Transcranial Magnetic Stimulation Provides a Means to Investigate Cortical Excitability and Plasticity in Autism Spectrum Disorder

Background: The etiology and neurobiology of Autism Spectrum Disorders (ASD) is complex and insufficiently understood. Recent studies across multiple research areas, including animal model research and human studies have implicated mechanisms of cortical excitability and plasticity in the pathophysiology of ASD. Our group has pioneered the development of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) metrics of cortical excitability and plasticity as putative endophenotypes in ASD. As compared with behavioral or neuroimaging methods, TMS offers the advantage of providing behaviorally independent results that are largely unaffected by attention or cognitive ability. Therefore, a TMS-based endophenotype may be applicable to all individuals across the autism spectrum: old as well as young, higher as well as lower functioning individuals.

Objectives:  Our group has pioneered the development of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS) metrics of cortical excitability and plasticity as putative endophenotypes in ASD. As compared with behavioral or neuroimaging methods, TMS offers the advantage of providing behaviorally independent results that are largely unaffected by attention or cognitive ability. Therefore, a TMS-based endophenotype may be applicable to all individuals across the autism spectrum: old as well as young, higher as well as lower functioning individuals.

Methods: Our published and ongoing studies employ TMS-based measures of cortical excitability and plasticity in children and adults with ASD.

Results: Across multiple studies, application of a rTMS protocol proposed to index non-Hebbian plasticity and GABAergic inhibitory tone (theta burst stimulation(TBS)) results in a prolonged modulation of corticospinal excitability in adults with ASD. Specifically, while controls show a modulation of the TMS-induced motor evoked potentials (MEPs) for approximately 30-40 minutes following TBS, the effect lasted for over 60 minutes in individuals with ASD. This group difference is so striking that when an independent sample of 15 adults with ASD and 15 age- and gender-matched controls was evaluated, using solely their response to TBS, the test was able to reliably classify the individual into either ASD or control with a sensitivity of 0.87 and a specificity of 0.93 based on the latency to return to baseline within 50 minutes following TBS. Additionally, we find that approximately a third of individuals with ASD show absent or paradoxical responses to paired pulse and rTMS protocols thought to be related to GABAergic tone.  In one paired pulse study we found that a subgroup of adults with ASD showed a reduced or absent intracortical inhibition response and in another study over a third of children with ASD displayed paradoxical facilitation to the continuous TBS protocol, also thought to engage GABAergic inhibitory mechanisms. 

Conclusions: We continue to explore the utility of TMS and rTMS indices of excitability and plasticity in an effort to develop a valid and reliable endophenotype that would facilitate ASD diagnosis early in life, enable efficient study of ASD risk factors, and eventually serve as a useful biomarker to inform the development of effective therapies and assess treatment response in future clinical trials.