Background: Transcranial Direct Current Stimulation (tDCS) is a form of non-invasive brain stimulation that has aroused increased interests in the past decade. Not only that it is transient with little side-effects, and can be well-tolerated by children, it is also affordable and readily accessible, making it an appealing treatment option for autism spectrum disorder (ASD).

Objective: (1) To assess the therapeutic effects of tDCS when combined with cognitive training for 10 consecutive weekdays on improving cognitive processing in adolescents with ASD, relative to control group receiving sham-stimulation, and (2) to evaluate the associated neural mechanisms underlying the treatment effect of tDCS on adolescents with ASD.

Methods: 105 adolescents with ASD will be randomly assigned to active- (n=35), sham- (n=35) tDCS, or no-treatment control (n=35) groups. Twenty minute sessions of 1 mA cathodal stimulation to the left dorsolateral prefrontal cortex (DLPRC) in conjunction with cognitive training exercise will be provided on 10 consecutive weekdays. EEGs, functional near-infrared spectroscopy, and neuropsychological tests will be administered before, 1 day and 6 months after the series of tDCS sessions.

Hypothesis: We hypothesized that cathodal (inhibitory) tDCS over the left DLPRC will induce (1) stimulation-linked facilitation of learning and enhanced processing speed and resultant improvement of cognitive functioning, in executive function, relative to the sham-tDCS and the wait-list controls, (2) active-tDCS, but not sham-tDCS and wait-list controls, will modulate the intra- and inter-hemispheric neural connectivity, indexed by altered level EEG theta coherence and aberrant fNIRS haemodynamic measures, across brain areas implicated in executive functioning.

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental disorder characterized by disturbances in communication, poor social skills, and aberrant behavior. ASD often causes considerable emotional and financial stress on the patients, their families and the community. Prevalence of ASD is high, with recent statistics reported at one in 68. Thus far, there is no cure for ASD and the disorder remains a highly disabling condition in spite of the existing treatment options. Hence, more effective novel therapeutic approaches are urgently needed. In the past 10 years, transcranial direct current stimulation (tDCS), a brain stimulation technique, has been intensively investigated regarding its physiologic mechanisms of action render empirical support of its application in clinical setting.

Cognitive and social deficits in ASD. Individuals with ASD often appear rigid and inflexible, show a strong liking for repetitive behaviour and elaborate rituals. One reason for the aberrant behaviour in ASD may be attributed to their deficient processing speed and resultant cognitive deficits. Slow processing speed relates to a reduced capacity of executive function to recall and formulate thoughts and actions automatically, with the result that autistic individuals with slow processing speed would have great difficulty learning or perceiving the relationships across multiple experiences. As a result, these individuals compensate for the impaired ability to integrate information from the environment by memorizing visual details or individual rules from each situation. This explains why individuals with the disorder tend to follow routines in precise details and show great distress with trivial changes in the environment.

Disordered functional connectivity underlies cognitive dysfunction in ASD: Neural connectivity problem has been widely reported in individuals with ASD. For example, diffusion tensor imaging (DTI) and Electrophysiological studies have reported reduced myelin integrity in the ventromedial prefrontal cortex and at the temporoparietal junctions. Similarly, functional imaging studies have found reduced synchronization between activated brain areas on tests of working memory, executive function, and interpretations of the affective meaning of actions in individuals with ASD.

Cortical inhibition and excitability (E/I ratio) in ASD: The significantly variability in symptom presentation in ASD can now be understood as a manifestation of a neural systems disorder, with abnormalities found in the interaction among different brain areas attributable to some brain connectivity disorder. Related to the underlying connectivity problem in ASD is the dysregulation of cortical excitability. One emerging principle is that the cognitive deficits in autism are caused by excessively high level of excitation within the neural circuits that mediate the different cognitive functions in ASD. The suggested role of the increased ratio of cortical cellular excitation to inhibition (E/I balance) in the pathophysiology of of ASD is supported by recent studies which have shown that a reduction in GABAergic signalling is a common feature in the brains of autistic individuals, with enhancement of excitatory glutamatergic signalling as the underlying mechanism. These findings are consistent with neural connectivity studies suggesting that cortical cellular E/I imbalance or hyper-excitability could disrupt the normal progressive differentiation and elaboration of functional connectivity in the developing brain.

Effects of Transcranial Direct Current Stimulation (tDCS) on modulating cortical excitation/inhibition balance: tDCS is a non-invasive neuromodulation method which influences cortical activity level, by applying low direct currents to the scalp through anodal and cathodal electrodes. Magnetic resonance spectroscopy (MRS) studies have reported that anodal tDCS increases cortical excitability by reducing local concentrations of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), whereas cathodal tDCS decreases cortical excitability by reducing excitatory glutamate levels. As cathodal tDCS can reduce cortical excitability caused by neuronal hyperpolarization, it is reasonable to assume that cathodal stimulation can be beneficial in ASD by decreasing the cortical excitability in the affected individuals with the disorder.

Therapeutic effect of tDCS on improving cognitive function: In the past decade, there has been a growing interest in studying the effect of tDCS to alter various central nervous system functions, including motor control, attention, memory, language, and emotion, and to modulate brain activity level and functional connectivity in healthy and patient population. To date, more than 100 tDCS studies have shown promising results and reported instant tDCS-induced positive effects on cognitive functions, without any safety problem or adverse side-effect. Additionally, synaptically driven aftereffects were induced with sufficient tDCS duration. It has been shown that a single-session of tDCS for 10-13 minutes could induce an hour of after-effect, and 10 repeated sessions of tDCS coupled with therapeutic task in children with perinatal stroke were associated with changes in spectroscopic biomarkers 1 week after stimulation and sustained clinical improvement at a 2-month follow-up visit. Interestingly, more significant behavioral/cognitive improvement have been reported when tDCS were paired with therapeutic task than receiving tDCS alone. These findings are consistent with the notion that performing therapeutic task during tDCS can direct the stimulation effect to the neural circuits involved. In which, the coupling of tDCS with therapeutic task can enhance learning through inducing long term potentiation-changes to underlying brain regions and modulates brain activity associated with the task. This in turn can lead to greater synaptic modification and improved task performance. Among the various tDCS protocols, stimulation on the dorsolateral prefrontal cortex (DLPFC) is one of the widely applied montages. tDCS over the DLPFC has been shown to improve cognitive functions such as working memory, inhibitory control, emotional state and processing in neuropsychiatric patients.

Although these preliminary findings in neuropsychiatric patients are encouraging, empirical studies on the application of tDCS on individuals with ASD are limited. The research that has been performed, however, is encouraging. For example, one clinical case study of autistic patient who received 10 consecutive daily 20-min sessions of 1.5mA cathodal tDCS over the left DLPFC, showed persisted significant improvement in his highly disabling behavioural symptoms at a 3-month follow-up visit. Additionally, tDCS over the left DLPFC has also been shown to modulate inhibitory control of behavioural outbursts and language acquisition in minimally verbal children with ASD. Given the promising outcomes of brain stimulation treatment of resistant neuropsychiatric disorders, the present study thus aims to explore the repetitive effect of tDCS on improving cognitive functions, with particular interest in enhancing functional connectivity, in adolescents with ASD.

Inclusion Criteria:

• Individuals who are confirmed by a clinical psychologist based on the Diagnostic and Statistical Manual of Mental Disorders-5th Ed (DSM-V) criteria of Autism spectrum disorder and structured interview with their parents or primary caregivers on their developmental history using the Autism Diagnostic Interview-Revised (ADI-R).
• Individuals with intelligence quotient above 70
• Individuals who demonstrate the ability to comprehend testing and stimulation instructions

Exclusion Criteria:

• Individuals with severe motor dysfunctions that would hinder their participation, and those with history of other neurological and psychiatric disorders and head trauma, or on psychiatric medication will be excluded from the study