rTMS in Child and Adolescent Psychiatry: A Literature Review.

H. BELHADGA, Z. MAATAOUI AND H. KISRA

Ar-Razi University Psychiatric Hospital, Salé.

Faculty of Medicine and Pharmacy.

Mohammed V University of Rabat- Morocco.

Abstract:

Transcranial magnetic stimulation (TMS) is an emerging neuropsychiatric tool with therapeutic and research applications. The three most common types of TMS delivery include single-pulse, paired-pulse, and repetitive transcranial magnetic stimulation (rTMS).

The largest trial to date was a multicenter, doubleblind, sham-controlled trial of 301 subjects with MDD which involved high frequency stimulation of the LDLPFC, five times per week at 120% motor threshold for 4 to 6 weeks. In 2008, this culminated in US Food and Drug Administration (FDA) clearance for rTMS treatment of adults with MDD who have failed one previous medication trial of an adequate dose and duration. Previously, rTMS has been approved for treatment refractory depression in other countries such as Israel and Canada.

The purpose of this paper is to present an overview of rTMS research in child and adolescent psychiatry. Literature was reviewed and collected with Sciencedirect, CAIRN, Google Scholar, NCBI and PubMed searches.

Keywords: rTMS, noninvasive, neurostimulation, child, adolescent.

Introduction:

Transcranial magnetic stimulation (TMS) is an emerging neuropsychiatric tool with therapeutic and research applications. Dr. Anthony Barker and his associates first developed transmagnetic stimulation (TMS) in 1985 when they observed movement in the right hand upon holding a conducting coil to the scalp above the left cerebral motor strip [1]. This involves the non-invasive stimulation of cortical neurons by means of a rapidly changing magnetic field which induces weak electric currents in the brain [2].

The three most common types of TMS delivery include single-pulse, paired-pulse, and repetitive transcranial magnetic stimulation (rTMS).

Overall, TMS is considered safe with the most serious risk involving the accidental induction of seizures. With proper safety precautions the risk of seizure from rTMS and TMS is low (0.1 – 0.6%). Other potential risks include syncope, scalp discomfort, and changes in auditory thresholds.

The largest trial to date was a multicenter, doubleblind, sham-controlled trial of 301 subjects with MDD which involved high frequency stimulation of the LDLPFC, five times per week at 120% motor threshold for 4 to 6 weeks. In 2008, this culminated in US Food and Drug Administration (FDA) clearance for rTMS treatment of adults with MDD who have failed one previous medication trial of an adequate dose and duration. Previously, rTMS has been approved for treatment refractory depression in other countries such as Israel and Canada[2].

Despite promising potential in the diagnosis, examination, and treatment of psychiatric disorders in adults, this technology has had somewhat limited use in children and adolescents thus far.

Methods:

The purpose of this paper is to present an overview of rTMS research in child and adolescent psychiatry. Literature was reviewed and collected with Sciencedirect, CAIRN, Google Scholar, NCBI and PubMed searches. Search terms included adolescent (including psychiatry and psychology), anxiety disorder, attention deficit hyperactivity disorder, autism spectrum disorder, bipolar disorder, child (including psychiatry and psychology) major depressive disorder, mood disorder, schizophrenia, Tourette’ s syndrome, transcranial magnetic stimulation. Articles describing the delivery of rTMS in children and adolescents were included.

Therapeutic rTMS in child and adolescent psychiatry :

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive brain stimulation tool with potential for broad application in individuals with neuropsychiatric conditions. As in adults, most rTMS research in youth has focused on treatment-resistant depression. A limited number of rTMS studies have also been conducted in children and youth with primary diagnoses of Autism Spectrum Disorder (ASD), Attention-Deficit/Hyperactivity Disorder (ADHD) or Tourette’s syndrome. Across the available rTMS literature, rTMS appears to be well tolerated with few adverse effects reported when applied to child and youth research samples. However, the potential efficacy of rTMS treatment for a variety of targets in children and youth remains unclear, due in part to limitations of the current literature, including studies using diverse protocols, potential for bias in existing clinical trial designs, variability in the research samples, and the use of heterogenous outcome measures. While rTMS is unlikely to take the place of more accessible treatments (e.g., psychopharmacological, psychosocial, psychotherapeutic), rTMS may provide a valuable alternative treatment option, particularly for those individuals where conventional treatments are inaccessible, poorly tolerated, or ineffective. A more robust body of well-designed, controlled trials, is needed in order to clarify rTMS treatment efficacy across relevant neuropsychiatric conditions, optimize treatment protocols, and meet the critical need for novel mental health interventions in children and youth[3].

In children and adolescents with autism spectrum disorder:

The term autism spectrum disorder (ASD) describes a range of conditions characterized by impairments in social interactions, communication, and by restricted and repetitive behaviors. Autism spectrum disorder may also present with symptoms suggestive of autonomic nervous system (ANS) dysfunction. A study which has the objective to determine the effect of 18 sessions of low frequency (LF) repetitive transcranial magnetic stimulation (rTMS) on autonomic function in children with ASD by recording electrocardiogram (ECG) and electrodermal activity (EDA) pre- post- and during each rTMS session is realised by M.F. Casanova et al. (USA; 2014). Behavioral evaluations post-18 TMS showed decreased irritability, hyperactivity, stereotype behavior and compulsive behavior ratings while autonomic measures indicated a significant increase in cardiac interval variability and a decrease of tonic SCL. The results suggest that 18 sessions of LF rTMS in ASD results in increased cardiac vagal control and reduced sympathetic arousal[4].

In a Short-Term Study on Non-Invasive Brain Stimulation for Children with Autism Spectrum Disorders. Twenty-four patients with ASD (mean age: 12.2 years) received 20 sessions of rTMS over the left dorsolateral prefrontal cortex. The total score on the Autism Behavior Checklist, Autism Treatment Evaluation Checklist, and the Autism Diagnostic Interview were used to determine the short-term outcome. A significant reduction in the total score on the three clinical scales was observed and maintained during the first six months after treatment, with a slight and non-significant tendency to increase the scores in the last evaluation. Twenty sessions of NIBS over the L-DLPFC improves autistic symptoms in ASD children, with a lasting effect of six months[5].

In the systematic review of MASUDA and al. examined literature on repetitive transcranial magnetic stimulation for children and adolescents with neurodevelopmental disorders published up to 2018, confirmed that No severe adverse effects were reported and that In patients with autism spectrum disorder, low-frequency repetitive transcranial magnetic stimulation and intermittent theta burst stimulation applied to the dorsolateral prefrontal cortex may have therapeutic effects on social functioning and repetitive behaviors[6].

Meta-analyses of Barahona and al. 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 integrated 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[7].

In A 4-week randomized blinded controlled trial followed by another 4-week open-label intervention, in a hitherto, largest sample of intellectually able children with autism realised on 78 patients. Continuous 8-week intermittent theta burst stimulation on the bilateral posterior superior temporal sulcus in children with autism is safe and tolerable, and it produced greater therapeutic efficacy, although, there is no significant effects of 4-week intermittent theta burst stimulation on core symptoms and social cognitive performances in autism. Further analysis revealed that participants with higher intelligence and better social cognitive performance, alongside less attention-deficit hyperactivity disorder severity at baseline, were more likely to be responders[8].

In a pilot randomized, double-blind, parallel, controlled trial evaluating repetitive transcranial magnetic stimulation (rTMS) for executive function’s deficits in ASD realised on 16-35-year-olds with ASD (28 male/12 female), without intellectual disability. No evidence for efficacy of active versus sham rTMS on EF performance was found. However, promising preliminary evidence of EF performance improvement following active versus sham rTMS in participants with ASD with more severe adaptive functioning deficits was found[9].

Table-1: Original studies on TMS use in children and adolescents with autism spectrum disorder.

Study	Year	Study Type	Sample size and type	rTMS type	Length	Results
Casanova and al.	2014	Prospective follow up study	18 children with ASD (mean age = 13,1 years; 14 boys and 4 girls)	18 weekly inhibitory LF rTMS to dorsolateral prefrontal cortex DLFPC	18 weeks	Decreased irritability, hyperactivity, stereotyped behaviors, and compulsive behaviors.
Gomez and al.	2017	Short term, controlled, randomized and partial crossover study	24 children with ASD (mean age = 12,2 years)	20 sessions of left DLPFC rTMS	2 years	Significant reduction in scores (autism behavior checklist, autism treatment evaluation checklist, and autism diagnostic interview). And lasting effect of 6 months.
Barahona and al.	2018	Systematic review and meta-analysis	23 studies (4 case reports, 7 non-controlled clinical trials and 12 controlled clinical trials	rTMS	–	Significant but moderate effect on repetitive and stereotyped behaviors, and number of errors in executive functions.
Masuda and al.	2019	Systematic review	14 studies included	Low frequency rTMS and theta burst stimulation of DLPFC	–	Evidence of therapeutic effect on social functioning and repetitive behaviors.
Ameis and al.	2020	Double blind, sham controlled, clinical trial	40 patients (28 males, 12 females; 16-35 years) with ASD	20 Hz rTMS targeting DLPFC	4 weeks	No significant efficacy on executive function’s performances in patients
Chang Ni and al.	2021	Single blind, sham controlled, parallel randomized, clinical trial	78 children with ASD, intellectually able.	8 weeks intermittent theta burst stimulation rTMS.	8 weeks	Safety of this protocol of rTMS. Significant therapeutic efficacy on core symptoms and social cognitive performance.

In children and adolescents with depression:

Transcranial Magnetic Stimulation (TMS), a form of Non-Invasive Brain Stimulation (NIBS), has gained popularity in the last couple of decades. It is approved for treating depression in adults and is under investigation in pediatric depression. Recent evidence suggests that in pediatric patients of treatment-resistant depression, repetitive Transcranial Magnetic Stimulation (rTMS) of the frequency of 10 Hz when applied to the left dorsolateral prefrontal cortex (DLPFC), can lead to remission, improvement in depressive symptoms, or decrease in recurrence of episodes. Existing literature also suggests that TMS’s adverse effects in the pediatric population are minimal and comparable to those in the adult population. However, the limitations of existing studies, including lack of double-blind sham-controlled randomized trials or RCTs (only one RCT exists to date), small sample sizes, absence of long term follow-ups, and lack of homogenous age distribution, render the evidence insufficient for approval of TMS use in pediatric depression[10].

Table-2: Original studies on TMS use in children and adolescents with treatment-resistant major depressive disorder (MDD) or depressive symptoms[10].

List of abbreviations: RCT: Randomized Control Trial; rTMS: Repetitive Transcranial Magnetic Stimulation; DLPFC: Dorsolateral prefrontal cortex; SEs: Side effects; SMA: Supplementary Motor Area; sp/pp TMS: Single-pulse/paired-pulse TMS; MDD: Major Depressive Disorder; Hz: Hertz

Another more recent systematic review summarized the findings of fourteen publications using rTMS in young people aged 12-25 years with depression. Thirteen of these studies included adolescents with treatment resistant depression (TRD) which was most commonly defined as at least one failed antidepressant trial. Eight of these 14 studies were independent open-label trials (uncontrolled) (total N=142 participants across studies), and six publications reported on secondary analyses using data acquired in the original open-label studies. Although the summarized research indicated that a course of rTMS reduced depression scores in adolescents, design challenges present in each of the available trials limit the ability to draw firm conclusions regarding treatment efficacy[11].

In children and adolescents with ADHD:

In the systematic review of MASUDA and al., In patients with attention deficit/hyperactivity disorder, low-frequency repetitive transcranial magnetic stimulation applied to the left dorsolateral prefrontal cortex and high-frequency repetitive transcranial magnetic stimulation applied to the right dorsolateral prefrontal cortex may target inattention, hyperactivity, and impulsivity.

Three studies in a recent systematic review have applied rTMS in children and youth with ADHD, targeting either motor or DLPFC sites; including two randomized sham-controlled studies and one open-label tolerability and safety study, each including ≦25 participants, age range=7-20 years, and using heterogeneous treatment protocols. While Weaver et al. showed reduced ADHD symptoms following active rTMS, differences between sham and active rTMS arms were not significant. Helfrich et al. suggested a decrease in intracortical inhibition but did not study change in clinical/behavioural symptoms after rTMS, and Gómez et al. noted that qualitative reports from parents and teachers revealed improvements in inattentiveness and hyperactivity/impulsivity[3].

In children and adolescents with Tourette’s syndrome and tic disorders:

Neurostimulation is an alternative to behavioral therapy and medication. The number and the range of Neuropsychiatric disorders treated with repetitive transcranial magnetic stimulation (rTMS) continue to grow. Several small studies have suggested improvement in tic severity after rTMS for TS, whereas others have found no change. A pilot study of rTMS in children with TS used a novel functional MRI (fMRI) targeting design for ADM targeting. This pilot study showed significant improvements in tic severity in all participants (N=10, 8M, mean age 11.52 years) after 15 sessions of low-frequency (1 Hz) rTMS on the SMA (1800 stims/session). The mean decrease in tic severity was 60.4% (range 38.1% to 74.1%) according to the Yale Global Tic Severity Scale (YGTSS)[12].

Three studies have used rTMS to reduce tics targeting the supplementary motor area (SMA) due to its connections with cortical and subcortical motor areas [13]. Only the study by Wu et al. involved a randomized, double blinded, sham controlled design. In this study, participants with Tourette syndrome/chronic tic disorders between 10 and 22 years of age (n=12) were randomized to functional MRI navigated sham or active 30Hz continuous theta burst stimulation (cTBS) on two consecutive days. No differences in tic reduction were identified between active and sham groups, though cTBS was well tolerated [14].

In a recent study, ten children with Tourette syndrome (eight males, two females; 9–15y) participated in an open-label, phase 1 clinical trial. Treatment consisted of 1800 low-frequency (1Hz) neuronavigated robotic rTMS (100% resting motor threshold) to the SMA, bilaterally for 15 sessions. The primary outcome was a decreasing in Yale Global Tic Severity Scale (YGTSS) total score from baseline to posttreatment and All procedures were well-tolerated[15].

In children and adolescents with schizophrenia:

Jardri et al. reported on the treatment of an 11-year-old boy with medication resistant schizophrenia. This patient had a high level of impairment, aggression, and had struggled with delusions and hallucinations for 2 years. Antipsychotic medications had been ineffective and problematic due to side effects. An fMRI scan displayed increased auditory cortex activity with concurrent auditory hallucinations. This boy subsequently received 10 sessions of 1 Hz rTMS administered to the left temporoparietal cortex. His auditory hallucinations decreased by 50% as assessed by the Auditory Hallucinations Rating Scale. His progress was maintained with repeated sessions over 5 weeks. Based on the Children’s Global Assessment Scale his functioning improved as well. As a result, he was discharged home, and returned to school. There were no side effects or adverse effects during the rTMS treatment course[16].

Expected benefits of rTMS in children and adolescents:

Currently, 40% of adolescents with major depressive disorder (MDD) fail to respond to treatment with an antidepressant medication or evidence-based psychotherapy, resulting in treatment-resistant depression. In successfully treated youth, the relapse rates for depression are as high as 50-75%. Additional limitations include the need for monitoring adherence to antidepressant medications which are often discontinued due to difficulties tolerating side effects. In autism, there are no effective biomedical interventions that target core symptoms. Although rTMS requires a commitment of time and resources up front, it is an attractive option as it targets specific brain circuitry, treatment can be personalized and its use may limit or eliminate the need for long term medication treatment or monitoring for adherence. rTMS may also be helpful in minimizing multiple psychotropic medication treatments used in treating refractory depression and the resulting exposure to adverse effects.

While rTMS is unlikely to take the place of more accessible treatments, rTMS may in future provide a valuable alternative mental health treatment option, particularly for those individuals where conventional treatments are inaccessible, poorly tolerated, or ineffective. The fact that at least half of mental health conditions have their onset in the adolescent period and evidence that ineffective treatment leads to long term morbidity underscores the critical need to develop promising new mental health treatments for children and youth. Thus, while rTMS is not clinic-ready for any mental health target in children and youth, for the above reasons, further research and development of rTMS intervention options are critically needed[3].

Conclusion:

rTMS is a non-invasive tool with applications in clinical and neurophysiological research. At present the majority of psychiatric studies involve adult depression. However, researchers are now utilizing this modality in pediatric populations. Ethical principles and mitigation of risks for vulnerable subjects must remain at the forefront of every study in this area.

Future work in this area could serve to develop rTMS as a clinical intervention in child and adolescent psychiatry and a tool for developmental neuroscience. This will involve optimization of stimulation site, stimulation parameters, and the role of rTMS in existing treatment guidelines.

References:

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