Abstract

Introduction

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with impairments in language acquisition, social functioning, motor skill abnormalities, restricted and repetitive behaviors, and executive functioning deficits. Despite considerable prior research efforts, there is a dearth of treatment options for the core features of ASD.¹1. Lord C, Bishop SL. Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu Rev Clin Psychol. 2015;11:53-70. Studies with pharmacologic agents have had disappointing results and often demonstrate an unacceptable side effect burden with long-term use.²2. Williams K, Wheeler DM, Silove N, Hazell P. Selective serotonin reuptake inhibitors (SSRIs) for autism spectrum disorders (ASD). Cochrane Database Syst Rev. 2010;8:CD004677. Effective, brain-based interventions for the core symptoms of ASD are lacking.¹1. Lord C, Bishop SL. Recent advances in autism research as reflected in DSM-5 criteria for autism spectrum disorder. Annu Rev Clin Psychol. 2015;11:53-70.

Noninvasive brain stimulation interventions such as repetitive transcranial magnetic stimulation have increasingly been considered in the treatment of ASD.³3. Ameis SH, Daskalakis ZJ, Blumberger DM, Desarkar P, Drmic I, Mabbott DJ, et al. Repetitive transcranial magnetic stimulation for the treatment of executive function deficits in autism spectrum disorder: clinical trial approach. J Child Adolesc Psyhcopharmacol. 2017;27:413-21. Protocols with theta burst stimulation (TBS) exert a more rapid effect on neuroplasticity, compared to standard rTMS protocols. During TBS sessions, a series of three magnetic pulses are delivered at 50 Hz with 200 ms intervals (5 Hz). Intermittent TBS (iTBS) sessions deliver 2 second trains with 30 pulses every 10 seconds for 190 seconds for a total of 600 pulses. In general, iTBS is purported to facilitate cortical excitability and promote long-term potentiation-like effects.⁴4. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45:201-6. Prior neurophysiological work suggests that adolescent and young adult patients with ASD have right hemispheric impairments in long-term potentiation-like plasticity.⁵5. Jung NH, Janzarik WG, Delvendahl I, Münchau A, Biscaldi M, Mainberger F, et al. Impaired induction of long-teram potentiation-like plasticity in patients with high-functioning autism and Asperger syndrome. Dev Med Child Neurol. 2013;55:83-9. Patients with ASD and obsessive-compulsive disorder often have shared clinical and neurophysiological features including deficits in cortical inhibition.⁶6. Radhu N, de Jesus DR, Ravindran LN, Zanjani A, Fitzgerald PB, Daskalakis ZJ. A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. Clin Neurophysiol. 2013;124:1309-20.,⁷7. Enticott PG, Kennedy HA, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB. GABAergic activity in autism spectrum disorders: an investigation of cortical inhibition via transcranial magnetic stimulation. Neuropharmacology. 2013;68:202-9. Herein we report on an open-label trial examining the feasibility, tolerability, and clinical effects of iTBS treatment in child and adolescent participants with ASD. A variety of rTMS and TBS treatment targets have been considered previously.⁸8. Desarkar P, Rajji TK, Ameis SH, Daskalakis ZJ. Assessing and stabilizing aberrant neuroplasticity in autism spectrum disorder: the potential role of transcranial magnetic stimulation. Front Psychiatry. 2015;6:124. We elected to stimulate the right dorsolateral prefrontal cortex with the goal of targeting impairments in cortical inhibition and long-term potentiation-like plasticity.⁵5. Jung NH, Janzarik WG, Delvendahl I, Münchau A, Biscaldi M, Mainberger F, et al. Impaired induction of long-teram potentiation-like plasticity in patients with high-functioning autism and Asperger syndrome. Dev Med Child Neurol. 2013;55:83-9.

6. Radhu N, de Jesus DR, Ravindran LN, Zanjani A, Fitzgerald PB, Daskalakis ZJ. A meta-analysis of cortical inhibition and excitability using transcranial magnetic stimulation in psychiatric disorders. Clin Neurophysiol. 2013;124:1309-20.-⁷7. Enticott PG, Kennedy HA, Rinehart NJ, Tonge BJ, Bradshaw JL, Fitzgerald PB. GABAergic activity in autism spectrum disorders: an investigation of cortical inhibition via transcranial magnetic stimulation. Neuropharmacology. 2013;68:202-9.

Methods

Study design

The ethics board at the Universidade de São Paulo, Brazil, approved the protocol and study procedures. During a screening visit, participants underwent a clinical assessment and the Schedule for Affective Disorders and Schizophrenia for School-Age Children (K-SADS-PL) was administered.⁹9. Kaufman J, Birmaher B, Brent D, Rao U, Flynn C, Moreci P, et al. Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. J Am Acad Child Adolesc Psychiatry. 1997;36:980-8. Diagnostic criteria for ASD were confirmed by three child and adolescent psychiatrists (CA, BBB, and HB). Age of language onset and psychotropic medication use were noted at this screening visit. During a baseline visit, participants completed a Wechsler Intelligence Scale for Children, 3rd ed. (WISC-III)¹⁰10. Wechsler D. The Wechsler Intelligence Scale for Children. 3rd ed. San Antonio: Psycholoogical Corporation. and underwent a brain magnetic resonance imaging (MRI) scan and an electroencephalography (EEG). Baseline parent report measures included the Repetitive Behavior Scale Revised (RBS-R)¹¹11. Lam KS, Aman MG. The Repetitive Behavior Scale-Revised: independent validation in individuals with autism spectrum disorders. J Autism Dev Disord. 2007;37:855-66. and the Yale-Brown Obsessive Compulsive Scale (YBOCS).¹²12. Goodman WK, Price LH, Rasmussen SA, Mazure C, Fleischmann RL, Hill CL, et al. The Yale-Brown Obsessive Compulsive Scale. I. Development, use, and reliability. Arch Gen Psychiatry. 1989;46:1006-11. The Wisconsin Card Sorting Test (WSCT)¹³13. Monchi O, Petrides M, Petre V, Worsley K, Dagher A. Wisconsin card sorting revisited: distinct neural circuits participating in different stages of the task identified by event-related functional magnetic resonance imaging. J Neurosci. 2001;21:7733-41. and the Stroop test¹⁴14. Stroop JR. Studies of interference in serial verbal reactions. J Exp Psychol. 1935;18:643-62. were administered on the first day of iTBS treatment immediately before the session. All outcome measures (RBS-R, YBOCS, WSCT, and Stroop test) were then repeated on the last day of iTBS treatment after the session and at a 3-month follow-up visit.

Participants

Ten male, right-handed, participants (ages 9-17) with ASD and impairing restricted and repetitive behaviors were recruited from the outpatient clinic at Instituto de Psiquiatria, Universidade de São Paulo. All participants had an intelligence quotient of 50 or greater on the WISC-III. Participants with any abnormalities on a brain MRI scan or EEG were excluded. Participants with unstable medical conditions or risk factors for seizure were also excluded.

iTBS intervention

Fifteen sessions of iTBS were delivered 5 days a week for 3 weeks. The right dorsolateral prefrontal cortex was located with neuronavigation (Vector Vision Brain LAB) on the first day of stimulation. Stimulations were performed with a Dantec MagPro2 stimulator (Medtronic, Minneapolis, MN, USA) and Neuro-MS Net Software (Neurosoft, Ivanovo, Russia). The iTBS sessions were delivered to the right dorsolateral prefrontal cortex over 300 seconds. Stimulation intensity was 100% of motor threshold with three pulses of 50 Hz bursts delivered at 5 Hz in 30 trains of 10 bursts with 8 seconds on and 2 seconds off.

Statistical analysis

The primary aims of the study were to examine clinical outcomes (RBS-R, YBOCS, WCST, Stroop test) after 15 sessions of iTBS and at a 3-month follow-up visit. Secondary aims considered feasibility based on participants’ ability to adhere to the iTBS protocol and tolerability based on patient and family reports. Data were expressed as means and standard deviations. Distributions for each outcome measure were assessed for normality with the Shapiro-Wilk test. The RBS-R, YBOCS, and Stroop data demonstrated normal distributions and paired t-tests of outcomes were performed with SPSS. The WCST data did not have a normal distribution and a nonparametric (Wilcoxon signed rank) test was used.

Results

Outcome results are summarized in Table 1. Three-month follow-up data were available in five participants and are presented descriptively. Mean RBS-R scores demonstrated significant improvement from baseline to posttreatment (t = 3.75, degrees of freedom [df] = 9, p = 0.005, Cohen’s d = 0.98). After iTBS treatments, the parent-report YBOCS revealed improvement in mean overall compulsion subscale scores (t = 2.70, df = 9, p = 0.02, Cohen’s d = 0.54). Participants demonstrated enhanced performance on WCST with improvement in perseverative errors (Wilcoxon Signed Rank Test, p = 0.02, Cohen’s d = 0.35) after iTBS treatment. Notably, there were no errors in Stroop test at baseline. However, total time for completion improved after treatment (t = 4.47, df = 9, p = 0.002, Cohen’s d = 0.72). Participants tolerated the iTBS protocol with no significant side effects. There were no seizures during treatment sessions. All 10 participants completed the treatment protocol.

Discussion

This exploratory, open-label trial of iTBS in male children and adolescents with ASD examined clinical outcomes, feasibility, and tolerability of 15 sessions applied to the right dorsolateral prefrontal cortex with neuronavigated coil location. Treatment with iTBS appeared to improve restricted, repetitive behaviors, compulsions, and neurocognitive functioning. These preliminary findings suggest that iTBS may be a promising, brain-based intervention for the core symptoms of ASD. However, any interpretation must be placed in the context of substantial limitations. The study had an open-label design with a small sample size and did not examine neurophysiological correlates. Prior work suggests that interventional trials in ASD are particularly disposed to a large placebo response, thereby presenting challenges to interpretation of data in open-label studies and executing randomized, controlled trials with ASD samples.¹⁵15. Masi A, Lampit A, Glozier N, Hickie IB, Guastella AJ. Predictors of placebo response in pharmacological and dietary supplement treatment trials in pediatric autism spectrum disorder: a meta-analysis. Transl Psychiatry. 2015;5:e640. This problem underscores the necessity of future objective, measurement-based approaches with target-engagement strategies. Feasibility and tolerability considerations are promising as our experience suggests that youth with ASD tolerated iTBS and were adherent to treatment. The present data will inform future biomarker-guided, controlled trials of iTBS for ASD.

Acknowledgements

PEC acknowledges support from National Institute of Mental Health (NIMH) under award number K23 MH100266 and a Brain and Behavior Research Foundation Young Investigator Award. The content of this report is the sole responsibility of the authors and does not necessarily represent the official views of the US Department of Health and Human Services, the National Institutes of Health, or the NIMH.

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