Transcranial magnetic stimulation (TMS) stands as a possible therapeutic modality for autism. Despite a number of positive studies, the FDA has not approved the same because of the lack of large scale trials that proving its safety and effectiveness. The possibility of conducting such studies is curtailed by FDA regulations requiring the acquisition of an Investigation Device Exemption (IDE) for the machine/technique under use.An IDE is required for any device that, according to the way it is used in a particular protocol, presents a potential for serious risk to the health, safety, or welfare of a subject.  The way the rules of the FDA are written, an IDE number can only be provided in applications having USA sponsors, meaning, that the manufacturers of the machine should have a presence within our country. This limits the possibility of acquiring an IDE as machines within the USA are highly expensive and often carry a heavy surcharge for every time you use the same.  In the end, even if TMS was approved for therapy in autism, the enormous cost of such a treatment would make it available to only a restricted portion of the population.  In the meantime, most researchers, myself included, that work with cheaper machines are unable to contribute to large scale clinical trials.

Before starting a discussion about the safety of TMS, primarily as applied to children, I should make a distinction between single pulse and repetitive (rTMS) therapy. rTMS has lasting aftereffects that could promote therapeutic benefits, while no such benefits can be derived from single and paired pulse TMS (Gilbert et al., 2004). Single pulse TMS is therefore not used in clinical therapeutic trials but rather as a means to study, among many possibilities, neurophysiological mechanisms, mapping motor cortical outputs, and determining central motor conduction time. Both rTMS and single pulse TMS are safe and well tolerated in the pediatric population (see discussion below).

I recently did a computerized search of the published literature regarding the safety of TMS in children and adolescents and will proceed to discuss the same while emphasizing results of 2 review articles on the subject. Our computerized search was based on PubMed and included the following combination of terms: TMS, safety, adolescents, and children. I eliminated the non-pertinent results and pursued those brought about as “similar” or being cited in the corresponding publications. The final list is enumerated in the reference section at the end of this document.

TMS appears to be a safe technique for use in the pediatric population. Indeed, conventional structural MRI and fMRI are normal even after long duration high-intensity rTMS. There are no adverse long-term effects or sustained changes in cognitive functions. More specifically, there are no adverse effect seen on subject’s performance on standard neuropsychological tests after either single pulse TMS or rTMS. Although a review of the animal literature falls outside of the scope of this response, there have been numerous studies showing no histological abnormalities in TMS treated rodents (for a review see Gilbert et al., 2004). Repetitive TMS has been applied in children with psychiatric disorders such as ADHD, ADHD with Tourette’s, and depression (Quintana, 2005). Although there are relatively limited studies using rTMS in children, these studies do not report significant adverse effects.

Gilbert et al. (2004) article was meant to be a useful reference to internal review boards (IRBs) for when they had to make a determination as to whether TMS is a minimal risk device when used in children. The study was based on a MEDLINE review (restricted in part to the terms HUMAN and ENGLISH) that attempted to establish any evidence of risk from TMS administration. The metaanalysis identified 28 studies involving over 850 children who underwent single or paired pulse TMS. Age range varied among the reported studies (2 to 26 years, but the majority were under 18 years of age). Site of stimulation varied among studies and were not tabulated. No changes in neuropsychological functions were reported. Mild transient side effects (e.g., scalp discomfort, headaches) resolved by the day following stimulation. The authors concluded that the experimental designs of the reviewed studies conveyed no more than minimal risk to children.

Rajalakse and Kirton (2013) did a metaanalysis reviewing all rTMS procols emphasizing those published since 2001. Among the many studies reported, 22 allowed for tabulation of both the TMS paradigm used and for reported significant side effects. The metaanalysis included 205 patients. Nine out of the 22 studies stimulated the prefrontal cortex or the dorsolateral prefrontal cortex. In only 1 of these studies the average age was over 18 (more specifically, 18.3 years). According to the authors, the reported studies collectively demonstrate the good safety and tolerability of rTMS. Indeed, only 1 subject withdrew from participating in a study due to scalp tenderness. The authors also added that, “Despite the wide variety of childhood neurological conditions being studied with TMS, including epilepsy and other conditions with lowered seizure thresholds, seizures have not been reported in children with single pulse TMS”.

The recent review of Krishnan et al. (2015) was an electronic search through, among others, MEDLINE, EMBASE, PubMed, and Web of Science. It covered any mention of TMS from its inclusion in the database up till 2014. From a total of 48 studies involving more than 513 children/adolescents (2.5-17.8 years range) indicate that the side effects of TMS were, in general, very mild and transient: headache (11.5%), scalp discomfort (2.5%), twitching (1.2%), fatigue (0.9%), etc. The duration or the interventions ranged from 1 day to 18 weeks, and the frequencies of stimulation ranged from 0.3 Hz to 10 Hz. Five studies stimulated over the frontal, DLPC or frontolateral area (Table 3 in their publication). No side effect as to the area of stimulation were reported.  The authors concluded that: “Our findings indicate that both repetitive TMS and tDCS are safe modalities in children with various neurological conditions”.

Oberman et al. (2015) reviewed the use of TMS specifically in autism spectrum disorders. Her studies covered a search in PubMed until May 2013 with the following key words: TMS autism, TMS Asperger, transcranial magnetic stimulation autism, and transcranial magnetic stimulation Asperger. A total of 17 studies were identified. From these studies rTMS was used in 8 as a therapeutic tool (Table 2 in their publication). These 8 studies involved 104 ASD individuals. Five of these studies used the dorsolateral prefrontal cortex as the site of stimulation. Side effects were minor. The authors called for more carefully designed and properly controlled studies to assess the therapeutic potential of TMS in ASD.

rTMS, when used in certain combinations of intensity and frequency, can provide for potential risks not seen with single pulse TMS.  The most significant of these complications is that of seizures. According to the Office of Good Clinical Practice when an IRB considers making a risk determination for a particular device. “The risk determination is based on the proposed use of a device in an investigation, and not on the device alone”. (http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM126418.pdf).

The FDA has drafted special control guidelines for the safe use of rTMS (http://www.fda.gov/RegulatoryInformation/Guidances/ucm265269.htm).  Table 2 of the aforementioned document describes the maximum safe train duration for avoiding seizures based on the available medical literature. At an intensity of 80-100% of motor threshold and a frequency of 1 HZ or less our studies fall on the safest published echelon. Our maximum safe train duration has been around 160 in comparison to the FDA’s reported train of over 1800 to ensure safety. Other commercial enterprises do not adhere to these safety standards and apply rTMS outside of research protocols. Families and individuals should be cognizant of all limitations before partaking in TMS trial having primarily a financial benefit for those using the technique.

References

Garvey MA, Mall V. Transcranial magnetic stimulation in children. Clin Neurophysiol 119(5):973-984, 2008.

Gilbert DL, Garvey MA, Bansal AS, Lipps T, Zhang J, Wassermann EM. Should transcranial magnetic stimulation research in children be considered minimal risk? Clin Neurophysiol 115(8):1730-9, 2004.

Helfrich C, Pierau SS, Freitag CM, Roeper J, Ziemann U, Bender S. Monitoring cortical excitability during repetitive transcranial magnetic stimulation in children with ADHD: a single-blind, sham-controlled TMS-EEG study. PLoS One 7(11):e50073, 2012.

Hong YH, Wu SW, Pedapati EV, Hom PS, Huddleston DA, Laue CS, Gilbert DL. Safety and tolerability of theta burst stimulation vs. single and paired pulse transcranial magnetic stimulation: a comparative study of 165 pediatric subjects. Frontiers Human Neuroscience 9:29, 2015

Krishnan C, SantosL, Peterson MD, Ehinger M. Safety of noninvasive brain stimulation in children and adolescents. Brain Stimul 8(1):76-87, 2015.

Oberman LM, Pascual-Leone A, Rotenberg A. Modulation of corticospinal excitability by transcranial magnetic stimulation in children and adolescents with autism spectrum disorder. Front Hum Neurosci 8:627, 2014., 2015.

Oberman LM, Rotenberg A, Pascual-Leone A. Use of transcranial magnetic stimulation in autism spectrum disorders. J Autism Dev Disord 45(2):524-

Quintana H. Transcranial magnetic stimulation in persons younger than the age of 18. J ECT 21(2):89-95, 2005.

Rajapakse T, Kirton A. Non-invasive brain stimulation in children: application and future directions. Transl Neurosci 4:217-223, 2013.

Rossi S, Hallet M, Rossini P, Pascual-Leone A, and The Safety of TMS Consensus Group. Clinical Neurophysiology 120:2008-2039, 2009.

Walter G, Tormos JM, Isrel JA, Pascual-Leone A. Transcranial magnetic stimulation in young persons: a review of known cases. J Child Adolesc Psychopharmacol 11(1):69-75, 2001.

Wassermann EM. Risk and safety of repetitive transcranial magnetic stimulation: report and suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic Stimulation, June 5-7, 1996. Electroencephalogr Clin Neurophysiol 108:1-16, 1998.