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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 3  |  Issue : 3  |  Page : 681-686

Long-term effects of repetitive transcranial magnetic stimulation on a sample of children with autism spectrum disorder


Department of Psychiatry, Faculty of Medicine, Al-Azhar University, Cairo, Egypt

Date of Submission15-Oct-2019
Date of Decision15-Oct-2000
Date of Acceptance17-Nov-2019
Date of Web Publication10-Feb-2020

Correspondence Address:
Amgad A Moshref Gabr
Department of Psychiatry, Faculty of Medicine, Al-Azhar University, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/sjamf.sjamf_83_19

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  Abstract 


Introduction Autism spectrum disorder (ASD) is one of the most common child psychiatric disorders, with a prevalence estimated at 1.1% of the population. Children diagnosed with ASD differ from typically developing children on many cognitive and behavioral dimensions, and therefore the term ‘spectrum’ is used to emphasize its full scope. Transcranial magnetic stimulation (TMS) is a promising, emerging tool for the study and potential treatment of ASD.
Aim To study long-term effects of repetitive transcranial magnetic stimulation (rTMS) on a sample of children with ASD.
Patients and methods The included sample consisted of 30 children with ASD, and their ages ranged from 4 to 10 years old. They were diagnosed clinically according to Diagnostic and statistical manual of mental disorders, fifth edition through a designed semistructured interview and through application of Childhood Autistic Rating Scale (CARS). There were five female children, representing a percentage of 16.7%, whereas 25 children were males, representing a percentage of 83.3%. All patients in the sample did not stop their medical or behavioral therapy for ASD. After 3-month follow-up, 24 children were reassessed again by CARS after stoppage of rTMS sessions.
Results The results of the study after the completion of 12 sessions of the rTMS showed that there is a significant difference and improvement in the severity of the clinical symptoms for ASD, except for the level of activity, listening response, and use of the body, by comparing the severity of symptoms before and after rTMS. On conducting statistical tests, the average measures of problems with respect to relationship with people, sensory responses, and verbal communication after sessions were relatively reduced. This relative decrease was found to be highly significant. The average measurements of problems such as imitation, emotional response and object use and visual response, fear or nervousness, nonverbal communication, level of consistency of intellectual response, general impression, as well as the total CARS score after conducting rTMS have relatively decreased, and it was found to be statistically significant. The average score in the CARS scale changed from 40.2 to 31.4 after 3 months of follow-up, and there was a change in the aforementioned results.
Conclusion This study concluded that rTMS over left dorsolateral prefrontal cortex may be a safe and effective way of providing temporarily relief of ASD symptoms, so maintenance therapy is recommended.

Keywords: autism spectrum disorder, neurobiology, repetitive transcranial magnetic stimulation, transcranial magnetic stimulation


How to cite this article:
Moshref Gabr AA. Long-term effects of repetitive transcranial magnetic stimulation on a sample of children with autism spectrum disorder. Sci J Al-Azhar Med Fac Girls 2019;3:681-6

How to cite this URL:
Moshref Gabr AA. Long-term effects of repetitive transcranial magnetic stimulation on a sample of children with autism spectrum disorder. Sci J Al-Azhar Med Fac Girls [serial online] 2019 [cited 2020 Feb 29];3:681-6. Available from: http://www.sjamf.eg.net/text.asp?2019/3/3/681/278047




  Introduction Top


Autism spectrum disorders (ASD) are organic neurodevelopmental disorders caused by genetic or neurobiological factors rather than by psychological or environmental ones [1]. ASD is manifested by deficits in social emotional reciprocity, deficits in nonverbal communicative behaviors used for social interaction, or deficits in developing, maintaining, and understanding relationships, with restricted and repetitive patterns of behavior [2]. The exact etiology is unknown, and it is likely that a combination of multiple genetic and environmental factors could result in ASD [3]. Nevertheless, significant progress has been made in characterizing the neuroanatomical underpinnings of ASD across the human life span, and in identifying the molecular pathways that may be affected in ASD. There is no pharmacotherapy that has shown to be effective in treating the core symptoms of ASD [4]. Treatments for the core symptoms of ASD focus on early intensive behavioral interventions [5]. Some clinical trials of pharmaceuticals or other interventions for core ASD symptoms are ongoing and many more are in the planning stages. Early and objective ASD diagnosis and improved understanding of the underlying ASD pathophysiology will be necessary. One way this may be accomplished is through transcranial magnetic stimulation (TMS), especially inhibitory repetitive transcranial magnetic stimulation (rTMS).


  Aim Top


The aim is to study the long-term effects of rTMS on a sample of children with ASD who attended the Al-Azhar University specialized hospital in the period from November 2018 to July 2019.


  Patients and methods Top


This prospective study was conducted at Al-Azhar University specialized hospital (Sayed Galal Hospital) on 30 children who were chosen randomly from those who came to the psychiatry clinic in Sayed Galal Hospital, Al-Azhar University, in the period from November 2018 to July 2019 to seek medical help and to complain about some behavioral and study problems. Their age ranged from 4 to10 years old. They were diagnosed clinically according to Diagnostic and statistical manual of mental disorders, fifth edition (DSM-5) through a designed semistructured interview and through application of Childhood Autistic Rating Scale (CARS). There were five female children, representing a percentage of 16.7%, whereas 25 children were males, representing a percentage of 83.3%. All patients in the sample did not stop their medical or behavioral therapy for ASD. All patients’ parents signed an informed written consent after explanation of the aim of the study and the study details and possible adverse effects.

The included children were subjected to three stages.

The first stage

  1. Taking a full medical history − general medical examination.
  2. Full psychiatric history to recruit and diagnose children with ASD clinically according to DSM-5 through a designed semistructured interview.
  3. Application of CARS.
  4. An assessment of the degree of clinical severity of ASDs (American Psychiatric Association, 2013) by Clinician-Rated Severity of Autism Spectrum and Social Communication Disorders.


The second stage

Application of TMS was done. The patients received rTMS over the left dorsolateral prefrontal cortex (DLPFC) for SIX sessions and then over the right DLPFC for six sessions, at low frequency of 1 Hz and intensity of 90% of motor threshold (15 trains×10 s, 150 pulse per session at 20–30 s interval) every week for a total of 12 consecutive weeks.

The third stage

Reapplication of the CARS to patients at the end of sessions and reassessment of the degree of clinical severity of ASD clinical evaluation were done, and the results are tabulated and processed statistically.

The fourth stage

Reapplication of the CARS to patients after 3 months from the last rTMS session to reassess the long-term effect of rTMS was done.

Inclusion criteria included the following:

Patients in the age range of 4–10 years, of both sexes, diagnosed as having ASD by the previously mentioned tools were included. All patients’ parents signed an informed written consent after explanation of the aim of the study and the study details and possible adverse effects. All patients in the sample did not stop their medical or behavioral therapy for ASD.

Exclusion criteria included the following:

Children with epilepsy, children with past or family history of seizures, children with history of brain lesions (posttraumatic or any pathology) who may have a lower seizure threshold, children with any other psychiatric or neurological disease, children with intracranial metallic or magnetic pieces, children with implanted medication pump, and children with intracardiac line or sever cardiac disease.

Ethical and approval considerations

Oral and written consent was taken from parents of children, taking into considerations maintaining the confidentiality of the data, consenting to visual footage and publications, and most importantly acknowledgement of the potential adverse effects. Moreover, approval of the psychiatry department in Sayed Galal Hospital, Al-Azhar University, was taken to do the research.

Statistical analysis

All data were collected and analyzed using SPSS program 15.0 edition (SPSS Inc., 233 South Wacker Drive, 11th Floor Chicago, IL 60606-6412, Printed in the United States of America) using t test. P value is considered significant when less than 0.05.


  Results Top


The results after the completion of 12 sessions of the rTMS show that there is a significant difference and improvement in the severity of the clinical symptoms of ASD, except for the level of activity and listening response and use of the body by comparing the severity of symptoms before and after rTMS. The average score in the CARS scale changed from 40.2 to 31.4. On comparing the results before and after rTMS by the level of clinical severity of autism according to DSM-5, at the level of severity in social communication, the improvement was statistically significant (P=0.001), and at the level of severity in restricted and repetitive behaviors, the improvement was statistically high significant (P<0.001). After 3 months of follow-up, in children who continued the study (24 children from the initial 30 children who started the study), there was a decrease in the effect of rTMS after discontinuation of the treatment and improvement in problems regarding relating to people and verbal communication; moreover, the total CARS score decreased from highly significant to significant. The improvement of problems such as emotional response, object use, adaptation to change, fear or nervousness, nonverbal communication, and level of consistency of intellectual response, worsened again, so there was no significant difference ([Table 1] and [Table 2]).
Table 1 Comparison between results of Child Autism Rating Scale before and after 12 sessions of transcranial magnetic stimulation and after 3 months of follow-up

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Table 2 Comparison between results of severity levels of autism spectrum disorder before and after 12 sessions of transcranial magnetic stimulation

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  Discussion Top


The current clinical study aimed to study the potential therapeutic long-term effect of rTMS in 30 patients diagnosed with ASD. The age of the participating children (N=30) ranged from 4 to 10 years old (M=5.33, SD=1.15). This is unlike other studies in choosing the participants, who were older in age and ranged between 13 and 33 years [6]. In this study, on comparing patients before starting the intervention and after finishing 12 sessions, DSM-5 severity levels were improved, and the improvement was statistically significant (P=0.001). At the level of severity in restricted and repetitive behaviors, the improvement was statistically highly significant (P<0.001).

In the current study, the reason for choosing participants younger in age was that early intervention refers to brain plasticity theory, and attempts to intervene earlier have better responses than intervening later in life [7]. Using a narrower age range in the current study makes the group homogenous, thus alleviating the age factor differences that may contribute to different response to rTMS.

The current study targeted both left and right DLPFC, similar to Casanova et al. [8]; however, targeted left DLPC only.

Selecting inhibitory rTMS as studies have shown that low-frequency rTMS (≤1 Hz) increases inhibition of stimulated cortex [9]. There is also a lower risk for seizures owing to lower rTMS frequency.

It has been suggested that the excitation/inhibition imbalance could be the key determinant in neuroplasticity abnormalities in neurodevelopmental disorders such ASD [10] and a deficit in inhibitory neurotransmission has been implicated in the pathogenesis of the ASD. It is believed that such deficit could develop during neuronal maturation [11].

The results of the study after the completion of 12 sessions of rTMS revealed that there is a significant difference and improvement in the severity of the clinical symptoms for ASD, except for the level of activity, listening response, and use of the body, by comparing the severity of symptoms before and after rTMS. By conducting statistical tests, the average measures of problems with relating to people, sensory responses (taste, smell and touch response and use), and verbal communication after sessions were relatively reduced. This relative decrease was found to be highly significant (P>0.001). The average measurements of problems, such as imitation, emotional response, object use, visual response, fear or nervousness, nonverbal communication, level of consistency of intellectual response, and general impression, as well as the total CARS score after conducting rTMS have relatively decreased and that has been found to be statistically significant (P>0.005). The average score in the CARS scale changed from 40.2 to 31.4, but these results were of limited effect for some symptoms, as after discontinuation of the treatment, these aforementioned symptoms worsened again.

Casanova and colleagues used TMS protocol similar to our study and showed that there was a significant difference between groups in reduction of repetitive and restricted behavior patterns following 12 sessions of bilateral rTMS as measured by the Repetitive Behavior Scale (RBS). There was also a statistically significant group difference in reduction in irritability as measured by the Aberrant Behavior Checklist. No changes in hyperactivity reached significance, and no changes in social awareness (unlike our study). They enrolled 45 autistic patients (age range, 9–19 years): 41 participants were high-functioning persons with autism diagnosis, and four had Asperger syndrome with less severe symptomatology than in our sample, which included low-functioning patients with significant behavioral and social problems, and we may see improvement in these domains being more significant. In other words, the high-functioning autism patients in Casanova and colleagues study did not have many problems, so there was not much change following rTMS, unlike in our study. It is supposed that using TMS in younger age as our study is a reason for better response than in other studies.

Sokhadze and colleagues reported following rTMS, reduced repetitive-ritualistic behavior, as measured by the RBS, but no changes in social awareness, and irritability, or hyperactivity were observed. The TMS treatment course was administered two times per week for 3 weeks (a total of six 0.5 Hz rTMS treatments, 150 pulse per session) over the left DLPFC only.

Our used study rTMS protocol was more extensive, with weekly sessions for 12 weeks with the first six treatments over the left DLPFC, whereas the remaining six treatments over the right DLPFC. TMS was administered inhibitory at 1 Hz frequency and 90% of motor threshold (15 trains x10 s, 150 pulse per session at 20–30 s interval between the trains. Better results were seen in the study by Sokhadze and colleagues, than our study.

A similar study to our study was conducted by Sokhadze and colleagues that used rTMS protocol but with completing 18 sessions rather than 12 sessions and used 1 Hz rTMS applied over the DLPFC in 27 individuals with ASD diagnosis. Post-TMS evaluations showed decreased irritability and hyperactivity on Aberrant Behavior Checklist, and decreased stereotypic behaviors on RBS-R. The study indicates that rTMS improves executive functioning in ASD as evidenced by normalization of ERP responses and behavioral reactions during executive function test.None of the children in the sample experienced significant adverse effects during the study.

Finally, it is important to note that it is unlikely that therapeutic TMS would reverse multiple aspects of the ASD phenotype, rather, it may improve specific core or associated symptoms related to an alteration in the functioning of a specific cortical region or circuit [12].


  Conclusion Top


This study concluded that repeated sessions of rTMS over left and right DLPFC have the potential to become an important therapeutic tool in ASD treatment and has shown significant benefits in treating core symptoms of ASD, but these benefits had time-limited effect for some symptoms, so we recommend a maintenance therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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American Psychiatric Association, Washington (APA, DC, USA). (2013) Diagnostic and Statistical Manual of Mental Disorders: fifth edition revised,DSM- 5. Arlington, VA: American Psychiatric Publishing. 5–25. ISBN 978-089042-554-1  Back to cited text no. 2
    
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Oberman LM, Rotenberg A, Pascual-Leone A. Use of transcranial magnetic stimulation in autism spectrum disorders. J Autism Dev Disord 2013; 43:1–13.  Back to cited text no. 3
    
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Oberman LM. mGluR antagonists and GABA agonists asnovel pharmacological agents for the treatment of autismspectrum disorders. Expert Opin Investig Drugs 2012; 21:1819–1825.  Back to cited text no. 5
    
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Sokhadze EM, El-Baz AS, Tasman A, Sears LL, Wang Y, Lamina EV, Casanova MF. Neuromodulation integrating rTMS and neurofeedback for the treatment of autism spectrum disorder: an exploratory study. Appl Psychophysiol Biofeedback 2014; 39:237–257.  Back to cited text no. 6
    
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Geoffray MM, Thevenet M, Georgieff N. News in early intervention in autism. Psychiatr Danubina 2016; 28(Suppl-1):66–70.  Back to cited text no. 7
    
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Casanova MF, Baruth JM, El-Baz A, Tasman A, Sears L, Sokhadze E. Repetitive transcranial magnetic stimulation (rTMS) modulates event-related potential (ERP) indices of attention in autism. Transl Neurosci 2012; 3:170–180.  Back to cited text no. 8
    
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Rajji TK, Rogasch NC, Daskalakis ZJ, Fitzgerald PB. Neuroplasticity-based brain stimulation interventions in the study and treatment of schizophrenia: a review. Can J Psychiatry 2013; 58:93–98.  Back to cited text no. 10
    
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Baroncelli L, Braschi C, Spolidoro M, Begeneisic T, Maffeib L, Sale A. Brain plasticity and disease: a matter of inhibition. Neural Plast 2011; 2011:286073.  Back to cited text no. 11
    
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Oberman LM, Enticott PG, Casanova MF, Rotenberg A, Pascual-Leone A, McCracken JT. TMS in ASD Consensus Group. Transcranial magnetic stimulation in autism spectrum disorder: Challenges, promise, and roadmap for future research. Autism Res 2016; 9:184–203.  Back to cited text no. 12
    



 
 
    Tables

  [Table 1], [Table 2]



 

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