Effects rTMS-Based Neuromodulation Dosage on Event-Related Potentials and Evoked and Induced Gamma Oscillations in Children with Autism Spectrum Disorder

Background: Autism is defined as a spectrum of behavioral disorders that have in-common impairments in social interaction and communication skills, language deficits, and a restricted repertoire of interests and stereotyped activities. There are several theoretical models of the neuropathology of autism spectrum disorders (ASD), and one of them suggests the presence of an excessive cortical excitation/inhibition (E/I) ratio that affects functional connectivity. This model explains atypical event-related potential (ERP) and evoked and induced gamma oscillations observed in ASD during task performance. Repetitive transcranial magnetic stimulation (rTMS), especially using low frequency inhibitory stimulation, can be considered as a method of modulating the E/I bias.

Objectives: In our prior exploratory studies we used different schedules of rTMS to investigate outcomes of rTMS in ASD. In this study, 124 high functioning ASD children (IQ>80, <18 years of age) were recruited and assigned to either a waitlist group or one of three different number of weekly rTMS sessions (i.e., 6, 12, 18) to investigate effects of dosage on functional and behavioral outcomes. The project was aimed at selection of more effective length of rTMS course.

Methods: TMS consisted of trains of 1.0 Hz pulses applied over dorsolateral prefrontal cortex. The experimental task was a three-stimulus visual oddball with illusory Kanizsa figures. Behavioral response variables included reaction time and error rate along with EEG indices such as ERP and evoked and induced gamma oscillations. One hundred and twelve patients completed the assigned number of rTMS sessions.

Results: We found significant positive changes from baseline to post-TMS treatment period in motor responses accuracy (lower percentage of committed errors, restored normative post-error slowing), in ERP indices and in evoked and induced gamma responses. Parental reports showed significant reductions in aberrant behavior scores as well as decreased scores of repetitive and stereotypic behaviors. The gains of outcomes increased with the total number of treatment sessions. Behavioral questionnaires (ABC,RBS-R, SRS-2) showed significant improvements in ratings of autism symptoms both post 12- and 18-session rTMS course.

Results of our clinical research study showed most significant changes from baseline in functional measures of performance in oddball task and in behavioral symptom ratings following 18 sessions of rTMS treatment. Several measures showed a difference from baseline and waitlist in reaction time and ERP/EEG variables after 12 sessions of rTMS, but only a few of them reached statistical significance post-6 session rTMS course.

Conclusions: Our results suggest that rTMS, particularly after 18 sessions, facilitates cognitive control, attention and target stimuli recognition by improving discrimination between task-relevant and task-irrelevant illusory figures in an oddball test. Improvement in executive functions and behavioral symptoms of autism further suggests that TMS has the potential to target core features of ASD. The results of this dosage-response study could serve as important pre-requisites that could inform the planning of a blinded randomized clinical trial. Among potential implications of the study should be considered potential of combining rTMS with neurofeedback training aimed at reinforcement of neuromodulation effects using operant conditioning.