Isabelle Mawby, BS (4th Year Medical Student)
Association for Science in Autism Treatment

Description:

Autism Treatments SummaryRepetitive transcranial magnetic stimulation (rTMS) is a non-invasive technique based on electro-physical principles (Iglesias, 2020). Although first discovered in 1985, non-invasive brain stimulation techniques such as rTMS have recently been gaining attention given their ease of application and tolerability (Camsari et al., 2022). The TMS device itself is made of one or two copper coils that induce a brief magnetic pulse to cortical and subcortical areas of the brain (Barker, 2017). While not fully understood, this magnetic pulse creates an electrical current and leads to neuronal depolarization, which activates the cortical and subcortical networks of the brain (Iglesias, 2020; Barker, 2017). It is thought that such activation of specific networks in the brain may assist in treating behavioral and cognitive manifestations of autism spectrum disorder (ASD) (Oberman et al., 2016).

Research Summary:

Limited evidence demonstrates the potential efficacy of rTMS for improving aspects of diseases such as fibromyalgia, Parkinson’s disease, motor strokes, post-stroke aphasia, multiple sclerosis, Alzheimer’s disease, and depression (Lefaucher et al., 2020; Iglesias, 2020). However, there has been limited research on rTMS as an ASD treatment. One 2014 double-blind randomized, placebo-controlled trial of 28 adults with ASD was performed to examine whether deep rTMS improved social relating in ASD (Enticott et al., 2014). The authors found that deep rTMS yielded a significant reduction in self-reported social-relating impairment and anxiety. However, this study was significantly limited by a small sample size and unclear generalizability to younger and severely intellectually disabled individuals with ASD (Enticott et al., 2014). Similarly, in 2019, 32 children with autism were enrolled in a preliminary pilot study to determine the effects of rTMS on behaviors such as sensory behaviors (e.g., covering ears at many sounds, poor use of visual discrimination when learning), social relating (e.g., social smile, does not reach out when reached for), body and object use (e.g., does not use toys appropriately, flaps hands), language and communication skills (i.e. has pronoun reversal, speech is atonal), and social and adaptive skills (e.g., difficulties with toileting, does not dress self without frequent help) (Kang et al., 2019). Sixteen children received rTMS twice every week and 16 children did not receive rTMS at all (waitlist control group). The study demonstrated that children who received rTMS showed significant increases in peak alpha frequency, which is a measurement of cognitive preparedness and may potentially be a neural marker of cognitive function for autism. The rTMS group also showed significant improvements on a parent-completed behavior rating scale (Autism Behavior Checklist) administered before and after rTMS treatment, with the most change specifically seen in improvement of social relating skills and total score (Kang et al., 2019).

Unfortunately, this study was also significantly limited by a small sample size, as well as the absence of important features such as inclusion of a sham rTMS control group (a fake procedure was performed on the control group to ensure that they experience the same incidental effects of the procedure)matching of the treatment group and controls for autism severity, and administration of the behavioral outcome measure to the control group. In fact, all literature on the use of rTMS for children and adolescents with ASD has been limited by sample size, and a large, randomized controlled trial of rTMS in children with ASD has yet to be performed (Masuda et al., 2019).

A 2020 review aimed at analyzing how rTMS may be used as a treatment for ASD looked at the potential therapeutic on a neuropathological level (Casanova et al., 2020). Through an analysis of multiple previously published studies, the authors explained that rTMS targets a cortical inhibitory neurotransmitter imbalance, which may play a role in the pathophysiology of autism (Casanova et al., 2020). Thus, based on our current (but limited) knowledge of autism neuropathology, the authors hypothesize that rTMS may hold the ability to improve a broad array of skills related to executive function (Casanova et al., 2020). Notably, the authors reiterated the need for large sample clinical trials with targeted inclusionary/exclusionary criteria and longitudinal clinical follow-up to better assess rTMS as a possible treatment for ASD (Casanova et al., 2020; Fetit et al., 2021).

Importantly, while the concept of brain stimulation may sound frightening, patients who received rTMS have reported experiencing relatively little discomfort (O’Reardon et al., 2007). Regarding additional side effects, it has been reported that rTMS has similar side effects in children, adolescents, and adults, all of which are generally limited. In a 2015 systematic review entitled “Safety of Noninvasive Brain Stimulation in Children and Adolescents,” authors Krishnan et al. examined the data from over 48 studies. The systematic review found that among 513 children/adolescents (2.5-17.8 years of age), the major side effects of TMS were mild and transient headache (11.5%), scalp discomfort (2.5%), twitching (1.2%), mood changes (1.2%), fatigue (0.9%), and tinnitus (0.6%). However, it is essential to note that of the 513 children/adolescents studied, only 138 of these individuals had previously been diagnosed with ASD. One must be cautioned side effects and outcomes of rTMS have not yet been thoroughly studied.

Officially, an international rTMS in Autism Consensus Group met in 2014 and has since met annually to discuss the potential of rTMS as an ASD treatment. In their most recent 2019 publication, a Consensus Statement described clear limitations in the use of rTMS in ASD treatment (Cole et al., 2019). In accordance with the prior studies discussed, such limitations included the need for further research on the dose, type, intersession intervals, and exact parameter setting of rTMS (Cole et al., 2019). The rTMS in Autism Consensus Group also noted that no studies have addressed the heterogenous nature of ASD when analyzing the efficacy of rTMS, which will be important to accommodate for in future research. Davis (2014) pleaded for extreme caution regarding the use of TMS on the developing brain, noting the potential promise but the unknown long-term effects and side effects, lack of clear dosing guidelines, and lack of translational studies from adults to children.

Recommendations:

There is currently no strong evidence demonstrating that rTMS is an effective treatment for autism. The studies on the utility of rTMS as an autism treatment have been significantly limited by small sample sizes, inconsistent use of placebo protocols, and subjective clinical assessments. As the Autism Consensus Group described, there are large gaps in the scientific knowledge of how rTMS works. This is a crucial point, as without detailed knowledge of the underlying mechanisms of rTMS and its role as an autism treatment, it is impossible to confidently recommend rTMS for children with ASD. There also remain significant gaps in our knowledge on proper dosing as well as the side effects of stimulation. Finally, it is important to note that other noninvasive brain modulation techniques such as intermittent theta burst stimulation, continuous theta burst stimulation, and transcranial direct current stimulation have been studied to a similar (if not lesser) extent as rTMS, and there is no strong evidence supporting their use as treatments for ASD, either. Ultimately, only with tremendous further research on the safety and efficacy of rTMS, alongside additional studies on its utility for a wide variety of individuals on the autism spectrum, does rTMS hold therapeutic potential.

Authors Note: We would like to thank Dr. Scott Myers for his feedback on prior drafts of this treatment summary.

Selected References

Systematic Reviews

Barker, A. T., & Shields, K. (2017). Transcranial magnetic stimulation: Basic principles and clinical applications in migraine. Headache, 57(3), 517-524. https://doi.org/10.1111/head.13002

Casanova, M. F., Sokhadze, E. M., Casanova, E. L., & Li, X. (2020). Transcranial magnetic stimulation in autism spectrum disorders: Neuropathological underpinnings and clinical correlations. Seminars in Pediatric Neurology, 35, 100832. https://doi.org/10.1016/j.spen.2020.100832

Doruk Camsari, D., Kirkovski, M., & Croarkin, P. E. (2018). Therapeutic applications of noninvasive neuromodulation in children and adolescents. The Psychiatric Clinics of North America, 41(3), 465-477. https://doi.org/10.1016/j.psc.2018.05.003

Fetit, R., Hillary, R. F., Price, D. J., & Lawrie, S. M. (2021). The neuropathology of autism: A systematic review of post-mortem studies of autism and related disorders. Neuroscience & Biobehavioral Reviews, vol. 129, 2021, pp. 35-62., https://doi.org/10.1016/j.neubiorev.2021.07.014.

Iglesias, A. H. (2020). Transcranial magnetic stimulation as treatment in multiple neurologic conditions. Current Neurology and Neuroscience Reports, 20(1), 1. https://doi.org/10.1007/s11910-020-1021-0

Lefaucheur, J. P., Aleman, A., Baeken, C., Benninger, D. H., Brunelin, J., Di Lazzaro, V., Filipović, S. R., Grefkes, C., Hasan, A., Hummel, F. C., Jääskeläinen, S. K., Langguth, B., Leocani, L., Londero, A., Nardone, R., Nguyen, J. P., Nyffeler, T., Oliveira-Maia, A. J., Oliviero, A., Padberg, F., … Ziemann, U. (2020). Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018). Clinical Neurophysiology: Official Journal of the International Federation of Clinical Neurophysiology, 131(2), 474-528. https://doi.org/10.1016/j.clinph.2019.11.002

Masuda, F., Nakajima, S., Miyazaki, T., Tarumi, R., Ogyu, K., Wada, M., Tsugawa, S., Croarkin, P. E., Mimura, M., & Noda, Y. (2019). Clinical effectiveness of repetitive transcranial magnetic stimulation treatment in children and adolescents with neurodevelopmental disorders: A systematic review. Autism: The International Journal of Research and Practice, 23(7), 1614-1629. https://doi.org/10.1177/1362361318822502

Oberman, L. M., Enticott, P. G., Casanova, M. F., Rotenberg, A., Pascual-Leone, A., McCracken, J. T., & TMS in ASD Consensus Group (2016). Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. Autism Research: Official Journal of the International Society for Autism Research, 9(2), 184-203. https://doi.org/10.1002/aur.1567

Selected Scientific Studies

Enticott, P. G., Fitzgibbon, B. M., Kennedy, H. A., Arnold, S. L., Elliot, D., Peachey, A., Zangen, A., & Fitzgerald, P. B. (2014). A double-blind, randomized trial of deep repetitive transcranial magnetic stimulation (rTMS) for autism spectrum disorder. Brain Stimulation, 7(2), 206-211. https://doi.org/10.1016/j.brs.2013.10.004

Kang, J. N., Song, J. J., Casanova, M. F., Sokhadze, E. M., & Li, X. L. (2019). Effects of repetitive transcranial magnetic stimulation on children with low-function autism. CNS Neuroscience & Therapeutics, 25(11), 1254-1261. https://doi.org/10.1111/cns.13150

O’Reardon, J. P., Solvason, H. B., Janicak, P. G., Sampson, S., Isenberg, K. E., Nahas, Z., McDonald, W. M., Avery, D., Fitzgerald, P. B., Loo, C., Demitrack, M. A., George, M. S., & Sackeim, H. A. (2007). Efficacy and safety of transcranial magnetic stimulation in the acute treatment of major depression: a multisite randomized controlled trial. Biological Psychiatry, 62(11), 1208-1216. https://doi.org/10.1016/j.biopsych.2007.01.018

Selected Reports of Side-Effects

Krishnan, C., Santos, L., Peterson, M. D., & Ehinger, M. (2015). Safety of noninvasive brain stimulation in children and adolescents. Brain stimulation, 8(1), 76-87. https://doi.org/10.1016/j.brs.2014.10.012

Oberman, L. M., Rotenberg, A., & Pascual-Leone, A. (2015). Use of transcranial magnetic stimulation in autism spectrum disorders. Journal of Autism and Developmental Disorders, 45(2), 524-536. https://doi.org/10.1007/s10803-013-1960-2

Position Statements and Warnings

Cole, E. J., Enticott, P. G., Oberman, L. M., Gwynette, M. F., Casanova, M. F., Jackson, S., Jannati, A., McPartland, J. C., Naples, A. J., Puts, N., & rTMS in ASD Consensus Group (2019). The potential of repetitive transcranial magnetic stimulation for autism spectrum disorder: A consensus statement. Biological Psychiatry, 85(4), e21-e22. https://doi.org/10.1016/j.biopsych.2018.06.003

Davis N. J. (2014). Transcranial stimulation of the developing brain: A plea for extreme caution. Frontiers in Human Neuroscience, 8, 600. https://doi.org/10.3389/fnhum.2014.00600

Citation for this article:

Mawby, I. (2023). A treatment summary of repetitive transcranial magnetic stimulation. Science in Autism Treatment, 20(03).

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