Non-invasive Brain Stimulation for Pediatric ADHD
Condition: ADHD
MeSH terms: Attention Deficit Disorder with Hyperactivity
Study type: Interventional

Summary: 
      The possibility of influencing brain activity and steadily enhancing behavioral performance
      through external intervention has long fascinated neuroscientists. One of these techniques,
      transcranial electrical stimulation (tES), has received great interest. Transcranial
      electrical stimulation (tES) in the current research includes two types of stimulation:
      transcranial direct current stimulation (tDCS) and transcranial random noise stimulation
      (tRNS).

      The tES techniques involve the application of constant weak direct current (e.g. 1-2 mA) to
      the brain via skin-electrode interface, creating electric field that modulates neuronal
      activity. The safety profile of tES is excellent.

      Despite effective pharmacotherapy for ADHD there is a need for improvement of cognitive
      dysfunction and behavioral symptoms that are only inadequately covered by pharmacological or
      psycho-social interventions. Since ADHD is the most common neurodevelopmental disorder in
      childhood with significant negative lifetime outcomes, non-invasive brain stimulation methods
      have been investigated in childhood and adolescents neuropsychiatric disorders showing
      promising results.

      If tES is significantly effective for certain symptoms of ADHD, it may offer many advantages
      as a therapy. Treatment of ADHD with non-invasive brain stimulation has recently been
      reviewed in the medical literature, concluding that this technique seems to have efficacy in
      ADHD, however, standardized study protocols are needed to determine it.

      In this study we intend to further examine the efficacy of tDCS and tRNS for children with
      ADHD and its effect on ADHD symptoms, memory, executive functions, in a randomized controlled
      crossover study.
    

Detailed description: 
      External influences on neuroplastic processes may be used for functional improvement of
      diseases, in particular for improving cortical functions. The possibility of influencing
      brain activity and steadily enhancing behavioral performance through external intervention
      has long fascinated neuroscientists. One of these techniques, transcranial electrical
      stimulation (tES), has received great interest because it has great potential use in basic
      research and clinical applications. Transcranial electrical stimulation (tES) in the current
      research includes two types of stimulation: transcranial direct current stimulation (tDCS)
      and transcranial random noise stimulation (tRNS). The tES techniques involve the application
      of constant weak direct current (e.g. 1-2 mA) to the brain via skin-electrode interface,
      creating electric field that modulates neuronal activity. This modulation is polarity
      dependent toward depolarization after anodal stimulation (excitatory) and toward
      hyperpolarization after cathodal stimulation (inhibitory), leading to transient changes in
      the resting membrane potential. The cumulative effect of longer stimulation results in a
      polarity-dependent facilitation or inhibition of the spontaneous neuronal firing rate and is
      considered neuromodulatory.

      tDCS, provokes a sub-threshold modulation of neuronal excitability without depolarizing
      action potentials5. Post stimulation effects of tDCS depends on the duration of stimulation
      (lasting from several minutes up to hours) and can be found in the areas under the electrodes
      and also remote by network changes.

      The mechanism by which tRNS influences brain activity differs from tDCS. The delivery of tRNS
      uses the same equipment as for tDCS. In tRNS, however, both electrodes can be used to
      stimulate either in homologous locations bilaterally or at different regions simultaneously.
      tRNS can be used to stimulate a region with a current that varies randomly in time. Such
      stimulation can induce excitability that lasts up to 60 minutes per 10 minutes of
      stimulation1. The most beneficial type of tRNS is at high-frequency (100-640Hz).

      This is a randomized, double blinded, placebo-controlled, crossover study in ADHD children.
      Eligible participants will be randomized into the 3 following groups:

        1. tDCS-placebo (sham) group to receive either tDCS or matching placebo (sham( during 5
           following days (one session each day). After a one week break, there will be a crossover
           between the control group and the sham group: those we received tDCS in the 1st week
           will get sham, while those who received sham in the 1st week will received tDCS at the
           3rd week.

        2. tRNS-sham group, who will receive the same type of intervention with the same intervals
           as above but with tRNS instead of tDCS.

        3. tDCS-tRNS group. Here the same intervention as above will be provided with the same
           intervals, but real tDCS and real tRNS will be provided in a counterbalanced fashion.
           This would allow to compare the different treatment in a within-subject design, as well
           as to compare the effect of those to sham stimulation in the first two groups in a
           between-subject design.

      The total duration of subject participation will be 4 weeks. The study is conducted in the
      ADHD clinic of the Neuro-Cognitive Centre, at Hadassah-Hebrew University Medical Center.

      tDCS: Stimulation would be applied using semi-dry 5X5 cm electrodes. The current would be
      0.75mA, which based on previous computational modeling of tDCS in children and is estimated
      to equal that of 1-1.5 mA in adults. This decision was made after considering the parameters
      that would influence current distribution and density at the site of stimulation such as
      thinner scalp, less cerebrospinal fluid, and smaller head size of the paediatric population.
      A similar dosage using tDCS was well tolerated by children, and was not associated with
      adverse effects29. The anodal electrode will be positioned above the dlPFC (F3 based on the
      International 10-20 system, while the cathodal electrode would be placed over the right
      supraorbital. tRNS: Children in the active tRNS group will received 0.75mA of tRNS
      (100-640Hz) to their left dorsolateral prefrontal cortex (dlPFC) and the right inferior
      frontal gyrus (IFG) via semi-dry 5cm X 5cm electrodes, attached under designated electrode
      positions (F3, F8) of a tES cap that followed the International 10-20 system (InnoSphere
      Inc., Haifa). The left dlPFC and right IFG were chosen, based on their contribution in
      executive control and inhibition. tRNS will be applied for 20 minutes per session during an
      iPad cognitive training. Similar duration has also been used in paediatrics using tDCS29.
      Similar to a previous tRNS study in children, and the rational provided for tDCS we will
      apply 0.75mA.

      Sham: For sham-tRNS we will use the same montage as in active tRNS. For sham-tDCS we will use
      the same montage as in active tDCS. The only difference between active and sham tES would be
      that in the case of the sham tES the 30 sec of ramp up of the current from 0 to 0.75mA would
      not be followed by 19 min of stimulation at 0.75mA as in active tES, but would immediately be
      followed by 30 sec ramp down period to 0mA. Such method has been shown to provide effective
      blindness of the stimulation condition as both active and sham tES would lead to slight
      itching sensation that would disappear due scalp habitation. No further stimulation would be
      provided in the sham group during the daily session.

      The study will include 60 boys aged 7 to 12 years. The participants will be recruited among
      children referred to the clinic by pediatricians, general practitioners, teachers,
      psychologists or parents.
    

Intervention name(s): tDCS; tRNS; sham
Intervention type(s): Device; Device; Device
Intervention description(s): Stimulation would be applied using semi-dry 5X5 cm electrodes. The current would be 0.75mA, which based on previous computational modeling of tDCS in children and is estimated to equal that of 1-1.5 mA in adults. This decision was made after considering the parameters that would influence current distribution and density at the site of stimulation such as thinner scalp, less cerebrospinal fluid, and smaller head size of the paediatric population. A similar dosage using tDCS was well tolerated by children, and was not associated with adverse effects29. The anodal electrode will be positioned above the dlPFC (F3 based on the International 10-20 system, while the cathodal electrode would be placed over the right supraorbital.; Children in the active tRNS group will received 0.75mA of tRNS (100-640Hz) to their left dorsolateral prefrontal cortex (dlPFC) and the right inferior frontal gyrus (IFG) via semi-dry 5cm X 5cm electrodes, attached under designated electrode positions (F3, F8) of a tES cap that followed the International 10-20 system (InnoSphere Inc., Haifa). The left dlPFC and right IFG were chosen, based on their contribution in executive control and inhibition. tRNS will be applied for 20 minutes per session during an iPad cognitive training. Similar duration has also been used in paediatrics using tDCS29. Similar to a previous tRNS study in children, and the rational provided for tDCS we will apply 0.75mA.; For sham-tRNS we will use the same montage as in active tRNS. For sham-tDCS we will use the same montage as in active tDCS. The only difference between active and sham tES would be that in the case of the sham tES the 30 sec of ramp up of the current from 0 to 0.75mA would not be followed by 19 min of stimulation at 0.75mA as in active tES, but would immediately be followed by 30 sec ramp down period to 0mA. Such method has been shown to provide effective blindness of the stimulation condition as both active and sham tES would lead to slight itching sensation that would disappear due scalp habitation. No further stimulation would be provided in the sham group during the daily session.
Allocation: Randomized
Intervention model: Crossover Assignment
Intervention model description: 'tDCS-tRNS' arm: a randomized controlled crossover study. 'tRNS-Sham' arm: a randomized controlled trial
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: ADHD; TRANS CRANIAL ELECTRIC STIMULATION