Transcranial Direct Current Stimulation in Autism Spectrum Disorder
Condition: Transcranial Direct Current Stimulation; Autistic Disorders Spectrum; Electroencephalography
MeSH terms: Autism Spectrum Disorder; Autistic Disorder
Study type: Interventional

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Active-tDCS; Sham-tDCS; Wait-list
Intervention type(s): Device; Device; Other
Intervention description(s): Active-tDCS over 10 sessions in 2 weeks (once per day, for 10 consecutive working days), while performing the executive function training tasks. Also, participants will complete an online cognitive training program while they receive active tDCS stimulation for 10 training sessions. The training session will last for 20 minutes and the online cognitive training program is comprised of 5 exercises targeting at information processing speed and executive function capacities. Each exercise lasts for approximately 4 minutes, totaling approximately 20 minutes.; Sham-tDCS stimulation over 10 sessions in 2 weeks (once per day, for 10 consecutive working days), while performing the executive function training tasks. Also, participants will complete an online cognitive training program while they receive sham-tDCS stimulation for 10 training sessions. The training session will last for 20 minutes and the online cognitive training program is comprised of 5 exercises targeting at information processing speed and executive function capacities. Each exercise lasts for approximately 4 minutes, totaling approximately 20 minutes.; No intervention
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Outcomes Assessor)
Primary purpose: Treatment