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Clinical application of Transcranic Magnetic Stimulation in Autism Spectrum Disorder. Preliminary results of a systematic review

Matteo Rocchetti1*, Jessica Monaco2, Letizia Casiraghi1, 2, Pierluigi Politi1 and Natascia Brondino1
  • 1 University of Pavia, Department of Brain and Behavioral Sciences, Italy
  • 2 IRCCS C. Mondino, National Neurological Institute, Brain Connectivity Center, Italy

Background Autism Spectrum Disorders (ASD) refer to clinical conditions characterised by A) persistent deficits in social communication and social interaction across multiple contexts and B) restricted and repetitive patterns of behaviour, interests, or activities. The signs and symptoms usually appear in early developmental period and cause significant functional impairment (APA, 2013). According with NICE guidelines no pharmacological treatment is recommended to treat the core symptomatology of the conditions (https://www.nice.org.uk/guidance/qs51). According with a recent consensus report by Oberman et al. (2016), transcranial magnetic stimulation (TMS) could represent an innovative approach to investigate in vivo the pathophysiology associated with symptoms of ASD and a possible innovative treatment deserving future investigations. However, to the best of our knowledge, no systematic review has been published to summarize with a meta-analytic approach the studies investigating the clinical impact of TMS in ASD. Methods We performed a two-step systematic search of the literature to retrieve all the randomised clinical trials (RCT) studying the clinical effect of TMS in ASD. The Web of Knowledge® databases (including Web of Science™, MEDLINE®, SciELO Citation Index, Russian Science Citation Index, KCI-Korean Journal Database) have been independently searched until Oct 2016 by two authors (MR, NB) through title and abstract reading using the following string ((autis* OR ASD OR Kanner OR Asperger OR "pervasive developmental disorder") AND (TMS OR rTMS OR "transcranial magnetic stimulation")). Full text reading of the retrieved publications and manual search of the cited references have been performed for study selection according with the following exclusion criteria: a) Not original RCT article investigating TMS efficacy; b) No ASD diagnosis; c) No sham control or waiting list; d) Not enough data for independent evaluation of the results. Discrepancies have been resolved through consensus. The Cochrane Collaboration tool for risk of bias assessment (Higgins et al., 2011) has been adopted. Results A total of 6 RCT investigating the clinical efficacy of TMS in ASD have been found (see Figure 1, PRISMA flow chart). The database included 182 subjects affected by ASD (n = 103 randomized to TMS, n =79 to control condition). Two studies adopted a sham control condition (Enticott et al., 2014;Panerai et al., 2014) while 4 studies adopted waiting list strategies (Sokhadze et al., 2009;Baruth et al., 2010;Casanova et al., 2012;Sokhadze et al., 2014). ASD diagnosis was performed according with DSM criteria in all the studies whereas only 4 studies (Sokhadze et al., 2009;Baruth et al., 2010;Casanova et al., 2012;Sokhadze et al., 2014) included a standardised assessment according with international recommendations (Lord et al., 1994). Only 2 of the included studies were designed to account for clinical efficacy as primary outcome (Enticott et al., 2014;Panerai et al., 2014). On the basis of the reported data the majority of the retrieved studies included a mixed population of both children and young adults (range from 9 to 59 years old). Female proportion of the included samples mirrored ASD gender distribution in the general population (see Table 1 for an overview of the included studies). According with the Cochrane risk of bias assessment tool the overall quality of the included studies was poor. Specifically, randomization sequence generation was unclear in each trial, blinding of personnel was missing and outcome assessment was blind only in 2 studies. Furthermore, outcome measures were not adequately reported to ensure independent evaluation of the trial results (Figure 2 and 3). Four studies were conducted by the same research group and the possibility of an overlapping sampling could not be excluded (Sokhadze et al., 2009;Baruth et al., 2010;Casanova et al., 2012;Sokhadze et al., 2014). There was no effect of TMS on social interaction and communication. However, Enticott et al. (2014) reported an improvement in the Social Relatedness subscale of the RAADS in the TMS group as compared with sham. This could not be deemed as reliable clinical outcome measure as the instrument rely on subjective report and as not been designed nor validated for clinical purposes. The main effect reported for TMS is the reduction of repetitive behaviour as measured with RBS (Sokhadze et al., 2009;Baruth et al., 2010;Casanova et al., 2012;Sokhadze et al., 2014). However only for Casanova et al. (2012) the effect of the TMS vs waiting list was reported on the paper. The other studies reported only the pre post change in the active treatment group without comparing the hypothesised statistical analysis. The second main effect was on Irritability as measured with ABC (Baruth et al., 2010;Casanova et al., 2012;Sokhadze et al., 2014). The aforementioned limitation applied also for this outcome measure. Of note (Sokhadze et al., 2014) reported a reduction in irritability and lethargy but again no direct between group comparison was performed. One study employed the PEP as a measure of clinical efficacy in ASD subjects with mental retardation (Panerai et al., 2014). Specifically, high frequency TMS improved performance as compared with both low frequency TMS and sham. However, this effect did not survive multiple comparison correction according with Bonferroni’s method. Discussion Three independent research groups have investigated the clinical effect of TMS in ASD with RCT. No clear effect on the social impairment has emerged so far when considering the validated clinical assessment tools. More promising findings regarding repetitive behaviour and irritability have been reported. However, the direct comparison between TMS and control conditions deserve further investigations. Overall, the significant risk of bias, the sparse use of an adequate sham control and short length of follow-up limited the generalizability of the results. Furthermore, the majority of the trials have not been specifically designed to address clinical outcome as primary aim. This is specifically true considering the small sample sizes enrolled and the short follow-up length which could increase the risk of type I and II statistical errors. Further stages of our study will include contacting the author of the retrieved studies to obtain additional information about possible overlapping datasets and missing data in order to perform a quantitative synthesis.

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Acknowledgements

The authors declare no conflict of interest.

References

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Keywords: TMS, ASD autism spectrum disorders, rct, Systematic review, Asperger Syndrome

Conference: The Cerebellum inside out: cells, circuits and functions , ERICE (Trapani), Italy, 1 Dec - 5 Dec, 2016.

Presentation Type: poster

Topic: Neuropathologies

Citation: Rocchetti M, Monaco J, Casiraghi L, Politi P and Brondino N (2019). Clinical application of Transcranic Magnetic Stimulation in Autism Spectrum Disorder. Preliminary results of a systematic review. Conference Abstract: The Cerebellum inside out: cells, circuits and functions . doi: 10.3389/conf.fncel.2017.37.000010

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Received: 28 Nov 2016; Published Online: 25 Jan 2019.

* Correspondence: MD. Matteo Rocchetti, University of Pavia, Department of Brain and Behavioral Sciences, Pavia, Italy, matteo.rocchetti@unipv.it