, and the handle of the coil was pointed backward at 45\u0026deg; from the mid-sagittal line. The stimulus intensity was set to 80% of the RMT. The detailed a-cTBS protocol was as follows: 60 cycles of 10 bursts of 3 pulses at 50 Hz were delivered in 2-second trains (5 Hz) with no intertrain interval (i.e., triplet standard cTBS, 1800 pulses, 120 seconds). Stimulation sessions were delivered hourly, and 10 sessions were performed per day (18,000 pulses/day) for 5 consecutive days (90,000 pulses in total) (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4 Clinical behavioral measurements\u003c/h2\u003e \u003cp\u003eThe primary outcome measure of clinical behavior was the Social Responsiveness Scale (SRS) [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e], which provides a multidimensional measure of social interaction allowing for the rating of social impairment in ASD patients. The SRS generates a total score and five subscale scores (social awareness, social cognition, social communication, social motivation, and autistic mannerisms); higher scores indicate greater social impairment. Parents were requested to complete the SRS at three time points (pre-intervention, post-intervention and 1 month follow-up) to monitor the children\u0026rsquo;s responses in the social domain to the rTMS intervention over time.\u003c/p\u003e \u003cp\u003eThree indicators were employed to evaluate children\u0026rsquo;s language improvements from baseline to the 1-month follow-up: the Chinese Communicative Development Inventory (CCDI, a powerful tool for assessing early vocabulary development and the language skills of older children with developmental disorders) [\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e], the Peabody Picture Vocabulary Test (PPVT, a standard test for measuring single-word comprehension) [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e] and the Multilingual Assessment Instrument for Narratives (MAIN, a test for assessing narrative comprehension and production skills) [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. In the MAIN test, children were asked to tell and retell several stories and answer some questions, which is applicable only to a subset of ASD children with adequate expressive ability (those able to at least use phrases).\u003c/p\u003e \u003cp\u003eOther clinical behavioral measurements included the Behavior Rating Inventory of Executive Function (BRIEF) [\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e] and the Conners Parent Rating Scale (CPRS) [\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e], which provided a quantitative picture of children's executive function, emotion and behavioral problems. Additionally, we used the Clinical Global Impression of Improvement (CGI-I) [\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e] to rate how much the patient\u0026rsquo;s illness improved or worsened relative to a baseline measurement before the intervention (a seven-point scale: 1 = \u0026lsquo;\u0026lsquo;very much improved\u0026rdquo; to 7 = \u0026lsquo;\u0026lsquo;very much worse\u0026rdquo;).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5 EEG acquisition and preprocessing\u003c/h2\u003e \u003cp\u003eBefore and after the 5-day intervention, resting-state EEG signals were collected from all participants while they were watching a simple 4-minute cartoon video. EEG data were recorded using a 128-channel high-density EEG system from Electrical Geodesics, Inc. (EGI), Eugene, OR, USA, with the reference electrode positioned at the vertex (channel Cz). Impedances were maintained below 100 kΩ. Prior to formal preprocessing, the raw EEG data in NetStation format were exported to MATLAB [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e]. Subsequently, offline data processing was conducted in a consistent manner using the EEGLab toolbox [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Continuous EEG data were subjected to bandpass filtering (0.5\u0026ndash;45 Hz) and a notch filter at 50 Hz. We excluded data from 46 'skirt channels' from all the collected EEG data as these channels are particularly sensitive to noise and muscle artifacts[\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e]. Data from the remaining 82 channels were included in analysis, with those from noisy electrodes removed and interpolated. The preprocessed EEG data were then segmented into 1-second epochs. After experienced EEG researchers visually confirmed the exclusion of artifacts, fast independent component analysis (fast ICA) was employed to identify and eliminate artifacts caused by eye blinks, movements, and muscle activities [\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e]. Finally, the data were rereferenced to the average reference.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003e2.6 EEG analysis\u003c/h2\u003e \u003cp\u003eAfter the above preprocessing, the power spectral density (PSD) within the alpha frequency band (8\u0026ndash;13 Hz) was calculated for each of the 82 EEG channels. This computation was performed by employing the Fast Fourier Transform (FFT) algorithm [\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e], after which the resultant frequency components were squared to derive the amplitude spectrum. Subsequently, the bilateral spectrum was converted into a unilateral spectrum, and the values were normalized by dividing them by the frequency resolution to obtain the final PSD estimates [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e]. For standardization, each subject\u0026rsquo;s alpha PSD value for each channel was divided by their own mean value of the whole-brain PSD.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e2.7 Assessment of adverse events\u003c/h2\u003e \u003cp\u003e A semistructured interview was administered following each treatment session and followed up by the rTMS technician. The standardized interview included an open-ended query for any adverse events or physical discomfort experienced. If any adverse events or physical discomfort were reported, detailed descriptions were recorded and the severity was graded as mild (no impairment, no need to stop the trial), moderate (some impairment, need to stop the trial but no need for intervention), or severe (evidence of impairment, need to stop the trial and intervention is needed).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e2.8 Sample size\u003c/h2\u003e \u003cp\u003eThe minimum total sample size was estimated using G*Power, which is powered (80% power and two-sided 5% significance) to detect a moderate-to-large standardized effect of treatment. The estimated effect size was guided by existing results on social behavior deficits (Ni HC, \u003cem\u003eet al\u003c/em\u003e., 2021; Barahona-Correa \u003cem\u003eet al\u003c/em\u003e., 2018) [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Considering the 10% dropout rate, the final sample size of this study was estimated to be at least 30.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e2.9 Statistical analysis\u003c/h2\u003e \u003cp\u003eAll clinical outcome analyses were conducted using SPSS version 25.0, and the statistical significance level was set at 0.05. To compare the changes in SRS, BRIEF and CPRS scores across three time points (pre-intervention, post-intervention, and 1 month follow-up), we used the one-way analysis of variance (ANOVA) with repeated measures or the Friedman test, followed by post hoc analyses incorporating Bonferroni correction to adjust for multiple comparisons. The Mann‒Whitney Wilcoxon test or paired-samples \u003cem\u003et\u003c/em\u003e test was used for the CCDI, PPVT and MAIN measurements at only two time points (pre-intervention vs. 1 month follow-up).\u003c/p\u003e \u003cp\u003eTo explore whether high/low-functioning (full-scale intelligence quotient (FSIQ)\u0026thinsp;\u0026ge;\u0026thinsp;70 as the cutoff point) moderated stimulation effects, a two-way repeated-measures ANOVA was performed to examine the effects of time, group and time-by-group interaction on our primary variables (i.e., SRS). Linear regression was also performed, with FSIQ score or age as the independent variable and SRS score change as the dependent variable.\u003c/p\u003e \u003cp\u003eFor the EEG data, we first compared the PSD within the alpha band between baseline and post-intervention across all the remaining channels using a paired \u003cem\u003et\u003c/em\u003e test. Subsequently, we stratified participants into two groups, a significantly effective (SE) group and a nonsignificantly effective (NE) group, based on the median reduction in SRS total score after the 5-day intervention. Then, we compared the alpha PSD values between the groups before and after the intervention. Furthermore, a Pearson correlation analysis was conducted to explore the relationship between neurophysiological effects of rTMS and clinical improvement by analyzing alpha PSD values and changes in SRS scores.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003e\u003cem\u003e3.1 Feasibility and acceptability\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eFrom July 2022 to December 2022, of the 36 patients who were assessed for eligibility, thirty children with ASD were enrolled and completed the full intervention course and follow-up assessments (Fig. 2). The average age of these 30 patients was 7.06 years (standard deviation, SD 1.55), and 80% were male (Table 1). Among them, EEG data were successfully collected from twenty-six children at pre-intervention and post-intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 1. Demographic and clinical characteristics of the participants at the baseline.\u003c/strong\u003e\u003c/p\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"464\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eTotal Sample (n=30)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge\u0026nbsp;\u003c/strong\u003e(years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e7.06\u0026plusmn;1.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u0026nbsp;\u003c/strong\u003e(male/female)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e24/6\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eFSIQ\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e74.97\u0026plusmn;24.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCARS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e33.48\u0026plusmn;2.59\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eADOS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eCommunication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e4.70\u0026plusmn;1.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSocial Interaction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e9.03\u0026plusmn;1.81\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003eSA_Total score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"50%\" valign=\"top\"\u003e\n \u003cp\u003e13.73\u0026plusmn;2.74\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eAbbreviations: FSIQ = full-scale IQ, CARS = Childhood Autism Rating Scale, ADOS = Autism Diagnostic Observation Schedule, SA_Total score = ADOS_Communication score + ADOS_Social Interaction score.\u003c/p\u003e\n\u003cp\u003eAdverse events were reported in a subset of participants. Six children showed agitation during the intervention period, three children complained of scalp pain during the first few stimulation treatments, and one child experienced transient nausea\u0026nbsp;during the follow-up period after completing the treatment. All adverse events were rated as mild and disappeared without any specific therapy, and no patient withdrew from the trial due to side effects.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.2 Clinical behavioral outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThere was a significant reduction in the SRS total score after the a-cTBS intervention, with a mean decrease of 12.77 (95% CI 7.58 to 17.95; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) between the pre-intervention and post-intervention assessments and 16.60 (95% CI 11.47 to 21.73; \u003cem\u003eP\u003c/em\u003e\u0026lt;.001) between the pre-intervention and one-month follow-up assessments (Table 2, Fig. 3A). Additionally, significant decreases were noted in the five subscales of the SRS (Table 2).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Changes in clinical outcomes from baseline (pre-intervention) to follow-up (post-intervention and one-month follow-up).\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"690\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.63768115942029%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eOutcome measures\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.507246376811594%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"45.21739130434783%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean (SD)/Median (interquartile range)\u003csup\u003ea\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.63768115942029%\" colspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value\u003csup\u003eb\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.532091097308488%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.532091097308488%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"21.532091097308488%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003e1mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.801242236024844%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003ePost\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.801242236024844%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePre*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"11.801242236024844%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost*\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e1mth\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eSRS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eTotal scores\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e94.27 (20.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e81.50 (21.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e77.67 (20.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eSocial awareness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e12.13 (2.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e11.50 (2.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e10.87 (2.27)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eSocial cognition\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e20.03 (3.84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e17.40 (4.45)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e16.40 (4.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.12\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eSocial communication\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e32.73 (7.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e28.07 (7.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e26.63 (7.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.36\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eSocial motivation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e13.47 (4.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e11.47 (4.02)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e11.47 (3.71)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.006\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026gt;.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eAutistic mannerisms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e15.90 (5.73)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e13.07 (5.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e12.30 (6.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.68\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eCCDI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\n \u003cp\u003e22\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eWords produced\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e733.00\u003c/p\u003e\n \u003cp\u003e(615.25, 789.50)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e771.50\u003c/p\u003e\n \u003cp\u003e(657.00, 793.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eSentence complexity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e69.00\u003c/p\u003e\n \u003cp\u003e(42.00, 76.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e71.00\u003c/p\u003e\n \u003cp\u003e(54.00, 79.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.07\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003ePPVT\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eRaw score\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e67.78 (27.23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e76.11 (26.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eIQ\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e100.63 (28.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e111.00 (30.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAIN_ Telling\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eStory Structure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e7.57 (2.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e8.96 (2.43)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eStructural Complexity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e2.11 (0.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e2.50 (0.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eInternal States Terms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e3.68 (2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e5.21 (3.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eComprehension Questions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e6.50 (1.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e8.32 (1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003e\u003cstrong\u003eMAIN_ Retelling\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eStory Structure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e9.07 (2.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e12.21 (2.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eStructural Complexity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e2.32 (0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e2.75 (0.38)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.04\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eInternal States Terms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e5.07 (2.13)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e6.14 (1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"24.602026049204053%\" valign=\"top\"\u003e\n \u003cp\u003eComprehension Questions\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"5.499276410998553%\" valign=\"top\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e6.46 (1.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.050651230101302%\" valign=\"top\"\u003e\n \u003cp\u003e8.21 (1.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003e.002\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"8.24891461649783%\" valign=\"top\"\u003e\n \u003cp\u003eNA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SRS, Social Responsiveness Scale; CARS, Childhood Autism Rating Scale; CCDI, Chinese Communicative Development Inventory; PPVT, Peabody Picture Vocabulary Test; MAIN, Multilingual Assessment Instrument for Narratives.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ea. Quantitative outcomes (CCDI) that were not normally distributed were expressed as medians (interquartile ranges);\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eb. Multiple comparisons were performed using Bonferroni correction;\u003c/p\u003e\n\u003cp\u003ec. Repeated measures ANOVA: SRS; Mann‒Whitney Wilcoxon test: CCDI, MAIN-SC, and MAIN-IST; paired-samples t test: PPVT, MAIN-SS, and MAIN-CQ.\u003c/p\u003e\n\u003cp\u003eWe also observed significant improvements in language-related indicator scores, such as the raw scores for CCDI words produced (\u003cem\u003eP\u003c/em\u003e=.001) and raw PPVT scores (\u003cem\u003eP\u003c/em\u003e\u0026lt;.001) (Table 2 and Fig. 3B). Among the 14 children who had sufficient expressive ability and who completed the MAIN test at baseline and at the one-month follow-up, the \u0026ldquo;story structure\u0026rdquo;, \u0026ldquo;structural complexity\u0026rdquo; and \u0026ldquo;comprehension questions\u0026rdquo; scores were found to significantly increase (Table 2).\u003c/p\u003e\n\u003cp\u003eThe CPRS and BRIEF scores showed no noticeable changes after the intervention, except for the emotional control score of the BRIEF (preschool version), which reached statistical significance but did not pass correction for multiple comparisons (sTable 1).\u003c/p\u003e\n\u003cp\u003eThe improvements in autistic symptoms were supported by the CGI-I at the one-month follow-up assessment (5 participants reached \u0026lsquo;\u0026lsquo;improved\u0026rsquo;, 22 participants reached \u0026lsquo;\u0026lsquo;slightly improved\u0026rdquo;) and by caregiver reports (sTable 2). Most caregivers reported that their children showed improvements in the social and/or language domains (e.g., social motivation, vocabulary size and sentence complexity) after the intervention. A summary of these improvements can be found in sTable 2.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.3 High-functioning and low-functioning subgroup analyses\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAt baseline, no differences were found in demographic characteristics or clinical severity of autistic symptoms between the high-functioning and low-functioning groups, except for FSIQ score (sTable 3).\u003c/p\u003e\n\u003cp\u003eThe SRS scores decreased significantly from baseline to follow-up in both groups (except for the social awareness score in the low-functioning group, the autistic mannerisms score in the high-functioning group and the social motivation score in both groups) (sTable 4 and sFig. 1). Two-way repeated-measures ANOVA revealed a significant time effect (\u003cem\u003eP\u003c/em\u003e\u0026lt;.001), no significant group effect (\u003cem\u003eP\u003c/em\u003e=.194), and no significant interaction effect (\u003cem\u003eP\u003c/em\u003e=.332) on SRS scores (sTable 5). The linear regression model also indicated that there was no significant effect of IQ or age (\u003cem\u003eP\u003c/em\u003e\u0026gt;.05) on SRS score change. The above results showed that the decrease in SRS score was not different between the two subgroups.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e3.4 PSD values in the alpha band\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWe successfully collected EEG data from 26 children before and after the intervention, and one patient was excluded after a quality control procedure. Using the 25 children\u0026rsquo;s median decrease in SRS total score after the 5-day intervention (10 points) as a threshold for treatment response, we categorized all the children into either the SE group (n = 13) or the NE group (n = 12). No statistically significant differences in age, sex, or FSIQ score were found between the two groups at baseline.\u003c/p\u003e\n\u003cp\u003eWe compared the PSD within the alpha frequency band across the whole brain before and after the intervention in 25 participants and found no significant difference (\u003cem\u003eP\u003c/em\u003e\u0026gt; .05). There was also no statistically significant difference in the alpha PSD across any of the remaining channels between the SE and NE groups before intervention (\u003cem\u003eP\u003c/em\u003e\u0026gt; .05), whereas the PSD in the alpha band of the right temporoparietal region at post-intervention was greater in the SE group (P\u0026lt; .05; Fig. 4A). Furthermore, a noteworthy positive correlation was detected between the PSD in the right temporoparietal region postintervention and the decrease in SRS score, particularly in relation to the social communication subscale score (Fig. 4B-C, sTable 6).\u003c/p\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eTo our knowledge, this was the first clinical trial in which a-cTBS was applied to the left M1 of children with ASD. We provided preliminary evidence for the safety and feasibility of the a-cTBS protocol and were delighted to find that the 5-day exploratory intervention yielded positive results in improving not only social communication but also language function, as measured by clinical behavioral outcomes, in these patients. Through the combination of EEG analysis, we found a positive correlation between improvements in social function scores and alpha power in the right temporoparietal region postintervention, revealing the potential neurophysiological effect of this rTMS intervention.\u003c/p\u003e\n\u003cp\u003eOur work revealed that 5-day a-cTBS to the left M1 could significantly improve social communication and language function in children with ASD. To reliably evaluate changes in SCI symptoms in ASD patients, several specific and sensitive behavioral outcome measurements were carefully selected. Our primary outcome measure was SRS, which not only quantifies the severity of social impairment associated with ASD but is also sensitive enough to detect even subtle changes in symptoms\u0026nbsp;[40].\u0026nbsp;The results showed that the SRS total score decreased by an average of 12.77 points immediately after the 5-day intervention and 16.60 points at the one-month follow-up. The scores of five subscales of the SRS also decreased significantly. Compared with previous clinical research that used the SRS as an indicator of social impairment\u0026nbsp;[19, 52, 53], our study revealed greater improvement in this short intervention period. The subgroup analysis showed that the SRS scores significantly decreased from baseline to follow-up in both the high-functioning and low-functioning groups,\u0026nbsp;and there was no significant effect of IQ on the change in SRS score, indicating that a-cTBS targeting the left M1 could contribute to similar improvements in clinical measurements in children with ASD at different functional levels. This finding suggested that our protocol might be broadly applicable among children with ASD. Notably, we found considerable improvements in language comprehension and expression among participants after 5 days of a-cTBS targeting the left M1; such improvement has not been reported in previous rTMS intervention studies of ASD. Language impairment is a common occurrence in children with ASD and can limit social development in these individuals\u0026nbsp;[54], making this impairment important and necessary to treat. However, significantly improving language capacity in a short period through drugs or behavioral interventions is very challenging. Although some therapies are effective, the effect sizes are relatively small and not robust\u0026nbsp;[55-58]. The clinical behavioral results mentioned above are encouraging but limited by the use of an open-label single-arm design; the efficacy of this rTMS protocol needs to be confirmed by future large-scale randomized controlled trials (RCTs).\u003c/p\u003e\n\u003cp\u003eThe TMS procedure employed in this work was scientifically designed to be well tolerated and suitable for children with ASD. According to previous physiological experiments in humans, high-frequency rTMS (\u0026gt;1 Hz) and low-frequency rTMS (\u0026le;1 Hz) can evoke LTP and LTD of synaptic transmission, respectively; moreover, it can subsequently alter cortical excitability, which is most likely modulated by GABAergic activities\u0026nbsp;[59-61]. These changes are not only restricted to the site of stimulation but also widely observed in the entire brain network\u0026nbsp;[62]. The evidence above suggests that rTMS treatment may benefit ASD patients, as the excitation/inhibition ratio (E/I) imbalance might underlie the pathogenesis of ASD\u0026nbsp;[63, 64], particularly in children with rapid neural development. However, most previous clinical trials of rTMS in ASD patients have been limited to intellectually capable youth or adults due to the traditional rTMS requirement of patient cooperation for at least 20 minutes\u0026nbsp;[11, 15, 16, 19]. Our study focused on individuals of early developmental age (4-10 years), which have greater neuroplasticity and a desire for functional improvement; however, given their poor cooperation, the acceptability and feasibility of the rTMS protocol were major challenges. The emergence of TBS solved this challenge, as it is a rapid form of rTMS cortical conditioning that produces a more controllable, long-lasting and powerful effect on cortex physiology and behavior after very short periods of overall low-intensity stimulation\u0026nbsp;[33]. Notably, our protocol had a short-term accelerated stimulation design. The multisession requirement has long been established, and many studies have shown that\u0026nbsp;repeated short training sessions are more effective than a single prolonged session\u0026nbsp;[37, 65, 66]. Therefore, our a-cTBS intervention course consisted of 50 sessions within 5 days to provide sufficient stimulation to the target.\u0026nbsp;The one-hour spacing used in the protocol was based on the evidence from basic neuroscience research and human physiology or behavioral data\u0026nbsp;[33, 67-69]. We expected this multiple, daily a-cTBS protocol to have an enhanced effect, and our results proved this to be the case.\u003c/p\u003e\n\u003cp\u003eAnother advantage of the current rTMS protocol is the targeted stimulation of M1, which is a crucial factor in determining treatment efficacy. M1 is easy to localize (it can be found by the MEPs recorded on the APB muscle of the contralateral hand, instead of requiring neurological navigation that is difficult for children with ASD to cooperate with). Although numerous previous studies have investigated the neuropathological mechanisms of ASD through stimulation of the left M1 region and found atypical neural plasticity\u0026nbsp;[31, 32], no relevant rTMS intervention study targeting the left M1 region in ASD patients has been conducted. This work highlighted the therapeutic potential of M1 as a viable target for treating ASD, and we speculated that the underlying mechanisms may be attributed to its modulation of related networks. Pertinently, the human brain exhibits a distinct spatiotemporal organization that supports brain function and can be manipulated via local brain stimulation\u0026nbsp;[70, 71]. There is growing evidence that M1 is not simply a static motor control region; it also plays a dynamic role in learning and cognition\u0026nbsp;[72]. Interestingly, M1 has been demonstrated to be closely linked to the processing of social information and social-related networks. For instance, some studies have reported that M1 excitability increases during emotion-related tasks\u0026nbsp;[24], and M1 is densely connected to some core regions of the network involved in emotion evaluation (e.g., occipitotemporal regions, the amygdala, the pulvinar cortex, the orbitofrontal cortex and the cingulate cortex)\u0026nbsp;[24, 73, 74]. In a system critical for social cognition and interaction, which contains mirror neurons (MNs), M1 is an essential region that allows humans to coordinate emotional actions and social behaviors\u0026nbsp;[21]. A recent study revealed that a somato-cognitive action network (SCAN) for whole-body action planning was intertwined with M1\u0026nbsp;[22], and a newly discovered major hub, the retrosplenial cortex (RSC), which is highly selective and specific for social behavior regulation, is inextricably linked to sensorimotor networks\u0026nbsp;[25], both of which support the importance of M1 in social function. Additionally, some evidence has demonstrated that the motor system plays a core role in semantic processing\u0026nbsp;[28, 29], which is an important part of language function and has a strong impact on social interaction. The clinical behavioral improvements in social and language functions in our study provided further evidence for the involvement of M1 in social language networks; EEG analysis also supported this finding.\u003c/p\u003e\n\u003cp\u003eThrough EEG analysis, we revealed the potential mechanism underlying the use of M1 stimulation as a treatment for ASD. In the present study, we found that participants with a greater decrease in SRS score had a significantly greater alpha PSD in the right temporoparietal region after 5 days of intervention than did those with a smaller decrease. Moreover, there was a significant positive correlation between the PSD in the right temporoparietal region postintervention and the reduction in SRS scores, suggesting that a greater alpha power in the right temporoparietal region after 5 days of a-cTBS may be associated with greater improvement in autistic social deficits, particularly in those related to social communication. Oscillations in the\u0026nbsp;alpha band are thought to indirectly reflect cortical excitability in brain regions, and higher alpha power at rest is considered to be correlated with lower neuronal excitability\u0026nbsp;[75-77]. However, another conception is that\u0026nbsp;high resting alpha power may reflect active preparation for information processing or task performance\u0026nbsp;[77-79], and some research has shown that greater resting alpha power is associated with positive behavioral outcomes, such as enhanced performance in cognitive tasks\u0026nbsp;[80, 81]\u0026nbsp;and good response inhibition\u0026nbsp;[82]. Some evidence of an association between an increase in alpha power after treatment and the improvement in ASD symptom indicators has also been found\u0026nbsp;[83-85], which is consistent with our present findings. The EEG data also indicated individual differences in the responsiveness of rTMS among children with ASD, which prompted further exploration of which individuals are likely to benefit from this rTMS protocol in future work. Notably,\u0026nbsp;the positive results of the alpha PSD analysis were concentrated in the right temporoparietal region. The right temporal lobe and parietal lobe have been extensively investigated in neuroimaging studies and animal experiments; these regions are important for regulating social behaviors or language processes, and they exhibit atypical morphological and functional alterations in individuals with ASD\u0026nbsp;[86-88]. After combining the findings of previous studies with the findings of our study, we can reasonably speculate that a-cTBS over the left M1 may impact patients\u0026rsquo; social responsiveness and language ability by indirectly modulating the \u0026ldquo;social/language brain network\u0026rdquo; (e.g., the right temporoparietal junction [rTPJ]\u0026nbsp;[89]\u0026nbsp;and STS)\u0026nbsp;[90]. However, due to the limitations of the low spatial resolution of EEG signals and the use of image analysis methods, these inferences need to be interpreted with caution. In the future, more advanced methods of image analysis (i.e., EEG source analysis) or imaging methods with higher spatial resolution, such as MRI, may need to be included in patient assessments to better explore the underlying neurological mechanism of the effects of cTBS over the left M1 in ASD children.\u003c/p\u003e\n\u003cp\u003eIn summary, our study showed that a-cTBS over the left M1 for 5 consecutive days is safe and effective at improving SCI and language deficits in children with ASD. This work suggested that the M1 may be a new therapeutic target for ASD, and the underlying mechanisms for the therapeutic affect may be attributed to the modulation of associated networks, providing further evidence for the association of M1 with the social/language network. Future large RCTs incorporating advanced neuroimaging analysis (e.g., EEG and MRI) methods are needed to validate the clinical efficacy of a-cTBS over the left M1and investigate the exact extent of brain network remodeling after M1 stimulation.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ea-cTBS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAccelerated theta-burst stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eADOS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutism Diagnostic Observation Schedule\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eADHD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAttention-deficit hyperactivity disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eANOVA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAnalysis of variance\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eAPB\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAbductor pollicis brevis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eASD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAutism spectrum disorder\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eBRIEF\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBehavior Rating Inventory of Executive Function\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCCDI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eChinese Communicative Development Inventory\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCGI-I\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClinical Global Impression of Improvement\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eCPRS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eConners Parent Rating Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ecTBS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eContinuous theta-burst stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDLPFC\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDorsolateral prefrontal cortical areas\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eDSM-5\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eDiagnostic and Statistical Manual of Mental Disorders, Edition 5\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eEEG\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectroencephalogram\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eEF\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eExecutive functioning\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eEGI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eElectrical Geodesics, Inc\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eFDA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFood and Drug Administration\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eFFT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFast Fourier Transform\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eFSIQ\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eFull-scale intelligence quotient\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eICA\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eIndependent component analysis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eLTD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLong-term depression\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eLTP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eLong-term potentiation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eM1\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePrimary motor cortex\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMAIN\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMultilingual Assessment Instrument for Narratives\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMEP\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMotor-evoked potential\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMNs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMirror neurons\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eMRI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eMagnetic resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eNE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eNonsignificantly effective\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePPVT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePeabody Picture Vocabulary Test\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003ePSD\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epower spectral density\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003epSTS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ePosterior superior temporal sulcus\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRCTs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRandomized controlled trials\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRMT\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eResting motor threshold\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRRBs\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRestricted repetitive behaviors\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eRSC\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRetrosplenial cortex\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003erTMS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eRepetitive transcranial magnetic stimulation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003erTPJ\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eright temporoparietal junction\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eSCAN\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSomato-cognitive action network\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eSCI\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSocial communication impairment\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eSE\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSignificantly effective\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003e\u003cb\u003eSRS\u003c/b\u003e\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSocial Responsiveness Scale\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe acknowledge the other students, teachers, and assistants on our research team who provided valuable assistance during this trial. We also thank the children and families for their participation and support in this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was supported by grants from the National Natural Science Foundation of China (82125032, 81930095 and 81761128035), the Science and Technology Commission of Shanghai Municipality (19410713500 and 2018SHZDZX01), the Foundation of Shanghai Municipal Commission of Health and Family Planning (GWV-10.1-XK07, 2020CXJQ01 and 2018YJRC03), the Shanghai Clinical Key Subject\u0026ensp;Construction\u0026ensp;Project (shslczdzk02902), the Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZDCX20211100), and the Guangdong Key Project (2018B030335001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors assert that all procedures were conducted in accordance with the guidelines for Good Clinical Practice and the principles of the Declaration of Helsinki and approved by the Xinhua Hospital Ethics Committee (XHEC-C-2022-008-4).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that there are any competing financial interests in relation to the work described.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors and Affiliations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Developmental and Behavioural Pediatric \u0026amp; Child Primary Care, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.\u003c/p\u003e\n\u003cp\u003eHangyu Tan, Mingyu Xu, Lin Deng, Lingli Zhang\u0026nbsp;\u0026amp;\u0026nbsp;Fei Li\u003c/p\u003e\n\u003cp\u003eBrain and Behavioural Research Unit of Shanghai Institute for Pediatric Research and MOE-Shanghai Key Laboratory for Children\u0026rsquo;s Environmental Health, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.\u003c/p\u003e\n\u003cp\u003eHangyu Tan, Mingyu Xu, Lin Deng, Lingli Zhang\u0026nbsp;\u0026amp;\u0026nbsp;Fei Li\u003c/p\u003e\n\u003cp\u003eDepartment of Developmental and Behavioural Pediatric \u0026amp; Child Primary Care, Zhengzhou Children\u0026rsquo;s Hospital, Henan, China.\u003c/p\u003e\n\u003cp\u003eShaowen Wang\u003c/p\u003e\n\u003cp\u003eInstitute of Science and Technology for Brain-Inspired Intelligence, Fudan University, Shanghai, China.\u003c/p\u003e\n\u003cp\u003eMiao Cao\u003c/p\u003e\n\u003cp\u003eKey Laboratory of Computational Neuroscience and Brain-Inspired Intelligence, Ministry of Education, Fudan University, Shanghai, China.\u003c/p\u003e\n\u003cp\u003eMiao Cao\u003c/p\u003e\n\u003cp\u003eShanghai Key Laboratory of Psychotic Disorders, Brain Health Institute, National Center for Mental Disorders, Shanghai Mental Health Center, Shanghai Jiao Tong University School of Medicine, Shanghai, China.\u003c/p\u003e\n\u003cp\u003eTi-Fei Yuan\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eContributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFL and TY supervised the design and protocol of the study and contributed to the interpretation and discussion of the results. HT, MX, LD and SW contributed to the study design, trial implementation, and collected the data. HT, MX, LD, SW and MC contributed to the data processing and statistical analysis. HT, MX, LD, LZ, MC and TY contributed to the writing of the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorresponding authors\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCorrespondence to Miao Cao, Ti-fei Yuan or Fei Li.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLord C, Brugha TS, Charman T, Cusack J, Dumas G, Frazier T, et al. Autism spectrum disorder. Nat Rev Dis Primers. 2020;6:5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHyman SL, Levy SE, Myers SM. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020, 145.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZeidan J, Fombonne E, Scorah J, Ibrahim A, Durkin MS, Saxena S, et al. Global prevalence of autism: A systematic review update. Autism Res. 2022;15:778\u0026ndash;90.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaenner MJ, Shaw KA, Bakian AV, Bilder DA, Durkin MS, Esler A, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2018. MMWR Surveill Summ. 2021;70:1\u0026ndash;16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMaenner MJ, Warren Z, Williams AR, Amoakohene E, Bakian AV, Bilder DA, et al. Prevalence and Characteristics of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2020. MMWR Surveill Summ. 2023;72:1\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou H, Xu X, Yan W, Zou X, Wu L, Luo X, et al. Prevalence of Autism Spectrum Disorder in China: A Nationwide Multi-center Population-based Study Among Children Aged 6 to 12 Years. Neurosci Bull. 2020;36:961\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrye RE. Social Skills Deficits in Autism Spectrum Disorder: Potential Biological Origins and Progress in Developing Therapeutic Agents. CNS Drugs. 2018;32:713\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaribeau D, Vorstman J, Anagnostou E. Novel treatments in autism spectrum disorder. Curr Opin Psychiatry. 2022;35:101\u0026ndash;10.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSharma SR, Gonda X, Tarazi FI. Autism Spectrum Disorder: Classification, diagnosis and therapy. Pharmacol Ther. 2018;190:91\u0026ndash;104.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLefaucheur JP, Aleman A, Baeken C, Benninger DH, Brunelin J, Di Lazzaro V, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014\u0026ndash;2018). Clin Neurophysiol. 2020;131:474\u0026ndash;528.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang J, Zhang H. Effects of non-invasive neurostimulation on autism spectrum disorder: A systematic review. Front Psychiatry. 2022;13:989905.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFitzsimmons SMDD, Oostra E, Postma TS, van der Werf YD, van den Heuvel OA. Repetitive transcranial magnetic stimulation-induced neuroplasticity and the treatment of psychiatric disorders: state of the evidence and future opportunities. Biol Psychiatry 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasanova MF, Sokhadze EM, Casanova EL, Opris I, Abujadi C, Marcolin MA, et al. Translational Neuroscience in Autism: From Neuropathology to Transcranial Magnetic Stimulation Therapies. Psychiatr Clin North Am. 2020;43:229\u0026ndash;48.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMasuda F, Nakajima S, Miyazaki T, Yoshida K, Tsugawa S, Wada M, et al. Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review. Transl Psychiatry. 2019;9:110.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBarahona-Correa JB, Velosa A, Chainho A, Lopes R, Oliveira-Maia AJ. Repetitive Transcranial Magnetic Stimulation for Treatment of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Front Integr Neurosci. 2018;12:27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmith JR, DiSalvo M, Green A, Ceranoglu TA, Anteraper SA, Croarkin P et al. Treatment Response of Transcranial Magnetic Stimulation in Intellectually Capable Youth and Young Adults with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis. Neuropsychol Rev 2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBaruth JM, Casanova MF, El-Baz A, Horrell T, Mathai G, Sears L, et al. Low-Frequency Repetitive Transcranial Magnetic Stimulation (rTMS) Modulates Evoked-Gamma Frequency Oscillations in Autism Spectrum Disorder (ASD). J Neurother. 2010;14:179\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi HC, Hung J, Wu CT, Wu YY, Chang CJ, Chen RS, et al. The Impact of Single Session Intermittent Theta-Burst Stimulation over the Dorsolateral Prefrontal Cortex and Posterior Superior Temporal Sulcus on Adults with Autism Spectrum Disorder. Front Neurosci. 2017;11:255.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNi HC, Chen YL, Chao YP, Wu CT, Wu YY, Liang SH, et al. Intermittent theta burst stimulation over the posterior superior temporal sulcus for children with autism spectrum disorder: A 4-week randomized blinded controlled trial followed by another 4-week open-label intervention. Autism. 2021;25:1279\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eEnticott PG, Fitzgibbon BM, Kennedy HA, Arnold SL, Elliot D, Peachey A, et al. A double-blind, randomized trial of deep repetitive transcranial magnetic stimulation (rTMS) for autism spectrum disorder. Brain Stimul. 2014;7:206\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBonini L, Rotunno C, Arcuri E, Gallese V. Mirror neurons 30 years later: implications and applications. Trends Cogn Sci. 2022;26:767\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGordon EM, Chauvin RJ, Van AN, Rajesh A, Nielsen A, Newbold DJ et al. A somato-cognitive action network alternates with effector regions in motor cortex. Nature 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFini C, Fischer M, Bardi L, Brass M, Moors A. Support from a TMS/MEP study for a direct link between positive/negative stimuli and approach/avoidance tendencies. Neuropsychologia. 2020;143:107496.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXia X, Wang D, Song Y, Zhu M, Li Y, Chen R, et al. Involvement of the primary motor cortex in the early processing stage of the affective stimulus-response compatibility effect in a manikin task. NeuroImage. 2021;225:117485.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlexander AS, Place R, Starrett MJ, Chrastil ER, Nitz DA. Rethinking retrosplenial cortex: Perspectives and predictions. Neuron. 2023;111:150\u0026ndash;75.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBorgomaneri S, Gazzola V, Avenanti A. Temporal dynamics of motor cortex excitability during perception of natural emotional scenes. Soc Cogn Affect Neurosci. 2014;9:1451\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLoi N, Ginatempo F, Carta M, Melis F, Manca A, Deriu F. Face emotional expressions influence interhemispheric inhibition. Psychophysiology 2022: e14234.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSolana P, Santiago J. Does the involvement of motor cortex in embodied language comprehension stand on solid ground? A p-curve analysis and test for excess significance of the TMS and tDCS evidence. Neurosci Biobehav Rev. 2022;141:104834.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWang X, Krieger-Redwood K, Zhang M, Cui Z, Wang X, Karapanagiotidis T, et al. Physical distance to sensory-motor landmarks predicts language function. Cereb Cortex. 2023;33:4305\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJannati A, Block G, Ryan MA, Kaye HL, Kayarian FB, Bashir S, et al. Continuous Theta-Burst Stimulation in Children With High-Functioning Autism Spectrum Disorder and Typically Developing Children. Front Integr Neurosci. 2020;14:13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDesarkar P, Rajji TK, Ameis SH, Blumberger DM, Lai MC, Lunsky Y, et al. Assessing and stabilizing atypical plasticity in autism spectrum disorder using rTMS: Results from a proof-of-principle study. Clin Neurophysiol. 2022;141:109\u0026ndash;18.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJannati A, Ryan MA, Block G, Kayarian FB, Oberman LM, Rotenberg A, et al. Modulation of motor cortical excitability by continuous theta-burst stimulation in adults with autism spectrum disorder. Clin Neurophysiol. 2021;132:1647\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHuang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45:201\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eElmaghraby R, Sun Q, Ozger C, Shekunov J, Romanowicz M, Croarkin PE. A Systematic Review of the Safety and Tolerability of Theta Burst Stimulation in Children and Adolescents. Neuromodulation. 2022;25:494\u0026ndash;503.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCole EJ, Stimpson KH, Bentzley BS, Gulser M, Cherian K, Tischler C, et al. Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. Am J Psychiatry. 2020;177:716\u0026ndash;26.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerera T, George MS, Grammer G, Janicak PG, Pascual-Leone A, Wirecki TS. The Clinical TMS Society Consensus Review and Treatment Recommendations for TMS Therapy for Major Depressive Disorder. Brain Stimul. 2016;9:336\u0026ndash;46.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSmolen P, Zhang Y, Byrne JH. The right time to learn: mechanisms and optimization of spaced learning. Nat Rev Neurosci. 2016;17:77\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldsworthy MR, Pitcher JB, Ridding MC. Spaced Noninvasive Brain Stimulation: Prospects for Inducing Long-Lasting Human Cortical Plasticity. Neurorehabil Neural Repair. 2015;29:714\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRossini PM, Burke D, Chen R, Cohen LG, Daskalakis Z, Di Iorio R, et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol. 2015;126:1071\u0026ndash;107.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCen CQ, Liang YY, Chen QR, Chen KY, Deng HZ, Chen BY, et al. Investigating the validation of the Chinese Mandarin version of the Social Responsiveness Scale in a Mainland China child population. BMC Psychiatry. 2017;17:51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTardif T, Fletcher P, Liang W, Kaciroti N. Early vocabulary development in Mandarin (Putonghua) and Cantonese. J Child Lang. 2009;36:1115\u0026ndash;44.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKrasileva KE, Sanders SJ, Bal VH. Peabody Picture Vocabulary Test: Proxy for Verbal IQ in Genetic Studies of Autism Spectrum Disorder. J Autism Dev Disord. 2017;47:1073\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKan RTY, Chan A, Gagarina N. Investigating Children's Narrative Abilities in a Chinese and Multilingual Context: Cantonese, Mandarin, Kam and Urdu Adaptations of the Multilingual Assessment Instrument for Narratives (MAIN). Front Psychol. 2020;11:573780.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRosenthal M, Wallace GL, Lawson R, Wills MC, Dixon E, Yerys BE, et al. Impairments in real-world executive function increase from childhood to adolescence in autism spectrum disorders. Neuropsychology. 2013;27:13\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoyette CH, Conners CK, Ulrich RF. Normative data on revised Conners Parent and Teacher Rating Scales. J Abnorm Child Psychol. 1978;6:221\u0026ndash;36.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ede Beurs E, Carlier IVE, van Hemert AM. Approaches to denote treatment outcome: Clinical significance and clinical global impression compared. Int J Methods Psychiatr Res. 2019;28:e1797.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArns M, Bruder G, Hegerl U, Spooner C, Palmer DM, Etkin A, et al. EEG alpha asymmetry as a gender-specific predictor of outcome to acute treatment with different antidepressant medications in the randomized iSPOT-D study. Clin Neurophysiol. 2016;127:509\u0026ndash;19.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDelorme A, Makeig S. EEGLAB: an open source toolbox for analysis of single-trial EEG dynamics including independent component analysis. J Neurosci Methods. 2004;134:9\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFrohlich J, Reiter LT, Saravanapandian V, DiStefano C, Huberty S, Hyde C, et al. Mechanisms underlying the EEG biomarker in Dup15q syndrome. Mol Autism. 2019;10:29.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGabard-Durnam LJ, Wilkinson C, Kapur K, Tager-Flusberg H, Levin AR, Nelson CA. Longitudinal EEG power in the first postnatal year differentiates autism outcomes. Nat Commun. 2019;10:4188.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAngulo-Ruiz BY, Ruiz-Mart\u0026iacute;nez FJ, Rodr\u0026iacute;guez-Mart\u0026iacute;nez EI, Ionescu A, Salda\u0026ntilde;a D, G\u0026oacute;mez CM. Linear and Non-linear Analyses of EEG in a Group of ASD Children During Resting State Condition. Brain Topogr; 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDai Y, Zhang L, Yu J, Zhou X, He H, Ji Y, et al. Improved symptoms following bumetanide treatment in children aged 3\u0026thinsp;\u0026ndash;\u0026thinsp;6 years with autism spectrum disorder: a randomized, double-blind, placebo-controlled trial. Sci Bull. 2021;66:1591\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi F, Wu D, Ren F, Shen L, Xue M, Yu J, et al. Effectiveness of Online-Delivered Project ImPACT for Children With ASD and Their Parents: A Pilot Study During the COVID-19 Pandemic. Front Psychiatry. 2022;13:806149.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHyman SL, Levy SE, Myers SM, Council On Children With Disabilities SOD, Behavioral P. Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. 2020, 145.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eViru\u0026eacute;s-Ortega J. Applied behavior analytic intervention for autism in early childhood: meta-analysis, meta-regression and dose-response meta-analysis of multiple outcomes. Clin Psychol Rev. 2010;30:387\u0026ndash;99.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSandbank M, Bottema-Beutel K, Crowley S, Cassidy M, Feldman JI, Canihuante M, et al. Intervention Effects on Language in Children With Autism: A Project AIM Meta-Analysis. J Speech Lang Hear Res. 2020;63:1537\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBrignell A, Chenausky KV, Song H, Zhu J, Suo C, Morgan AT. Communication interventions for autism spectrum disorder in minimally verbal children. Cochrane Database Syst Rev. 2018;11:Cd012324.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRossignol DA, Frye RE. Cerebral Folate Deficiency, Folate Receptor Alpha Autoantibodies and Leucovorin (Folinic Acid) Treatment in Autism Spectrum Disorders: A Systematic Review and Meta-Analysis. J Pers Med 2021, 11.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry. 2002;159:1093\u0026ndash;102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePascual-Leone A, Valls-Sole J, Wassermann EM, Hallett M. Responses to rapid-rate transcranial magnetic stimulation of the human motor cortex. Brain. 1994;117(Pt 4):847\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardenas-Morales L, Nowak DA, Kammer T, Wolf RC, Schonfeldt-Lecuona C. Mechanisms and applications of theta-burst rTMS on the human motor cortex. Brain Topogr. 2010;22:294\u0026ndash;306.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFox MD, Halko MA, Eldaief MC, Pascual-Leone A. Measuring and manipulating brain connectivity with resting state functional connectivity magnetic resonance imaging (fcMRI) and transcranial magnetic stimulation (TMS). NeuroImage. 2012;62:2232\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCasanova MF, Buxhoeveden D, Gomez J. Disruption in the inhibitory architecture of the cell minicolumn: implications for autism. Neuroscientist. 2003;9:496\u0026ndash;507.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChao HT, Chen H, Samaco RC, Xue M, Chahrour M, Yoo J, et al. Dysfunction in GABA signalling mediates autism-like stereotypies and Rett syndrome phenotypes. Nature. 2010;468:263\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarew TJ, Pinsker HM, Kandel ER. Long-term habituation of a defensive withdrawal reflex in aplysia. Science. 1972;175:451\u0026ndash;4.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLisanby SH. Transcranial Magnetic Stimulation in Psychiatry: Historical Reflections and Future Directions. Biol Psychiatry; 2023.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKramar EA, Babayan AH, Gavin CF, Cox CD, Jafari M, Gall CM, et al. Synaptic evidence for the efficacy of spaced learning. Proc Natl Acad Sci U S A. 2012;109:5121\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoldsworthy MR, Pitcher JB, Ridding MC. The application of spaced theta burst protocols induces long-lasting neuroplastic changes in the human motor cortex. Eur J Neurosci. 2012;35:125\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNyffeler T, Cazzoli D, Hess CW, Muri RM. One session of repeated parietal theta burst stimulation trains induces long-lasting improvement of visual neglect. Stroke. 2009;40:2791\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGollo LL, Roberts JA, Cocchi L. Mapping how local perturbations influence systems-level brain dynamics. NeuroImage. 2017;160:97\u0026ndash;112.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBeynel L, Powers JP, Appelbaum LG. Effects of repetitive transcranial magnetic stimulation on resting-state connectivity: A systematic review. NeuroImage. 2020;211:116596.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanes JN, Donoghue JP. Plasticity and primary motor cortex. Annu Rev Neurosci. 2000;23:393\u0026ndash;415.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePessoa L, Adolphs R. Emotion processing and the amygdala: from a 'low road' to 'many roads' of evaluating biological significance. Nat Rev Neurosci. 2010;11:773\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLivneh U, Resnik J, Shohat Y, Paz R. Self-monitoring of social facial expressions in the primate amygdala and cingulate cortex. Proc Natl Acad Sci U S A. 2012;109:18956\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePfurtscheller G. Event-related synchronization (ERS): an electrophysiological correlate of cortical areas at rest. Electroencephalogr Clin Neurophysiol. 1992;83:62\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeuper C, Wortz M, Pfurtscheller G. ERD/ERS patterns reflecting sensorimotor activation and deactivation. Prog Brain Res. 2006;159:211\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathewson KJ, Jetha MK, Drmic IE, Bryson SE, Goldberg JO, Schmidt LA. Regional EEG alpha power, coherence, and behavioral symptomatology in autism spectrum disorder. Clin Neurophysiol. 2012;123:1798\u0026ndash;809.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlimesch W. EEG alpha and theta oscillations reflect cognitive and memory performance: a review and analysis. Brain Res Brain Res Rev. 1999;29:169\u0026ndash;95.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnyazev GG, Savostyanov AN, Levin EA. Alpha synchronization and anxiety: implications for inhibition vs. alertness hypotheses. Int J Psychophysiol. 2006;59:151\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathewson KE, Gratton G, Fabiani M, Beck DM, Ro T. To see or not to see: prestimulus alpha phase predicts visual awareness. J Neurosci. 2009;29:2725\u0026ndash;32.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarceglia S, Mrakic-Sposta S, Rosa M, Ferrucci R, Mameli F, Vergari M, et al. Transcranial Direct Current Stimulation Modulates Cortical Neuronal Activity in Alzheimer's Disease. Front Neurosci. 2016;10:134.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKlimesch W, Sauseng P, Hanslmayr S. EEG alpha oscillations: the inhibition-timing hypothesis. Brain Res Rev. 2007;53:63\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJuarez-Martinez EL, Sprengers JJ, Cristian G, Oranje B, van Andel DM, Avramiea AE, et al. Prediction of Behavioral Improvement Through Resting-State Electroencephalography and Clinical Severity in a Randomized Controlled Trial Testing Bumetanide in Autism Spectrum Disorder. Biol Psychiatry Cogn Neurosci Neuroimaging. 2023;8:251\u0026ndash;61.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAmatachaya A, Jensen MP, Patjanasoontorn N, Auvichayapat N, Suphakunpinyo C, Janjarasjitt S et al., \u003cem\u003eThe short-term effects of transcranial direct current stimulation on electroencephalography in children with autism: a randomized crossover controlled trial. Behav Neurol. 2015, 2015: 928631.\u003c/em\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSusam BT, Riek NT, Beck K, Eldeeb S, Hudac CM, Gable PA, et al. Quantitative EEG Changes in Youth With ASD Following Brief Mindfulness Meditation Exercise. IEEE Trans Neural Syst Rehabil Eng. 2022;30:2395\u0026ndash;405.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWallace GL, Dankner N, Kenworthy L, Giedd JN, Martin A. Age-related temporal and parietal cortical thinning in autism spectrum disorders. Brain. 2010;133:3745\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGendry Meresse I, Zilbovicius M, Boddaert N, Robel L, Philippe A, Sfaello I, et al. Autism severity and temporal lobe functional abnormalities. Ann Neurol. 2005;58:466\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarin JC, Moura PJ, Cysneiros RM, Colugnati DB, Cavalheiro EA, Scorza FA, et al. Temporal lobe epilepsy and social behavior: an animal model for autism? Epilepsy Behav. 2008;13:43\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLombardo MV, Chakrabarti B, Bullmore ET, Baron-Cohen S. Specialization of right temporo-parietal junction for mentalizing and its relation to social impairments in autism. NeuroImage. 2011;56:1832\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZilbovicius M, Meresse I, Chabane N, Brunelle F, Samson Y, Boddaert N. Autism, the superior temporal sulcus and social perception. Trends Neurosci. 2006;29:359\u0026ndash;66.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Autism spectrum disorder, Repetitive transcranial magnetic stimulation, Clinical trial, Social communication, Language, Children","lastPublishedDoi":"10.21203/rs.3.rs-4140990/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4140990/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eSocial communication impairment (SCI) is a defining feature in autism spectrum disorder (ASD) but remains difficult to treat. Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) is a potential method for treating this aspect of ASD, but the stimulation protocols used vary widely, and limited effects of these protocols on SCI have been reported, particularly in younger children with ASD. Thus, we developed an accelerated rTMS protocol and investigated its feasibility, efficacy and potential neural mechanism for the treatment of SCI in ASD children.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn the open-label study, thirty children aged 4\u0026ndash;10 with ASD received accelerated theta-burst stimulation (a-cTBS) over the motor cortex for 5 consecutive days. Before and after the intervention, all participants underwent a battery of clinical assessments regarding SCI, and 26 of them cooperated and participated in the collection of electroencephalogram (EEG) data. The primary clinical efficacy outcome was the Social Responsiveness Scale (SRS) score.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAll participants completed the trial and the adverse effects were low-incidence and mild. Repeat measurement analysis showed a significant improvement in the Social Responsiveness Scale (SRS) score with a mean decrease of 12.77 (95% CI 7.58 to 17.95; P\u0026thinsp;\u0026lt;\u0026thinsp;.001) between pre-intervention and post-intervention, and 16.60 (95% CI 11.47 to 21.73; P\u0026thinsp;\u0026lt;\u0026thinsp;.001) between pre-intervention and one-month follow-up, respectively, and the improvement was associated with the observed EEG signal changes of right temporoparietal region. Paired tests showed significant increases in language-related indicators scores from baseline to the one-month follow-up (all P\u0026thinsp;\u0026lt;\u0026thinsp;0.05).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThis study indicated that a-cTBS over the motor cortex is a safe, feasible and efficient protocol for treating SCI in children with ASD, and provided further evidence for the association of the motor cortex with the social/language network.\u003c/p\u003e\u003ch2\u003eTrial registration\u003c/h2\u003e \u003cp\u003eThe trial was registered at ClinicalTrials.gov (NCT05472870) on 22th July, 2022.\u003c/p\u003e","manuscriptTitle":"Accelerated theta-burst stimulation over the motor cortex improves social communication impairment in children with autism spectrum disorder: An open-label trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-01 16:17:57","doi":"10.21203/rs.3.rs-4140990/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b3c242c9-4df9-4537-a98b-e449b9e1befd","owner":[],"postedDate":"April 1st, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-05-02T01:40:43+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-01 16:17:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4140990","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4140990","identity":"rs-4140990","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}