Repetitive Transcranial Magnetic Stimulation for Treatment of Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

J Bernardo Barahona-Corrêa, Ana Velosa, Ana Chainho, Ricardo Lopes, Albino J Oliveira-Maia, J Bernardo Barahona-Corrêa, Ana Velosa, Ana Chainho, Ricardo Lopes, Albino J Oliveira-Maia

Abstract

Background: Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder manifesting as lifelong deficits in social communication and interaction, as well as restricted repetitive behaviors, interests and activities. While there are no specific pharmacological or other physical treatments for autism, in recent years repetitive Transcranial Magnetic Stimulation (rTMS), a technique for non-invasive neuromodulation, has attracted interest due to potential therapeutic value. Here we report the results of a systematic literature review and meta-analysis on the use of rTMS to treat ASD. Methods: We performed a systematic literature search on PubMed, Web of Science, Science Direct, Bielefeld Academic Search, and Educational Resources Information Clearinghouse. Search terms reflected diagnoses and treatment modalities of interest. Studies reporting use of rTMS to treat core ASD or cognitive symptoms in ASD were eligible. Two researchers performed article selection and data extraction independently, according to PRISMA guidelines. Changes in ASD clinical scores or in cognitive performance were the main outcomes. Random effects meta-analysis models were performed. Results: We found 23 eligible reports, comprising 4 case-reports, 7 non-controlled clinical trials, and 12 controlled clinical trials, comparing the effects of real TMS with waiting-list controls (n = 6) or sham-treatment (n = 6). Meta-analyses showed a significant, but moderate, effect on repetitive and stereotyped behaviors, social behavior, and number of errors in executive function tasks, but not other outcomes. Most studies had a moderate to high risk of bias, mostly due to lack of subject- and evaluator-blinding to treatment allocation. Only 5 studies reported stability of these gains for periods of up 6 months, with descriptions that improvements were sustained over time. Conclusions: Existing evidence supports that TMS could be useful to treat some dimensions of ASD. However, such evidence must be regarded with care, as most studies did not adequately control for placebo effects. Moreover, little is known regarding the most effective stimulation parameters, targets, and schedules. There is an urgent need for further randomized, double-blind, sham-controlled trials, with adequate follow-up periods, to test the efficacy of transcranial magnetic stimulation to treat these disorders. Available evidence must be regarded as preliminary and insufficient, at present, to support offering TMS to treat ASD.

Keywords: Asperger's; TBS; TMS; autism; meta-analysis; non-invasive brain stimulation; rTMS.

Figures

Figure 1
Figure 1
Article selection flowchart (according to PRISMA Statement).
Figure 2
Figure 2
Effects of rTMS on repetitive and restricted behavior in non-controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). The latter gives the range in which, in 95% of the cases, the outcome of a future study will fall, assuming that the effect sizes of studies are normally distributed. (B) Funnel-plot. There is evidence of significant publication bias. Square-shaped dots represent studies imputed by trim-and-fill analysis.
Figure 3
Figure 3
Effects of rTMS on repetitive and restricted behavior in controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot. There is evidence of significant publication bias. Square-shaped dots represent studies imputed by trim-and-fill analysis.
Figure 4
Figure 4
Effects of rTMS on social behavior deficits in non-controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot.
Figure 5
Figure 5
Effects of rTMS on social behavior deficits in controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot. There is evidence of possible significant publication bias, with 2 imputed studies (square-shaped dots) estimated by trim-and-fill analysis.
Figure 6
Figure 6
Effects of rTMS on hyperactivity in non-controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot.
Figure 7
Figure 7
Effects of rTMS on irritability in non-controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot.
Figure 8
Figure 8
Forest-plot of controlled studies that assessed the effects of rTMS on irritability. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval).
Figure 9
Figure 9
Effects of rTMS on reaction time during performance of executive control tasks, in controlled studies. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot.
Figure 10
Figure 10
Effects of rTMS on total number of errors during performance of executive control tasks. (A) Forest-plot. Dots represent each study, with dot size reflecting study weight in the model and error bars indicating the effect size (with confidence interval). The lower line represents the combined effect size with its confidence interval (narrow interval) and its 95% prediction interval (wide interval). (B) Funnel-plot. There is evidence of possible significant publication bias, with 3 imputed studies (square-shaped dots) estimated by trim-and-fill analysis.

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