Synaptic plasticity and non-invasive brain stimulation in autism spectrum disorders

The functional neurobiology of autism spectrum disorders ([ASD] including autism and Asperger syndrome) remains largely undetermined and there are few biomedical treatments available that target the core symptoms. As prevalence rates for ASD continue to increase, studies that contribute toward our understanding of specific pathological brain processes in ASD are critical to the identification of possible treatment targets and promotion of novel interventions. Though the exact aetiology of autism is unknown, and is likely a combination of multiple genetic and environmental factors, recent studies across multiple levels of analysis implicate synaptic maturation and plasticity (strengthening and weakening of synaptic connections) in the pathogenesis of ASD.

Until recently, synaptic mechanisms including excitation, inhibition, and plasticity, were only possible to evaluate through slice electrophysiology or animal models. However, the recent development of novel protocols using non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation have emerged as unique methods for functional, in vivo investigations of neurochemical and plasticity-related processes in clinical populations. Jung et al.¹ have conducted an important initial study in this area, examining a paradigm assessing a specific type of Hebbian synaptic plasticity in ASD. Results suggest reduced long-term potentiation within sensorimotor circuitry among individuals with ASD.

As with any research into the neuropathophysiology of psychiatric and neurological disorders, a key question concerns the clinical significance of this impairment. The authors rightly suggest that it may reflect difficulties in sensorimotor integration, but sample-size limitations prevent a thorough investigation. Whether it might reflect broader plasticity impairments in non-sensorimotor regions, particularly fronto-temporo-parietal networks involved in social processes, is also of interest. Indeed, such questions will perhaps be best answered by continued clinical neuroscience research that employs large patient samples combined with detailed phenotypic and genotypic information, but also emerging techniques that allow an examination of synaptic plasticity outside of sensorimotor circuitry (e.g. transcranial magnetic stimulation combined with electrophysiology or functional neuroimaging).

While there have been few studies using NIBS to assess in vivo mechanisms around synaptic plasticity, there are already conflicting findings. For instance, in a recently published study, Oberman et al.² found longer-lasting (rather than absent) motor cortical neuroplastic effects in individuals with Asperger syndrome. This study, however, used a different paradigm (theta burst stimulation) that is designed to explore non-Hebbian plasticity and specifically GABAergic influence. The conflicting findings could reflect paradigmatic differences (i.e. Hebbian vs non-Hebbian plasticity) or the heterogeneity of ASD, but in any case the effects are opposite (i.e. absent vs long-lasting) and further suggests the importance of large studies, with detailed clinical and genetic information, to examine functional neurobiology in ASD. This will also allow an examination of the relationship between neurobiology and ASD phenotypes. Although Jung et al.¹ did not find support for a GABAergic mechanism underpinning these results, other research has shown evidence for GABA_A deficits in high-functioning autism^3,4 which would also be consistent with the enhanced modulation reported by Oberman et al.²

The translational aspects of this research are of greatest importance. NIBS in ASD is very much in its infancy, and we must be extremely cautious when predicting long-term outcomes. Nevertheless, the study by Jung et al. illustrates one form of clinical research into functional neurobiology that is critical to the identification of novel treatment targets and the development of novel biomedical interventions in ASD. This could include therapeutic NIBS techniques that have been shown to alter plasticity and that have been used with success in other psychiatric and neurological disorders, including repetitive transcranial magnetic stimulation and transcranial direct current stimulation. Elucidation of neurochemical mechanisms involved in this process, although not borne out in the current study, would also highlight a potential for pharmacological intervention, either in isolation or possibly combined with NIBS. Although unlikely to offer any sort of cure or complete remission of symptoms, previous clinical trials involving NIBS among other clinical populations suggest that there is a potential for symptom improvements in ASD that may improve quality of life for affected individuals and their families. If further results demonstrate sufficient specificity to ASD, it also raises the possibility of a biological indicator that could be used to aid screening or diagnosis.