[protected]by Aksha M. Memon, MD, MPH

Dr. Memon is an Assistant Professor with the Department of Foundational Medical Studies at Oakland University William Beaumont School of Medicine in Rochester Hills, Michigan.

FUNDING: No funding was provided for this study.

DISCLOSURES: The author has no conflicts of interest relevant to the content of this article.

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ABSTRACT: Attention deficit/hyperactivity disorder (ADHD), one of the most common neurodevelopmental disorders, affected 3.3 million adolescents in the United States (US) in 2016. Ten to 30 percent of these patients do not respond to standard pharmacotherapy and, as a result, suffer adverse physical/mental health and socioeconomic consequences. Despite being approved by the US Food and Drug Administration (FDA) for treatment of adult depression, with evidence suggesting positive outcomes in children and adults in treatment of ADHD and good safety and tolerability records, there is no existent literature reviewing the efficacy, safety, and feasibility of use of transcranial magnetic stimulation (TMS) in the treatment of adolescent ADHD. Thus, We have conducted this review for which a thorough literature search was conducted on PubMed and PsycInfo databases using a combination of MeSH terms that yielded 32 articles, five of which satisfied the inclusion criteria. We observed objective improvements in ADHD treatment outcomes in adolescent patients who participated in a randomized, sham-controlled, crossover pilot study that assessed the safety and efficacy of TMS. The study participants did not suffer any major adverse events, which was also supported by findings from other studies. However, since only one study out of five included in the review is an interventional study with limited number of study participants, there is a need to conduct large-scale clinical trials that recruit a greater number of study participants to explore the clinical efficacy and safety of TMS in the treatment of adolescent ADHD patients who do not respond to or tolerate standard pharmacotherapy based on the preliminary data extracted to this end.

Keywords: TMS, transcranial magnetic stimulation, ADHD, attention deficit/hyperactivity disorder, adolescent

Innov Clin Neurosci. 2021;18(1–3):

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Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopment disorders in children in the United States (US), affecting 6.1 million children ages 2 to 17 years in 2016.¹ Of these, 3.3 million were adolescents, between the ages of 12 and 17 years.² In the US, with an average yearly increase of five percent, the percentage of ADHD diagnosis in children 4 to 17 years by a healthcare provider, as reported by parents, increased by 42 percent between 2003 and 2011.³ Children and adolescents diagnosed with ADHD, compared to their peers without the disorder, are at a higher risk of adverse academic, socioeconomic, and health consequences, such as poor school performance and social functioning, increased risk of hospitalizations, substance abuse and substance use disorder, and reduced earnings in adulthood.^4–6 The resulting healthcare costs and decreased individual and family productivity has a negative economic impact and adds to health care expenditure in the US.⁷ 

The US Food and Drug Administration (FDA) approves stimulants such as methylphenidate and amphetamine as conventional pharmacotherapy of children as young as 6 years of age and also adults with ADHD. These medications enhance the levels of dopamine, thus reducing hyperactivity in patients with ADHD. These drug treatments are effective in improving social and academic performance in patients with ADHD over the long term.⁸ However, 10 to 30 percent of patients do not respond to the conventional pharmacotherapy, and untoward adverse effects and potential for abuse can restrict the use in some.^9–11 The alternative medications approved by the FDA for the use in patients who do not tolerate stimulants are nonstimulants, such as atomoxetine, guanfacine, and clonidine. Besides medications and psychotherapy, patient and family education are other modalities that are employed in treating ADHD either singly or in combination with medications.¹²  Given the latency of therapeutic effects of psychotherapy and nonresponsiveness and intolerance to medications in some, transcranial magnetic stimulation (TMS) of the brain can emerge as an alternative therapeutic tool with better safety and tolerability in treating adolescents with ADHD.

An established neurophysiological research tool since its inception in 1985, TMS involves noninvasive brain stimulation by passing an electric current through conductive wires of an insulated coil that transfers energy through the skull; this generates an electric current in the brain, thus modulating cortical excitability via an induced magnetic field.^13,14  

Single pulse, paired pulse, and repetitive TMS (rTMS) are the three known methods of TMS delivery. Single pulse and paired pulse TMS protocols are diagnostic tools used to probe the neurophysiological correlates of hyperactivity in the motor cortex of patients with ADHD. rTMS, when used regularly, is a potential therapeutic tool capable of inducing long-term changes in targeted neural circuits.¹⁵ In 2008, the FDA approved the use of rTMS in treating adult patients with medication refractory major depressive disorder (MDD).¹⁶ Unlike adults, the use of rTMS in adolescents lacks any FDA-approved indication to date. Clinical trials are actively being conducted to investigate the role of rTMS as an alternative therapeutic modality in adolescents with medication refractory depression.¹⁷ With regard to treatment of medication refractory ADHD in adolescents, however, only a limited number of exploratory randomized clinical studies have been performed.¹⁸ Hence, I put together the existing published literature in this narrative review, examining the efficacy, safety, and feasibility of the use of TMS in clinical management of ADHD in adolescents. 

Methods

An electronic literature search was conducted on PubMed and PsycInfo databases in May 2020 without time limits using the combination of following MeSH terms in title, abstract, or as other terms to maximize sensitivity: “((“Adolescent”[Mesh]) OR teen* OR adolescen* OR “high school” OR “high schools” OR “young adult” OR “young adults” OR youth)) AND “Attention Deficit Disorder with Hyperactivity”[Mesh]) AND “Transcranial Magnetic Stimulation”[Mesh]”

This search yielded 32 references on PubMed that included all 21 references found on PsycInfo, plus additional 11 references with no exact duplicates. The following inclusion criteria were applied on these 32 references:

Publication type: Only peer-reviewed journal publications.  

Age: Studies including adolescents aged 13 to 17 years.

Studies examining the efficacy, safety, and feasibility of transcranial magnetic stimulation as a treatment modality in adolescents with ADHD. 

Articles published in nonpeer reviewed journals or published in languages other than English or including participants exclusively under 13 and/or over 18 years of age were excluded.^{15,18,19,21,22} Only five out of the 32 publications satisfied the above documented inclusion criteria and were selected for further detailed review and data extraction. The remaining 27 publications were excluded.

Results

The major finding of the literature search and review suggests that there are few clinical studies conducted to investigate the use of TMS as an alternative to drug treatment in adolescents suffering from ADHD that do not respond to standard pharmacotherapy. The following studies discussed the efficacy, safety, feasibility, and challenges surrounding the use of TMS as a therapeutic alternative.  

Rubio et al. A study conducted by Rubio et al¹⁵ reviewed literature around the use of non-invasive brain stimulation. It included TMS and transcranial direct current stimulation (tDCS) with regard to diagnostic and therapeutic applications and the safety and ethics of their use in pediatric ADHD. With regards to therapeutic efficacy of TMS in ADHD, the review draws the same conclusion that there are limited numbers of exploratory studies probing the use of TMS in treatment of pediatric including adolescent ADHD. 

A current study is underway on exploring the use of TMS for ADHD.²³ According to the safety data derived from studies on adult patients, common and less serious side effects include headache and scalp discomfort following TMS application. Preventable hearing loss and seizures induction mounts for rare and serious side effects secondary to rTMS use.²⁴ 

When used in 800 normal and more than 300 neurologically impaired children, TMS was associated with good safety and tolerability data without any reported hearing loss. Single or paired pulse TMS use in a pediatric population, including patients with epilepsy or cerebral palsy, did not induce seizures, concluding it’s safe use in children older than 2 years.²⁵ However, the use of rTMS for treatment of depression in an adolescent patient with multiple risk factors for seizures, including alcohol use during the previous night of TMS treatment, was associated with seizure induction.¹⁷ Thus, rTMS use is not recommended in children and adolescents in absence of compelling clinical indications due to a paucity of clinical safety data. 

The use of TMS is associated with induction of potentially irreversible changes in neural circuits that can be both good and bad, causing potential long-term effects on brain and cognitive development.^26,27 The pediatric population is especially sensitive to such exogenous neuromodulation given the plasticity of a developing brain, so the use of TMS in children and adolescent ADHD patients is also offset by ethical challenges. 

Weaver et al. Weaver et al¹⁸ conducted a randomized sham-controlled crossover trial to test the efficacy and safety of TMS as a treatment tool in patients diagnosed with ADHD based on Diagnostic and Statistical Manual, Fourth Edition, Text Revision (DSM – IV- TR) criteria. Six out of nine participants included in the study that satisfied the inclusion/exclusion criteria were 18 years of age or younger. The trial included a screening phase followed by two treatment phases of two weeks each; one phase had active treatment and the other was the sham phase with a one-week no-treatment interval in between. The participants were randomized on a 1:1 basis between the phases in this crossover trial. The participants underwent a washout from all types of medications prescribed for treatment of ADHD for duration of 7 to 12 days before the screening phase and during the rest of the trial. 

TMS was administered to the right dorsolateral prefrontal cortex (DLPFC) of participants at 10Hz, at 100 percent of the observed motor threshold, 2,000 pulses per session, five sessions per week, for 10 sessions total during the active phase. The primary efficacy outcome measure, the change in the Clinical Global Impression-Improvement Scale (CGI-I), and the secondary efficacy outcome measure, change in ADHD-IV scale, were assessed at baseline, midpoint, and at the end of the trial. TMS safety was assessed by testing air conduction audiometry, electroencephalogram (EEG) testing, and by performing a battery of neuropsychological tests at baseline, midpoint, and conclusion of the trial. The participants wore earplugs during all TMS sessions to reduce the risk of auditory damage. 

SAS 9.2 was used for statistical analysis of the final data, which suggested an improvement in CGI-I and ADHD-IV scales across both phases combined. However, no significant efficacy differences were observed between active and sham phases, which made it difficult to conclude about the efficacy of active TMS exclusively with a 95 percent confidence interval. On safety lines, TMS was well tolerated and safe, without any adverse events, such as seizures, EEG and audiometry changes, or any other serious adverse events leading to discontinuation of treatment. No adverse events potentially related to TMS were discovered in the month following the trial. 

The study findings are plagued by limitations of a small sample size, short course of treatment, and the crossover study design limitations showing overall improvement in efficacy across both phases due to the placebo effect thus hindering the generalizability of the findings. However, the study uncovers clinically relevant effects of TMS as a potential treatment option for adolescent ADHD, demanding further large-scale exploration . 

Croarkin et al. An article published by Croarkin et al¹⁹ summarized the therapeutic and research applications of TMS in child and adolescent psychiatry. Given the inadequacy of treatment options in this population, certain psychiatric conditions are difficult to treat, leading to multiple medication trials and frequent hospitalizations that enable adverse socioeconomic and health consequences for the affected individuals. This demands exploration of the use of rTMS as an alternative treatment option in the vulnerable adolescent patients with ADHD based on encouraging results discovered by Bloch et al²⁰ in their study on adult patients with ADHD.

Boes et al. The factors to be considered, in addtion to safety and efficacy, in promoting TMS as an alternative treatment modality for adolescent ADHD is feasibility of treatment in terms of cost effectiveness and time commitment. Unlike most medications, TMS cannot be self administered at home. TMS is yet to be completely explored and utilized, as an alternative treatment modality for ADHD. Thus, there is insufficient provider and patient education in this regard. A snapshot into these factors is presented in a paper published by Boes et al.²¹ Despite being approved by the FDA for treatment of medication refractory depression since 2008, many providers do not consider this as a treatment option given the lack of adequate education.¹⁶ This is why it is imperative to educate the current and future psychiatrists about the details of rTMS application to investigate and consider it as an alternative treatment option for adolescent ADHD. 

Masuda et al. A systematic review conducted by Masuda et al²² reviewed literature to investigate the clinical effectiveness of rTMS treatment in children and adolescents diagnosed with autism spectrum disorder (ASD), tic disorder, and ADHD. Per this latest review, trials conducted by Gomez et al⁹ and Weaver et al¹⁸ used rTMS as a treatment modality in children (aged 7–12 years) and adolescents (aged 14–21 years), respectively, for treatment of ADHD. Despite their differences in evaluation methods, behavioral rating scores demonstrated improvement following rTMS application in patients with ADHD. 

Research has established that changes in DLPFC play a vital role in pathophysiology of ADHD as measured by functional magnetic resonance imaging (fMRI) studies, which is supported by results from both these clinical trials. Low frequency rTMS application on left DLPFC and high frequency rTMS applied to the right DLPFC improved inattention, hyperactivity, and impulsivity in test subjects.^9,18,28

Discussion

To my knowledge, this is the first review of existing literature conducted to study the efficacy, safety, and feasibility of TMS in ADHD exclusively in adolescent patients. Most of the current studies, including literature reviews, have been conducted on children, in children and adolescents included, and some in adolescents including young adults. The literature search identified five publications that satisfied inclusion criteria.^{15,18,19,21,22}  Out of these, only one study by Weaver et al¹⁸ is a randomized control clinical trial, which happened almost 10 years ago. All other studies included are literature reviews.^15,19,21,22 Thus, the current number of randomized clinical trials performed to evaluate the efficacy, safety, and feasibility of TMS in treatment of adolescent ADHD is limited. Greater number of exploratory studies needs to be performed in adolescents with larger sample sizes because of the following compelling evidence that was uncovered from this literature review:

Existent literature suggests positive outcomes of TMS use in treatment of ADHD in children and young adults, including improvement in inattention at school and hyperactivity/impulsivity at home.^9,18 

There is a paucity of options to treat medication refractory ADHD in adolescents, as well as patients exhibiting intolerable adverse effects to medications demanding treatment cessation. Such adolescents are likely to suffer adverse mental, physical, and socioeconomic consequences leading to social and occupational dysfunctioning into adulthood due to untreated ADHD.^19,22 

TMS use in children and adults has been documented to be safe with minor side effects, such as scalp discomfort and headache.^15,18 Hearing loss can be prevented by using earplugs and has not been reported with cautious use. Seizure induction is a rare and serious occurrence, with the use of rTMS reported once in an adolescent patient who also had other risk factors favouring seizure induction.¹⁷ Overall, the safety data derived from the use of single- and paired-pulse TMS and rTMS for differing clinical indications has been satisfactory in trials conducted this far. 

Despite being FDA approved for use in treatment of depression in adults and the available safety data around its use in children, many providers do not consider TMS as a treatment option even in cases of compelling clinical indications.¹⁶ This is due to inadequate knowledge and a lack of formal training surrounding the use of TMS as a treatment modality.²¹ When treating adolescents with ADHD, one needs to consider other factors, such as the cost of treatment sessions and the time commitment required because, unlike most medications, TMS cannot be self administered. This can pose a major time constraint that affects treatment feasibility. 

Limitations

The strength of this review is that it collects all the existing literature surrounding the use of TMS exclusively in adolescent ADHD. However, this study does have limitations, particularly based on the fact that only one study out of the five included is an interventional study. Additonally, this review was conducted by only one author, so there is risk of selection bias with regard to article screening and selection. 

Conclusions

With the existing evidence regarding the efficacy and safety around the use of TMS in treatment of ADHD, more large-scale studies must be conducted to investigate its use in treating medication refractory and medication intolerance ADHD in adolescent patients. Current and future mental healthcare providers must be formally educated and trained about using TMS as an alternative to medications and/or behavioral interventions in adolescents in presence of compelling clinical indications including but not limited to ADHD.

 

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