Introduction
Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by alterations in social interaction, communication, and repetitive behaviors (APA, 2013). Additionally, people with ASD experience cognitive alterations (Demetriou et al., 2010) and sleep problems (Baglioni et al., 2016), which all tremendously impact their social and occupational functioning (Chiang & Wineman, 2014). Etiologically, ASD is a multifactorial disorder, with genetical, immunological, inflammatory and neurofunctional processes involved (Meltzer et al., 2017). From a neural point of view, structural and functional changes have been correlated with ASD symptomatology (Ecker et al., 2015). However, not a single brain region can be accounted for its pathophysiology (Rane et al., 2015). Indeed, brain networks, such as the Default Mode Network, and circuities are likely to be involved (Padmanabhanet al., 2017).
Neuromodulation techniques, specifically Transcranial Magnetic Stimulation (TMS), assumes a key role in ASD research and treatment, for their ability to probe and modulate neural circuitries (Valero-Cabré et al., 2017). TMS is non-invasive neurostimulation technique that, applied over the head, involves the generation of a brief magnetic pulses, which generates an electrical field able to penetrate the underlying brain tissue, generating electrical currents (Klomjai et al., 2015). These currents, in turn, depolarize neurons and lead to the initiation of action potentials (Klomjai et al., 2015). The controlled and targeted stimulation of neural circuits allows researchers and clinicians to modulate brain activity in a precise and localized manner. Indeed, depending on the protocol of stimulation, TMS represents an investigational, diagnostic or therapeutic tool (Valero-Cabré et al., 2017).
In this article, the rationale for TMS adoption in autism research and treatment will be described, as well as the first evidence in literature about TMS as an investigational tool and therapy in ASD.
TMS in autism: rationale
In order to understand the rationale for TMS use in patients with ASD, a comprehension of some key ASD-related alterations is needed. ASD is a circuit-dysfunction disorder (Port et al., 2014). Individuals with autism often exhibit atypical patterns of neural connectivity, affecting communication between different regions of the brain (Rane et al., 2015). TMS allows researchers to investigate and potentially influence these neural circuits, offering insights into the underlying neurobiology of autism and providing a platform for targeted interventions.
From a clinical point of view, repetitive TMS (rTMS) has shown efficacy in the treatment of behavioural rigidity, impulsivity, repetitive thoughts, which are frequent symptoms of ASD, in other disorders, such as Obsessive-Compulsive Disorder (Greenberg et al., 1997). Moreover, an early disturbance in the serotonin system affecting brain development is a potential etiological mechanism of autism (Chugani, 2004). In an animal study, chronic rTMS has been shown to induce subsensitivity of presynaptic serotonergic autoreceptor activity in rat brain (Gur et al., 2000), providing another reason for testing the efficacy of rTMS as a treatment in ASD.
TMS research in ASD: first studies
In this paragraph, the beginnings of TMS research in ASD are described. Specifically, first studies using TMS to explore brain plasticity and investigate the neural mechanisms underpinning ASD are described. Then, the first clinical findings are reported.
TMS as an investigational tool in ASD
The first study of TMS in autism dates back to 2005. Theoret and colleagues (2005) applied TMS over the motor cortex to determine if the neural mechanism matching action observation and execution is anomalous in individuals with ASD. This neural mechanism refers to the mirror neuron system and subtends the ability to understand actions. They reported that this system was impaired in ASD patients. Specifically, the processing of other-directed movements was impaired. With this study, they shed light onto the neural substrates of the social deficits inherent in ASD and potentially, these deviations could contribute to diminished empathy and reciprocal social abilities (theory of mind).
An important neurophysiological factor in ASD is represented by increased excitation/inhibition ratio (Rubenstein and Merzenich, 2003), which results in plastic abnormalities. A direct confirmation of this hypothesis (beyond animal models) came from a TMS study (Oberman et al., 2010). In this study, a particular type of TMS, i.e. Theta-Burst Stimulation, was applied and results showed that ASD is characterized by abnormalities in plasticity and metaplasticity as well as heterogeneity in intracortical inhibition. Cortical inhibition deficits in ASD were then confirmed by another preliminary TMS study (Enticott et al., 2010).
TMS as a therapy in ASD
The first who suggested the potential therapeutic effect of TMS in autism was Tsai in 2005. However, the first clinical study was published only in 2009 by Sokhadze et al (2009). The same group showed years before (Casanova et al., 2003; 2006) inhibitory deficits in prefrontal regions in autism. For this reason, they decided to apply rTMS at slow frequency (which has inhibitory properties over the Dorsolateral Prefrontal Cortex. Clinically, they observed a reduction in repetitive-ritualistic behaviors after the intervention (Sokhadze et al., 2009). Moreover, excessive gamma oscillations (i.e. increased brain activity in gamma brain waves) was also reduced at the end of the treatment. Although, this first study had some limitations in terms of sample size and dosing, it showed for the first time the potential of TMS as a therapy in ASD. These results were then confirmed by a subsequent study (Baruth et al., 2010), with a larger number of participants. This study showed that rTMS at 1 Hz improved inhibitory functioning, gamma oscillations as well as behavioural aspects, such as irritability and repetition. Among the first reports of TMS as a therapy in ASD, a case report received a specific attention for its novelty (Enticott et al., 2011). Indeed, a new type of rTMS for that time was adopted. It was deep TMS, a technique which is also able to modulate the activity of deeper brain regions. In this study, authors reported the case of a woman with ASD, treated with dTMS, who showed an improvement in the domain of social relating and interpersonal understanding.
Conclusion
The history and beginnings of TMS in autism represent a fascinating intersection of technological innovation, neuroscientific research, and clinical application. TMS allowed to study the foundations of neurostructural and neurofunctional substrates of ASD, contributing to the understanding of plasticity alterations, inhibitory deficits and mirror system abnormalities. Moreover, these studies have inspired the application of this technique also for the first therapeutic studies here reported. All these findings have defined the basis for following research and clinical practice.
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