The present protocol is being reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement (8). This protocol has been submitted within the International Prospective Register of Systematic Reviews (PROSPERO) database (date: 20/11/2021). Any amendments made to this protocol when conducting the study will be outlined in PROSPERO and reported in the final manuscript. When this systematic review and meta-analysis being completed, it will be reported in accordance with the reporting guidance provided in the PRISMA statement (9). Since there is no human or animal experiment, the study will not require an ethical approval.
Eligibility criteria
Studies will be included according to the following criteria: participants, interventions and comparators, outcome(s) of interest and study design.
Participants
Patients diagnosed with autism spectrum disorder based on a valid method will be included. The Diagnostic and Statistical Manual of Mental Disorders (DSM) is used predominantly in the United States (US) and has been updated to the fifth version (DSM-5) (10). The World Health Organization International Classification of Diseases, 10th revision (ICD-10) is used in other countries other than the US (11). Other diagnostic tools include the Autism Diagnostic Interview-Revised (ADI-R) (12), the Autism Diagnostic Observation Schedule (ADOS) (13), etc.
Interventions
Noninvasive neurostimulations including both transcranial direct current stimulation and transcranial magnetic stimulation will be included. Variation of tDCS like transcranial alternating current stimulation (tACS) will also be included. As for TMS studies, we will include low-frequency rTMS (LF-rTMS), high-frequency rTMS (HF-rTMS), intermittent theta burst stimulation (iTBS), continuous theta burst stimulation (cTBS), paired associative stimulation (PAS), as well.
Comparators
Sham stimulation. For tDCS, to make sure the participant was blinded to the procedure, the power indicator which was visible to the participants was lit up for both active and sham stimulation. However, in the sham stimulation condition, the current was discontinued normally after 30 seconds (14). For TMS, the sham stimulation was delivered with the coil tilted one-wing 90° off the head, which is a valid sham condition commonly used in double- or single-blind, sham-controlled trials (15).
Outcomes of interest
Based on our preliminary searches, a variety of effect measurements have been used to evaluate the outcomes of noninvasive neurostimulation. These outcomes will be measured pre-and post-intervention. We will categorize these measurements into two major kinds, as test/scale/tasks and objective outcome measurements.
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Test/scale/tasks includes but not limits to the Wisconsin Card Sorting Test (WCST), the Autism Spectrum Quotient (AQ), the Probabilistic Reversal Learning Task (PRLT), the Behaviour Rating Inventory of Executive Functioning (BRIEF; shift subscale), the Repetitive Behaviour Questionnaire 2A (RBQ-2A; total score), the Wechsler Memory Scale, 3rd Edition (WMS-III), the Brief Test of Attention (BTA), the Boston Naming Test (BNT), the Raven’s Progressive Matrices (Raven, 2000), the the Movement Assessment Battery for Children-2 (MABC-2), the theory of mind test (TOMT), the featuring self-report clinical scales with good psychometric properties (RAADS), the Interpersonal Reactivity Index (IRI), the Childhood Autism Rating Scale (CARS), the Autism Treatment Evaluation Checklist (ATEC), the Clinical Global Impression-Improvement (CGI-I), the Aberrant Behavior Checklist (ABC), the Social Responsiveness Scale (SRS), the Repetitive Behavior Scale—Revised (RBS), the Eye-tracking apparatus, the Conner’s Continuous Performance Test (CCPT), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS), the Frith–Happe animations task, the Reading the Mind in the Eyes test (RMET), the Global Clinical Impression Scale (GCIS), the Autism Diagnostic Interview, Revisited Edition (ADI-R), the 3-back task, Empathy Quotient (EQ), the facial emotion recognition and processing (FERP) test, the verbal fluency (VF) test, the Test of Adolescent Social Skills-Modified (TASSK-M), Children’s Sleep Habits Questionnaire (CSHQ), the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Mini International Neuropsychiatric Interview (MINI), etc.
- Objective outcome measurements includes the metabolites levels, the functional magnetic resonance imaging (fMRI), and Electroencephalogram (EEG).
Study design
We will consider randomized controlled trials, nonrandomized control trials, open-label trials, crossover trials. Cohort, case-control, case series, and case reports will also be searched for but not be included in the final paper. Only studies published in English will be included. No limitations will be imposed on publication status (unpublished studies will be eligible for inclusion) or study conduct period.
Information sources and search strategy
PubMed, Embase (1996 to 2021 Week 43), and Cochrane library databases will be retrieved according to the search strategy. No limitations regarding the study design, publication time, and age or sex of participants will be set when searching for the records. A draft search strategy is present in supplementary table 1.
Study selection
Studies will be selected based on the following inclusion criteria: (1) Sham-controlled designed studies comparing the effects of any noninvasive neurostimulations with that of a sham stimulation group; (2) Studies enrolling patients with solid diagnosis of autism spectrum disorder; (3) Studies providing outcomes measuring the therapeutic or side effects. Exclusion criteria will be: (1) Studies reported in language other than English; (2) Studies published in the form of editorial, comments, or conference abstract, which details of PICOS were not reported; (3) Studies comparing the responses of patients with ASD to noninvasive neurostimulations with that of other human subjects.
Records from database searches will be exported into EndNote and duplicates removed. Two reviewers will independently screen titles and abstracts for potentially eligible studies. The reviewers will then independently screen the full text of potentially eligible studies. Reasons for exclusions will be reported. At each stage of the review process, disagreements will be resolved by discussion or, if not achieve consensus, consulting a third review author acted as an arbitrator. The reviewers were not blinded to names of authors, institutions, outcomes, or journals.
Data extraction
Two authors will extract data independently from the included articles, using a pre-developed form adapted from the Cochrane data collection form for intervention reviews and extracted data form published by Ulrike Schmidt et al. (16, 17):
General information
First author of study, published date, published journal, DOI, author's contact information (if available).
Study details
Study design; country; setting; sample size; inclusion and exclusion criteria; comparability of groups; study period; stratification; stopping rules; funding source; conflict of interest.
'Risk of bias' assessment and justification for this judgement: sequence generation; allocation concealment; blinding (participants, personnel, outcome assessors); incomplete outcome data; selective outcome reporting; and other bias (recall bias). Characteristics of participants: age; gender; ethnicity; the number randomized, analyzed and lost to follow-up; and dropouts in each arm (with reasons).
Interventions: experimental and control interventions; details of noninvasive stimulation procedures (for current stimulation: anode site, cathode site, Current, Electrode size; for magnetic stimulation: coil placement, frequency, motor threshold, pulses); timing of intervention; uptake of intervention (acceptance of stimulation), whether studies assessed adherence (compliance) with interventions.
Outcomes measured
Tests, scales, tasks, EEG, metabolites measurement.
Risk of bias in individual studies
We will use the revised Cochrane risk-of-bias 2 (RoB-2) tool to assess the quality of each trial (18). Two reviewers will independently score each trial, each quality item will be graded as low risk, high risk, or unclear risk. We will resolve any discrepancies by consulting a third review author. We will assess the risk of bias for the 7 domains: randomization sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting, and other bias. The included trials will be graded as low quality, moderate quality or, high quality based on the evaluation. To evaluate the possibility of publication bias, we will use funnel plots for analyses that contained more than 10 studies.
Data synthesis
We will perform a narrative synthesis around the features of existing evidences investigating the effects of noninvasive neurostimulation on ASD patients. All eligible trials will be summarized in narrative form. Tables will be constructed based on the information extracted (Table 1). These tables will include key study characteristics such as study design, population, diagnosis tool, randomization methods, intervention parameters, sham stimulation methods, outcomes, etc.
Table 1 Data extraction form
General
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Paper title
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Date form completed
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Reference citation
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Publication type
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Reviewer signature
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Notes
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Study details
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Aims
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Study dates
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Study design (randomized, non-randomized, crossover)
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Blinding (Single, double, triple)
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Allocation concealment
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Comparison (Sham control, waiting list)
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Primary outcome measures
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Secondary outcome measure
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Assessment time point
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Missing data
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Limitations
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Participants
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Number started
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Number completed
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A priori power calculation
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Age (Mean, SD) and range
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Gender
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Ethnicity
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Inclusion Criteria
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Exclusion Criteria
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ASD diagnosis tools
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Treatment setting
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Severity of illness
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Group sub-division
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Intervention – general
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Was neurostimulation given as an add-on treatment? Details of basic treatment
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Was neurostimulation coupled with cognitive or other tasks?
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Intervention – TMS
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Type of TMS used (high-frequency, low-frequency, deep TMS, cTBS, iTBS)
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Number and frequency of sessions
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Site of stimulation
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TMS frequency (Hz)
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Coil type
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% of resting motor threshold
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Number of trains
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Train duration
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Inter-train interval
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Neuro-navigation use? Yes/No
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Compliance with TMS regimen (number of sessions missed for exclusion)
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Intervention – tDCS
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tDCS machine used
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Number and frequency of sessions
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Site of stimulation
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Current
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Duration of current
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Compliance with rTMS regimen (number of sessions missed for exclusion)
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Outcomes
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Main clinical outcomes
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Secondary outcomes
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Adverse outcomes
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Main conclusion
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Outcome measurement tools
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There may be a chance for meta-analysis to pool the estimates of studies included if three studies or more meet the requirements for meta-analysis. If so, a random-effects model maybe applied. And we will evaluate heterogeneity between studies using the I² statistic. We planned not to pool data where there was considerable heterogeneity (I² ≥ 75%) that could not be explained by the diversity of methodological or clinical features among studies.
Subgroup analyses
If there are sufficient data provided by the qualified studies, we will do meta-analyses stratified by: age; sex; stimulation site, randomization procedures, stimulation intensity, montage, duration, number of stimulation session. We will use the test for subgroup differences available in RevMan 5 to determine whether there was evidence for a difference in treatment effect between subgroups.
Sensitivity analyses
Potential reasons for heterogeneity will be explored in sensitivity analyses; the pre-specified subgroup analyses, if feasible, will be examined to determine potential reasons for any observed statistical heterogeneity.
Strength of evidence
The overall quality of evidence for all outcomes will be evaluated using the Grading, Recommendations, Assessment, Development and Evaluation (GRADE) framework, estimating individual risk of bias, meta-bias, precision, consistency, directedness and the magnitude of effect (19). These indicators will determine the certainty of the estimated effect, which will be rated as either very low, low, high or very high.