Single-session tDCS in Cerebral Palsy
Condition: Cerebral Palsy; Perinatal Stroke; Periventricular Leukomalacia
MeSH terms: Cerebral Palsy; Leukomalacia, Periventricular
Study type: Interventional

Summary: 
      The goal of this study is to characterize individual responses to a single application of
      transcranial direct current stimulation (tDCS) in children with unilateral cerebral palsy
      (UCP), and to test which electrode configuration produces changes in brain excitability and
      motor function. Participants with UCP, ages 7-21 years, will be assigned to one of four tDCS
      groups. Using single-pulse transcranial magnetic stimulation, the investigators will assess
      cortical excitability before and at regular intervals up to 1 hour following tDCS. The
      knowledge gained from this study will advance the field through more targeted approaches of
      neuromodulatory techniques in this population and others, using individual characteristics to
      guide optimal treatment
    

Detailed description: 
      Hemiparesis, or weakness on one side of the body, is common following stroke early in life.
      The broader clinical diagnosis for this type of childhood movement impairment is unilateral
      cerebral palsy (UCP). Cerebral palsy effects about 3 out of every 1000 live births in the
      Unites States, and produces lifelong motor, sensory, and cognitive disability.

      Neurorehabilitation has primarily focused on intensive motor training to encourage use of the
      affected extremities in an effort to produce use-dependent neuroplasticity in the brain. Such
      interventions are effective, but require a burdensome amount of time, 60-90 hours per week,
      for both the child and therapist. Furthermore, some children do not respond at all to such
      training.

      Neuromodulation is a relatively new field that aims to influence the brain's neuronal
      activity through direct application of magnetic (TMS) or electric (tDCS) energy. It is
      thought the combination of neuromodulation and motor training may reduce the dosage of
      training needed, and would promote recovery to a greater extent for more individuals. Indeed,
      previous work in adult stroke demonstrate a benefit of combining repetitive TMS (rTMS) and
      tDCS with motor training, compared to training alone. These types of synergistic
      interventions are just beginning to be used in children with UCP, with some preliminary data
      showing potential benefit.

      One of the many questions surrounding neuromodulatory interventions like tDCS is how to
      reliably predict changes in neuronal activity. The currently hypothesized effects of tDCS are
      polarity-specific: anodal tDCS depolarizes membranes resulting in increased in neuronal
      excitability; cathodal tDCS hyperpolarizes tDCS resulting in decreased neuronal excitability.
      Furthermore, these effects scale with the intensity of stimulation: the larger the direct
      current delivered, the greater the change in excitability. This framework has been used to
      guide almost all studies using tDCS to produce a change in brain function and resulting
      behavior.

      More recently, the field is beginning to appreciate that this framework may be overly
      simplistic. For example, when a cognitive task is performed concurrently with tDCS, there are
      reported non-linear effects related to current intensity and direction of change in
      excitability. Such work has a significant impact on the use of tDCS in rehabilitation, which
      advocates for the pairing of stimulation with on-going activity.

      One common approach to using tDCS in individuals with stroke is to target the non-lesioned
      hemisphere. Following stroke, there is an imbalance of communication between brain
      hemispheres. This communication, known as interhemispheric inhibition (IHI), is a normal
      control process whereby the activated motor cortex sends an inhibitory command to the
      opposite motor cortex to momentarily interrupt its activity, allowing for the execution of
      controlled unilateral movements. IHI is exaggerated in the non-lesioned hemisphere after
      stroke, resulting in increased inhibition on the lesioned hemisphere. Applying inhibitory
      current to the non-lesioned hemisphere may disinhibit this side and allow for recovery in the
      lesioned hemisphere.

      IHI is mediated through fibers passing through the corpus callosum and can be examined
      non-invasively using TMS. First and foremost, IHI has been shown to exist in children and
      young adults, indicating that this mechanism is not exclusively a feature of the developed
      adult nervous system. The effect of NIBS to modulated IHI has been demonstrated in adults
      with stroke, but less clearly in children. One reason for this is a lack of data
      characterizing IHI in children after perinatal brain injury. It is feasible, through ongoing
      adaptive and maladaptive neuroplasticity, that IHI is weakly present (or not at all) in these
      children as compared to adults. As studies continue to focus on NIBS interventions targeting
      the non-lesioned hemisphere, a more comprehensive understanding of the motor control
      mechanisms present in children with UCP is needed to guide these interventions. Therefore,
      one objective of this study is to characterize IHI of both brain hemispheres in children with
      UCP.

      At the moment, it is unclear what the acute effects of a single session tDCS are, when paired
      with motor training, on brain excitability or motor performance in children with and without
      UCP. This leads this investigative team to design the proposed study, which will offer
      insight into the mechanisms of tDCS and lead the field toward a better understanding of how
      tDCS be implemented in a neurorehabilitation setting for both children and potentially
      adults.

      Purpose: To characterize motor cortex neurophysiology and to understand how one form of
      non-invasive brain stimulation (NIBS) called transcranial direct current stimulation (tDCS)
      changes brain excitability and behavior in children diagnosed with cerebral palsy, as
      compared to children with typical development (CTD).

      Aim 1: Using transcranial magnetic stimulation (TMS), characterize brain excitability,
      specifically interhemispheric inhibition, in children with CP and CTD.

      Aim 2: Evaluate the immediate effect of tDCS on brain excitability and motor performance in
      children with UCP and CTD.

      Aim 3: Compare the responses to tDCS in each with individual estimated electric field
      intensity from computational modeling.

      Procedures:

      This is a randomized, sham-controlled, double-blinded study. The intervention consists of a
      single, 20 minute session of tDCS paired with motor training (see Figure 2). Participants
      will be randomized to either real or sham tDCS. The participants and the members of the
      research team involved in assessments and testing will be blinded to intervention group (real
      or sham tDCS), but the other research staff/PI/Co-Is will be unblinded.

      The investigators will complete TMS assessments of cortical excitability at Pre-test, as well
      as an MRI of the brain. Behavioral assessments of hand function and performance will also be
      included.

      The intervention will last a total of 30 minutes, including preparatory time. Participants
      will be randomly assigned to receive real or sham tDCS. Children with presence of a lesioned
      hemisphere motor evoked potential (MEP) response may receive 1) ipsilesional anodal; 2)
      contralesional cathodal tDCS or 3) sham tDCS. Children without a lesioned hemisphere MEP may
      receive 1) contralesional anodal or 2) sham tDCS. Participants and their families will be
      blinded to group assignment. Participants will be unblinded after completing the study.

      Immediately following the intervention, TMS and Behavioral assessments will be performed at
      0, 15, 30, and 60 minutes following the intervention.

      Study Duration: Each participant will complete the study in either one day (MRI and
      intervention, four hours total) or on two separate days (one hour MRI, and three hours
      intervention). If done on two days, the MRI and intervention will be separated by no longer
      than a two week (14 day) period.
    

Intervention name(s): Active tDCS; Sham tDCS
Intervention type(s): Device; Device
Intervention description(s): Low-level (1.5 milliampere) current delivered to the scalp using saline-soaked sponges.; Sham-setting--no electrical current delivered.
Other intervention name(s): transcranial direct current stimulation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: non-invasive brain stimulation; rehabilitation; pediatrics