Single-session tDCS in Cerebral Palsy

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

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.

Participants and families will be masked to intervention group. The research team members performing assessments will be masked to intervention group.

Anodal tDCS (excitatory) applied to the lesioned hemisphere. Participant must have lesioned hemisphere MEP.

Cathodal tDCS (inhibitory) applied to the non-lesioned hemisphere. Participant must have lesioned hemisphere MEP.

Anodal tDCS (excitatory) applied to the non-lesioned hemisphere. Participant must not have lesioned hemisphere MEP.

Motor evoked potential is a measure of cortical excitability using transcranial magnetic stimulation. MEP is measured as the amplitude of electrical activity from finger muscles. Outcome is reported as the percent change in MEP amplitude from pre-intervention to immediately post-intervention.

Finger tracking was measured using an instrumented goniometer that recorded finger position, which was then used to control a cursor on a laptop computer. The outcome is reported as the percent change in accuracy from pre-intervention to 60 minutes post-intervention.

Inclusion Criteria (for all participants): Ages 7-21 Able to follow two-step commands. Presence of an MEP in the non-lesioned hemisphere Exclusion Criteria (for all participants): Evidence of seizure within 2 years Other neurological or metabolic conditions Is pregnant (females only) Presence of indwelling metal in the head (e.g. aneurysm clip) or medical device. Inclusion Criteria (for participants with cerebral palsy): Clinical diagnosis of unilateral cerebral palsy Radiological evidence of stroke or periventricular leukomalacia Exclusion Criteria(for participants with cerebral palsy): Treatment with injectable agents (e.g. Botox) for spasticity management within 2 months

Christensen D, Van Naarden Braun K, Doernberg NS, Maenner MJ, Arneson CL, Durkin MS, Benedict RE, Kirby RS, Wingate MS, Fitzgerald R, Yeargin-Allsopp M. Prevalence of cerebral palsy, co-occurring autism spectrum disorders, and motor functioning - Autism and Developmental Disabilities Monitoring Network, USA, 2008. Dev Med Child Neurol. 2014 Jan;56(1):59-65. doi: 10.1111/dmcn.12268. Epub 2013 Oct 1.

Bolognini N, Vallar G, Casati C, Latif LA, El-Nazer R, Williams J, Banco E, Macea DD, Tesio L, Chessa C, Fregni F. Neurophysiological and behavioral effects of tDCS combined with constraint-induced movement therapy in poststroke patients. Neurorehabil Neural Repair. 2011 Nov-Dec;25(9):819-29. doi: 10.1177/1545968311411056. Epub 2011 Jul 29.

Figlewski K, Blicher JU, Mortensen J, Severinsen KE, Nielsen JF, Andersen H. Transcranial Direct Current Stimulation Potentiates Improvements in Functional Ability in Patients With Chronic Stroke Receiving Constraint-Induced Movement Therapy. Stroke. 2017 Jan;48(1):229-232. doi: 10.1161/STROKEAHA.116.014988. Epub 2016 Nov 29.

Antal A, Terney D, Poreisz C, Paulus W. Towards unravelling task-related modulations of neuroplastic changes induced in the human motor cortex. Eur J Neurosci. 2007 Nov;26(9):2687-91. doi: 10.1111/j.1460-9568.2007.05896.x. Epub 2007 Oct 26.

Duque J, Hummel F, Celnik P, Murase N, Mazzocchio R, Cohen LG. Transcallosal inhibition in chronic subcortical stroke. Neuroimage. 2005 Dec;28(4):940-6. doi: 10.1016/j.neuroimage.2005.06.033. Epub 2005 Aug 9.

Murase N, Duque J, Mazzocchio R, Cohen LG. Influence of interhemispheric interactions on motor function in chronic stroke. Ann Neurol. 2004 Mar;55(3):400-9. doi: 10.1002/ana.10848.

Zewdie E, Damji O, Ciechanski P, Seeger T, Kirton A. Contralesional Corticomotor Neurophysiology in Hemiparetic Children With Perinatal Stroke. Neurorehabil Neural Repair. 2017 Mar;31(3):261-271. doi: 10.1177/1545968316680485. Epub 2016 Nov 24.

Kirton A, Deveber G, Gunraj C, Chen R. Cortical excitability and interhemispheric inhibition after subcortical pediatric stroke: plastic organization and effects of rTMS. Clin Neurophysiol. 2010 Nov;121(11):1922-9. doi: 10.1016/j.clinph.2010.04.021.

Collange Grecco LA, de Almeida Carvalho Duarte N, Mendonca ME, Galli M, Fregni F, Oliveira CS. Effects of anodal transcranial direct current stimulation combined with virtual reality for improving gait in children with spastic diparetic cerebral palsy: a pilot, randomized, controlled, double-blind, clinical trial. Clin Rehabil. 2015 Dec;29(12):1212-23. doi: 10.1177/0269215514566997. Epub 2015 Jan 20.

Nitsche MA, Paulus W. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology. 2001 Nov 27;57(10):1899-901. doi: 10.1212/wnl.57.10.1899.

Gillick BT, Krach LE, Feyma T, Rich TL, Moberg K, Thomas W, Cassidy JM, Menk J, Carey JR. Primed low-frequency repetitive transcranial magnetic stimulation and constraint-induced movement therapy in pediatric hemiparesis: a randomized controlled trial. Dev Med Child Neurol. 2014 Jan;56(1):44-52. doi: 10.1111/dmcn.12243. Epub 2013 Aug 21.

Kirton A, Chen R, Friefeld S, Gunraj C, Pontigon AM, Deveber G. Contralesional repetitive transcranial magnetic stimulation for chronic hemiparesis in subcortical paediatric stroke: a randomised trial. Lancet Neurol. 2008 Jun;7(6):507-13. doi: 10.1016/S1474-4422(08)70096-6. Epub 2008 May 1.

Ciechanski P, Kirton A. Transcranial Direct-Current Stimulation Can Enhance Motor Learning in Children. Cereb Cortex. 2017 May 1;27(5):2758-2767. doi: 10.1093/cercor/bhw114.

Kirton A, Ciechanski P, Zewdie E, Andersen J, Nettel-Aguirre A, Carlson H, Carsolio L, Herrero M, Quigley J, Mineyko A, Hodge J, Hill M. Transcranial direct current stimulation for children with perinatal stroke and hemiparesis. Neurology. 2017 Jan 17;88(3):259-267. doi: 10.1212/WNL.0000000000003518. Epub 2016 Dec 7.

Bikson M, Grossman P, Zannou AL, Kronberg G, Truong D, Boggio P, Brunoni AR, Charvet L, Fregni F, Fritsch B, Gillick B, Hamilton RH, Hampstead BM, Kirton A, Knotkova H, Liebetanz D, Liu A, Loo C, Nitsche MA, Reis J, Richardson JD, Rotenberg A, Turkeltaub PE, Woods AJ. Response to letter to the editor: Safety of transcranial direct current stimulation: Evidence based update 2016. Brain Stimul. 2017 Sep-Oct;10(5):986-987. doi: 10.1016/j.brs.2017.06.007. Epub 2017 Jul 12. No abstract available.

Giacobbe V, Krebs HI, Volpe BT, Pascual-Leone A, Rykman A, Zeiarati G, Fregni F, Dipietro L, Thickbroom GW, Edwards DJ. Transcranial direct current stimulation (tDCS) and robotic practice in chronic stroke: the dimension of timing. NeuroRehabilitation. 2013;33(1):49-56. doi: 10.3233/NRE-130927.

Lazzari RD, Politti F, Santos CA, Dumont AJ, Rezende FL, Grecco LA, Braun Ferreira LA, Oliveira CS. Effect of a single session of transcranial direct-current stimulation combined with virtual reality training on the balance of children with cerebral palsy: a randomized, controlled, double-blind trial. J Phys Ther Sci. 2015 Mar;27(3):763-8. doi: 10.1589/jpts.27.763. Epub 2015 Mar 31.

Gillick BT, Feyma T, Menk J, Usset M, Vaith A, Wood TJ, Worthington R, Krach LE. Safety and feasibility of transcranial direct current stimulation in pediatric hemiparesis: randomized controlled preliminary study. Phys Ther. 2015 Mar;95(3):337-49. doi: 10.2522/ptj.20130565. Epub 2014 Nov 20.

Antal A, Alekseichuk I, Bikson M, Brockmoller J, Brunoni AR, Chen R, Cohen LG, Dowthwaite G, Ellrich J, Floel A, Fregni F, George MS, Hamilton R, Haueisen J, Herrmann CS, Hummel FC, Lefaucheur JP, Liebetanz D, Loo CK, McCaig CD, Miniussi C, Miranda PC, Moliadze V, Nitsche MA, Nowak R, Padberg F, Pascual-Leone A, Poppendieck W, Priori A, Rossi S, Rossini PM, Rothwell J, Rueger MA, Ruffini G, Schellhorn K, Siebner HR, Ugawa Y, Wexler A, Ziemann U, Hallett M, Paulus W. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines. Clin Neurophysiol. 2017 Sep;128(9):1774-1809. doi: 10.1016/j.clinph.2017.06.001. Epub 2017 Jun 19.

Krishnan C, Santos L, Peterson MD, Ehinger M. Safety of noninvasive brain stimulation in children and adolescents. Brain Stimul. 2015 Jan-Feb;8(1):76-87. doi: 10.1016/j.brs.2014.10.012. Epub 2014 Oct 28.

Gillick B, Rich T, Nemanich S, Chen CY, Menk J, Mueller B, Chen M, Ward M, Meekins G, Feyma T, Krach L, Rudser K. Transcranial direct current stimulation and constraint-induced therapy in cerebral palsy: A randomized, blinded, sham-controlled clinical trial. Eur J Paediatr Neurol. 2018 May;22(3):358-368. doi: 10.1016/j.ejpn.2018.02.001. Epub 2018 Feb 11.