Advancing non-invasive neuromodulation clinical trials in ...First principles of neuromodulation...

Original article

Advancing non-invasive neuromodulation clinicaltrials in children: Lessons from perinatal stroke

Adam Kirton

Departments of Pediatrics and Clinical Neurosciences, Cumming School of Medicine, Hotchkiss Brain Institute andAlberta Children's Hospital Research Institute, 2888 Shaganappi Trail NW, Calgary, AB T3B6A8, Canada

Keywords:

Neuroplasticity

Developmental plasticity

Brain stimulation

Cerebral palsy

Perinatal stroke

Transcranial magnetic stimulation

Transcranial direct current stimula-

tion

Clinical trials

a b s t r a c t

Applications of non-invasive brain stimulation including therapeutic neuromodulation are

expanding at an alarming rate. Increasingly established scientific principles, including

directional modulation of well-informed cortical targets, are advancing clinical trial

development. However, high levels of disease burden coupled with zealous enthusiasm

may be getting ahead of rational research and evidence. Experience is limited in the

developing brain where additional issues must be considered. Properly designed and

meticulously executed clinical trials are essential and required to advance and optimize

the potential of non-invasive neuromodulation without risking the well-being of children

and families. Perinatal stroke causes most hemiplegic cerebral palsy and, as a focal injury

of defined timing in an otherwise healthy brain, is an ideal human model of developmental

plasticity. Advanced models of how the motor systems of young brains develop following

early stroke are affording novel windows of opportunity for neuromodulation clinical tri-

als, possibly directing neuroplasticity toward better outcomes. Reviewing the principles of

clinical trial design relevant to neuromodulation and using perinatal stroke as a model, this

article reviews the current and future issues of advancing such trials in children.

© 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights

reserved.

1. First principles of neuromodulationclinical trials

Non-invasive brain stimulation applications are exploding.There is great and justified concern that the rate of growth inthe number of brains being stimulated is already far exceedingthe level of science that supports the approach. There are

major issues of unregulated use across broad and oftenvulnerable populations with immoral marketing of unproven,

potentially dangerous devices. Examples range from shame-less promotion of enhanced gaming performance to teenagersto do it yourself tDCS machines being made in people's base-ments. Ethical issues specific to the application of brain

stimulation in children must also be considered. For thesereasons, and in order to advance the responsible scientificstudy of neuromodulation in the developing brain, severalprinciples merit discussion here.

It is highly unlikely that introducing a focal magnetic fieldor local current into a functional area of human cortex will

E-mail address: [email protected].

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magically create new, clinically relevant function. Instead, an

endogenous substrate for neuroplasticity thatmight be alteredby such neuromodulation seems a much more likely mecha-nism by which brain stimulation might produce lasting, ther-apeutic alterations in brain function. This fundamentaltenet also helps correct for the known and large heterogeneitybetween subjects inevitably enrolled in such trials. That a TMSmeasurement as simple as the rest motor threshold can rangefrom 20 to over 60% of maximum stimulator output across asample of normal subjects of the same age and gender pointsto anevenmore enormous inter-subject variability in clinicallydiseased populations. However, if such subjects share funda-

mental neuroplasticity mechanisms within their cortex (e.g.long termpotentiation) and are induced to activate them in thecontext of desired, functional activity, the potential for neu-romodulation is likely greater.

In a similar context, an informed cortical target for mod-ulation is also essential. Identification of such functionallyrelevant cortical regions is often difficult. As outlined below,studies of enhancement of motor learning with brain stimu-lation and have often logically targeted the primary motorcortex. This has logically extended to clinical populationswithmotor disability, targeting the motor cortex and related

network components in common populations of motordisability such as adult stroke hemiparesis.1 Importantly, thisevolving process has not rested on such simplistic anatomicallocalization alone. Instead, neurophysiological models havebeen developed to first understand what happens to the sys-tem of interest in the disease state. These often include largebodies of evidence from preclinical animal models combinedwith human studies using advanced neuroimaging and otherneurophysiology tools. Such an example for perinatal strokewill be presented below.

Such models not only identify potential targets but also a

desired direction for change. For example, the lesioned motorcortexmay be underactivewhile the homologous region of thecontralateral, non-lesioned hemisphere may be relativelyoveractive. Such a model of “imbalanced interhemisphericmotor inhibition” is probably over simplified but is well sup-ported by large volumes of neurophysiological evidence andhas driven the majority of non-invasive brain stimulationtrials in adult stroke.1,2 Recent summative evidence of rTMStherapeutic trials highlights this point by comparing modal-ities and targets across a wide range of such conditions.3

Importantly, each these three principles of modulating aninformed target in a specific direction during activation of endoge-

nous plasticity are arguably still not well defined in relativelyconcrete examples like adult stroke. In fact, such principlesare often not entirely obvious (or even theoretically welldefined) in many other stimulation clinical trials. While suchfailure should raise immediate concerns of validity, theirpresence is relatively sparse in the most defined therapeuticnon-invasive brain stimulation population: adult majordepression. High frequency rTMS of the dominant dorsolat-eral prefrontal cortex (DPFC) is FDA and Health Canadaapproved and rapidly expanding as an insured service. Whilebased on some human evidence of regional dysfunction in

this broad, highly connected areawith functional implicationsfor some symptomology, it could be argued that the ability ofdepression to satisfy the above criteria is modest at best.

This raises a final principle consideration of disease spec-

ificity. As a very common, disabling, and highly studied dis-ease, major depression carries well-defined diagnostic andclassification criteria. Despite this, there are innumerablefactors, both measureable and unknown, that would likelyinfluence response to neuromodulation. In contrast, autism isa heterogeneous disorder of social and communicationdevelopment that is likely due to hundreds of different geneticdisorders in addition to other etiologies. This does not meanthat informed, symptom-specific targeting of cortical regionsto enhance other therapies or learning is impossible. Howev-er, the breadth of heterogeneity must be acknowledged and

adjusted for whenever possible if meaningful trials are to bedesigned. Trials of autism due to one specific mutation bringlimitations of recruitment and sample size and are still notideal; consider the phenotypic variability of tuberous sclerosisalone. However, striving for disease specificity wheneverpossible will likely advance progress in paediatric neuro-modulation trials much faster. Extricating the very specificforms of perinatal stroke from the more complex world ofcerebral palsy for motor learning neuromodulation trialsprovides a practical example.

2. Perinatal stroke

You will not likely incur a higher period of risk for ischaemicstroke than the week you are born.4 A term newborn carries arisk >1:3500,5 three-fold higher than a week in the life of adiabetic, hypertensive, smoking adult and eight-fold above alladults.6 An additional 50% of perinatal stroke presents later in

infancy.7 Perinatal stroke is the leading cause of hemiplegiccerebral palsy (HCP) and most survivors suffer additionalneurological sequelae including intellectual disabilities, lan-guage impairments, developmental and behavioural disor-ders, and epilepsy.8e10 Frequent occurrence combined withlifelong morbidity generates large global burdens. Identifica-tion of a causative factor remains elusive in most cases11 andwith no means of prevention, perinatal stroke and HCP willburden thousands of children for decades to come.

An essential first step in improving outcomes from peri-natal brain injury is to understand the underlying disease. We

have defined distinct clinical-radiographic perinatal strokesyndromes,11,12 refining perinatal stroke research towardspecific disease states. Two main types predominate. Theseare summarized in Fig. 1. We have validated this imaging-based classification system and demonstrated it's researchapplications including the prediction of long-term neurolog-ical outcomes,12,13 recognition of novel risk factors,14e16 im-aging markers of disease processes, and new targets fortherapeutic interventions.14,17Arterial ischaemic strokes (AIS)are large brain injuries secondary to occlusion of major cere-bral arteries. Some present at birth with acute seizures (calledsymptomatic neonatal AIS) while others are not recognized

until infancy when hemiparesis becomes evident (calledarterial presumed perinatal ischaemic stroke).7,18e20 Incontrast, periventricular venous infarctions (PVI) are subcor-tical white matter lesions acquired well before birth. Sec-ondary to germinal matrix bleeds with subsequent medullaryvenous infarction, these lesions occur in utero before 34 weeks




gestation.21e26 MRI work by our group and others can detectthese remote foetal bleeds, facilitating accurate diag-nosis.12,26,27 Our recent work has begun elucidating the path-

ophysiological and plasticity mechanisms in PVI.12,14,27 Ourimaging and population-based data12 suggest AIS and PVIprevalence are similar. Most relevant here, both AIS and PVIinjure primary components of the motor system early in life,resulting in HCP. This commonality of focal motor injury in ahealthy brain, combined with distinct differences in lesiontiming and location, makes perinatal stroke the ideal humanmodel for the study of developmental plasticity.

3. Perinatal stroke outcomes

Neurodevelopmental deficits occur in ~75% of perinatal strokesurvivors.8,10,19,28e34 Hemiparetic CP is the most commonterm-born cerebral palsy35 and stroke is the leading cause.36,37

Motor deficits are the most prominent and disabling

symptom, present in 30e60% of acute symptomaticNAIS31,38,39 and >80e90% of presumed perinatal ischaemicstrokes including PVI.12,18,19,31 Clinical, laboratory, and EEG

variables are limited in their abilities to predict motoroutcome,9,10,29,34,40 but neuroimaging has improved the earlyidentification of the most affected children.31,33,34,41e44 Weand others have described how corticospinal tract diffusionMRI in NAIS45,46 and structural MRI in PPIS12 can predictmotoroutcomes in infancy. This has opened the window for inter-vention earlier in development. Deficits in language, vision,cognition, behaviour and epilepsy also occur, present in20e60%8,10,18,19,47e49 of arterial strokes. The morbidity ofperinatal stroke lasts a lifetime, amplifying the burden onchild, family, and society.50 Physical disability contributes

across this realm of consequences and current interventionshave limited efficacy.51 There is therefore an urgent need fornew treatment strategies founded upon our best possibleunderstanding of the neurophysiology that underlies theclinical dysfunction.

Fig. 1 e Developmental plastic motor organization following perinatal stroke. (A) Arterial perinatal strokes (NAIS or APPIS)acquired near term result in damage to cortical and subcortical structures. (B) Periventricular venous infarction (PVI) areacquired in utero prior to 34 weeks gestation resulting in isolated injury to the subcortical white matter. Both lesionsdamage corticospinal tracts, leading to contralateral hemiparetic CP. (C) Animal and human evidence has constructedworking models of developmental motor organization following such early unilateral injury. Control of the weak right hand(W) often relies on both contralateral corticospinal pathways from the left (lesioned) motor cortex (LM1) and ipsilateralprojections from the unlesioned (right) motor cortex (RM1, dashed line). These two inputs compete to establish synapseswith anterior horn spinal motor neuron pools (circles) during development. Each M1 may also influence the other via IHI(coloured dashed arrows). The relative interhemispheric balance is associated with clinical function with contralateralcontrol associated with better function. Interventions that promote the success of contralateral (or inhibit the success ofipsilateral) upper motor neuron systems to compete for spinal motor neurons could result in better motor function.

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4. Plastic organization following unilateralperinatal brain injury: an integrated model

In 1936, Kennard described better outcomes in younger pri-mates following unilateral motor cortex lesions.52 This Ken-nard principle has fostered efforts to understand and harnessage-related plasticity. Common occurrence and focal injury inan otherwise healthy brain makes perinatal stroke an ideal

humanmodel. Terms like “repair” and “reorganization” implythe existence of inherent restorative mechanisms thatevolutionary models suggest would not exist.53 Instead, plas-tic adaptation may represent alterations of normal, ongoingdevelopmental processes occurring after injury. Elegant ani-mal work and human studies have solidified a model thatcreates novel avenues for therapeutic interventions in hemi-paretic CP.54e56 The model consists of 3 primary components(see Fig. 1): The lesioned (A) and non-lesioned (B) motor cortex(and their intra and inter-hemispheric connections) and theirinfluence on spinal motor neuron pools (C).

A. The lesioned hemisphere: contralateral projections tothe paretic hand. Adult stroke and animal studies sug-gest that, on average, motor control in the lesionedhemisphere is associated with better function.57e61 A

small childhood stroke study showed that recruitmentof perilesional motor area may be associated withhigher function.62 We have further correlated thepresence of contralateral projections from the lesionedhemisphere with better function.63,64 Rare hemipareticCP studies have shown decreased excitability in thelesioned hemisphere65 while maintained motor activa-tions approximate typical motor areas.66 PVI-like le-sions have associated this contralateral arrangementwith better function.67 Small studies have suggestedrehab-induced clinical gains may be associated withincreases in lesioned motor cortex activations in

HCP.68,69 Enhancing motor control in the lesionedhemisphere should favour improved function.

B. Role of the unlesioned hemisphere: ipsilateral pro-jections to the paretic hand. Abnormal projections fromthe unlesioned hemisphere to the paretic hand arecommon in hemiparetic CP70e75 but inconsistent intheir physiology.70e73,76e78 Ipsilateral projections arepresent in equal proportion at birth but are subse-quently withdrawn during normal development.79

Ipsilateral projections likely arise from homologous re-gions of primary motor cortex (M1).67,76,77,13 Our work

suggests the same in both childhood64,78 and perinatalstroke.81 In HCP,70e74,77,13 arterial,73e75,82,174 and PVI-likelesions67,73,74 ipsilateral projections are associated withpoorer motor function. Over-activity of the non-lesioned M1 may be associated with larger defi-cits.67,73,82 In the largest TMS study of perinatal stroke(n ¼ 52), we recently described the neurophysiology ofthe contralesional hemisphere, validating many ofthese observations (Zewdie et al., under review).

Recruitment of ipsilateral projections may thereforerepresent an example of maladaptive plastic organization

not compatible with normal hand function. A patho

logically overactive contralesional M1 controlling the ipsi-

lateral weak hand represents a potential therapeutic targetin hemiparetic CP.55,84 Decreasing pathological over-activity of non-lesioned M1 may enhance motor learningin adult stroke.85e88 In the original Kennard experiments,lesioning the contralesional M1 months after initial injuryin young primates improved function of the originallyparetic limb.52 Complex cortical motor circuits within andbetween the hemispheres also mediate neuroplasticityincluding interhemispheric inhibition (IHI)89,90 and intra-cortical inhibitory and facilatory circuits.65,91,92 Alterationsin these have provided insight to adult stroke recov-

ery.93e97 Each of these model components representneurophysiological outcomes measurable with moderntechnologies (below).98We havemeasured such systems inchildren with paediatric99 and perinatal81 stroke, confirm-ing their relevance to clinical function.C. Synaptic competition model. The target of these devel-

oping upper motor neuron systems are the spinal lowermotor neurons, control of which determines function.Continuous competition between contralateral andipsilateral corticospinal tract projections to establishsynapses with these cells occurs through development

with eventual contralateral domination andwithdrawalof ipsilateral projections.54,55 Primate studies confirm aprotracted developmental period for such organ-ization56,100e102 spanning childhood and into adult-hood.103 Injury likely reduces the normal contralateraladvantage, allowing ipsilateral projections to establishcontrol in more severe hemiparetic CP.

Cortical stimulation or inhibition can modulate this pro-cess. Pharmacological inhibition of M1 alters spinal motorneuron innervation and enhances ipsilateral pro-jections104,105 as seen in hemiparetic CP.55 Daily M1 elec-

trical stimulation can also preserve the corticospinalconnections normally withdrawn during early develop-ment in cats.106 These findings complement evidence ofactivity-dependent enhancement of corticospinal connec-tions in animal,105 histopathological,107 and neurophysio-logical studies.71,79 Interventional strategies to enhancecontralateral (or inhibit ipsilateral) corticospinal pro-jections might therefore enhance motor development andfunction.56 This might be achieved in two ways e stimu-lation of the lesioned M1 or inhibition of the unlesionedM1. The latter approach carries stronger animal evidence56

with authors concluding that: “activity-dependent pro-

cesses later in development can be harnessed to restore amore normal pattern of corticospinal connectivity andfunction.”

5. The window of opportunity indevelopmental neuroplasticity

Modern definitions of CP suggest deficits are static and non-progressive.108 However, neonates with stroke usuallydemonstrate no observable neurological deficits.109 Asym-metry is not appreciated until 4e6 months12,19 with the fullseverity typically appreciated years later.110 Consistent with




the model above, progressive loss of contralateral control

through early developmentmay result in imbalance of corticalcontrol and motor networks, resulting in impaired function.Both animal100,111 and TMS studies of motor development byourselves99 and others73,112 agree that plastic motor organi-zation continues well beyond adolescence. New trials areproving that the plasticity of even the aged adult brain ismodifiable with multiple interventions.113 Whether or not theoptimal window for interventional modulation suggested inanimal models falls within the earliest years of humandevelopment remains to be determined. Before brain stimu-lation can be advanced toward this very young age of possible

maximal plasticity, the neurophysiology, efficacy, and safetyof modulatory interventions must first be established in olderchildren. Hence, school age children represent the ideal pop-ulation in which brain stimulation and modulation of brainplasticity should be explored. Before invasive, permanent in-terventions (e.g. stem cells)114 can be advanced, non-invasivemeans need to demonstrate efficacy of the approach whileelucidating the neurophysiological principles on which theyare based.

6. Therapeutic neuromodulation inhemiparetic CP

6.1. Intensive motor learning, manual therapy

Owing to an increasing number of clinical trials, evidence foremerging hemiparetic CP therapies is increasing. Constraintinduced movement therapy (CIMT) promotes functional use

of an impaired limb by constraint of the less-impaired limbcoupled with repetitive motor practice.113,115e118 In adultstroke, 2 weeks of CIMT can generate gains lastingyears.113,118,119 Multiple paediatric trials support CIMT effec-tiveness in hemiparetic CP.51,120e128 Consistent with themodel below, functional imaging suggests CIMT shifts motorfunction toward the lesioned hemisphere.68,129e132 CIMT-induced cortical reorganization has been demonstrated inadults with fMRI130,133e135 and TMS129,136e142 and small hem-iparetic CP studies.68,69,132 CIMT limitations include a some-what invasive nature and the exclusion of bimanual learning.

Bimanual approaches can also improve function in hemi-paretic CP trials.143,144 Hand-arm Intensive Bimanual Therapy(HABIT) is an evidence-based, safe, valid, and effective motorlearning therapy in children with hemiparetic CP.124,144e147

Efficacy appears equal to CIMT144 but the absence ofconstraint facilitates functional bimanual motor learning andremoves the complications of casting in our outpatient pop-ulation. Comparisons of CIMT and HABIT suggest possiblegreater achievement of self-directed goals with HABIT.144

Models for intensive motor learning may combine ap-proaches with early CIMT (e.g. week 1) to induce new func-tions in the paretic limb followed immediately (week 2) by

bimanual therapy to encourage incorporation of new functioninto more functional tasks.

How such therapies are delivered has also evolved. Inten-sive, camp-based models are increasingly popular, both forpsychosocial and programming benefits but also to deliverhigh doses of structured motor learning therapy that may

optimize use-dependent changes in brain plasticity and

function. Such programs should be based on best availableevidence and structured according to standardized elementssuch as the TiDIER criteria.105 Consistency of intensity, dosing,and methodology can be increased by strict adherence to amanual of operations by a limited number of trained thera-pists.144 Structured home programs based on the same prin-ciples with ongoing therapist support may be provided duringlonger-term follow-up periods. Therapy programs should bedesigned and delivered by experienced paediatric occupa-tional therapists. The cost of using such highly qualifiedpersonnel for so many hours of 1:1 therapymay be restrictive.

We recently used final year therapy students supervised by 2experienced paediatric OT's to deliver such therapy in campmodel with good success, broader knowledge translation tolearners, and much lower costs.

Providing such intensive, goal-directed, evidence-basedtherapy to all participants provides numerous potential ad-vantages. These go beyond the primary principle above thatan endogenous substrate for plastic change may well be anessential requirement for brain stimulation to be effective.That all subjects receive individualized, “best available”treatment facilitates randomization to such additional in-

terventions where there is equipoise regarding efficacy andminimal, but not zero, risk of adverse events. It creates op-portunity for active, motivated participation focused on aimsthat matter to the individual patient. Limitations include thedosage of therapy achieved over focused time frames wherethe optimal number of hours, both total and divided betweenfocused and more general training, remain to be determined.The balance of unimanual versus bimanual and the timing ofhow the two should be integrated is also imprecise and inneed of better evidence. Lastly, the potential psychologicaland social benefits of such group-based participation with

grouping of participants by developmental level should not beunderestimated. This may be optimized by inclusion of groupactivities within camp based day programs or, alternatively,incorporated into smaller time frames within after schoolprograms, possibly with the addition of group weekends ses-sions. When asked, most children with hemiparesis have notpreviously met a peer with the same disability. Workingtogether to achieve personal goals alongside similarlyaffected, motivated peers likely carries large psychosocialbenefits, themore accuratemeasurement of which is a goal offuture trials.

As outlined below, we have completed two clinical trials of

non-invasive brain stimulation in children with perinatalstroke and hemiparesis. This included a total of 68 partici-pants between the ages of 6 and 18 years: 45 in an rTMS trial105

and 24 in a tDCS intervention (unpublished). All participatedin child-centred, goal-directed, age-appropriate intensivemotor learning programs over 2 weeks.

6.2. Non-invasive brain stimulation: repetitivetranscranial magnetic stimulation (rTMS)

TMS given repeatedly can produce lasting changes in brainfunction. rTMS studies have established this principle inhealth and disease over the past 20 years148e150 with recentevidence-based summaries of therapeutic efficacy.3 High




frequency rTMS (~10 Hz) stimulates cortex which both ani-

mal151e154 and adult148 stroke studies suggest can facilitatemotor function. Similarly, low frequency rTMS (~1 Hz) typi-cally inhibits cerebral cortex though there are exceptions toboth these rules.155e157 rTMS is amenable to randomized,sham-controlled clinical trials.158 Accumulating evidencesuggests rTMS can modulate neural networks159 to enhancemotor function in chronic adult stroke.160,161 Limitations ofrTMS include very focal administration and burdensome,immobile hardware that prevents simultaneous rehabilitationand co-activation of endogenous motor learning systems.

Despite both the high burden of motor disability and

greater brain plasticity in children, rTMS studies have beenlimited. Completed rTMS studies have reported favourabletolerability with no significant adverse events.162e164 DailyrTMS for weeks in animals,165 adults with stroke149,160,166e170

and our recent paediatric stroke trials63,81,160,171 further sup-port this safety. Evidence from our group and others hasshown no adverse effect of non-lesioned M1 inhibitory rTMSon normal (unaffected) hand function in hemiparetic sub-jects.57,63 We completed the first paediatric rTMS randomizedtrial where 8 days of non-lesional inhibitory rTMS improved

hand function in with chronic subcortical stroke acquired

during childhood.63

We recently completed the PLASTIC CHAMPS trial(Fig. 3).172 This was a factorial, controlled randomized trialdesigned to test the ability of contralesional, inhibitory rTMSand CIMT to enhance motor learning in children with peri-natal stroke and hemiparesis. Forty-five children aged 6e18years completed all outcome measures from baseline to 6months. There were no serious adverse events or drop outsand tolerability measures were favourable. An additive effectof rTMS and CIMT was observed on the primary objectiveoutcome of change in AHA at 6 months where the addition of

both therapies more than doubled the chances of a clinicallysignificant improvement (Fig. 2). Subjective, psychosocial andquality of life gains were also observed. This trial alsoconfirmed the feasibility of measuring both baseline ANDpost-intervention plastic neurophysiology using advancedimaging and TMS neurophysiology (see below). This trialprovides class II evidence for rTMS and CIMT enhancement ofmotor learning therapy while supporting the overall safetyand feasibility of conducting non-invasive stimulation trialsin children with perinatal stroke-induced hemiparesis.

Fig. 2 e Timeline of evaluations, interventions, and outcomes. Baseline neurophysiology and motor function studies areperformed within a month of intervention. HABIT therapy (90 min) with TDCS or sham (first 30 min) intervention occursdaily for 10 consecutive weekdays. Both Jebsen Taylor hand function test (JT) and safety outcomes (S) are evaluated daily. Alloutcomes are repeated the week following intervention. Patients enter a home maintenance therapy program with clinicaloutcomes retested at 2 and 6 months. See text for details. Abbreviations: fMRI: Functional MRI; rsfMRI: Resting state fMRI;TMS: Transcranial magnetic stimulation; TDCS Transcranial direct current stimulation; HABIT: Hand-arm bimanualintensive therapy; AHA: Assisting Hand Assessment; COPM: Canadian occupational performance measure; TST: TDCSsafety test; JT: Jebsen Taylor Test of Hand Function; MA: Melbourne Assessment of Unilateral Upper Extremity Function; BB:Box and blocks test; PP: Perdue pegboard test; PMAL: Paediatric Motor Activity Log; QOL: Quality of life measures.




6.3. Non-invasive brain stimulation: transcranial directcurrent stimulation (tDCS)

tDCS applies scalp electrodes (anode and cathode) to generateweak direct currents (1e2 mA) that induce polarity-dependent

changes in brain excitability.173 tDCS induces regional, tran-

sient modulation of resting membrane potential and corticalneuronal excitability.174 In general, anodal stimulation increases

cortical excitability while cathodal stimulation decreases it.

Modern commercial tDCS systems are painless, inexpensive,

and portable, allowing patients to remain mobile during activerehabilitation. tDCS safety and tolerability in adults is well

established with thousands of tested and published safety

guidelines.175e177 Seizure or other serious adverse events have

notbeenreported.Subjectsmayreportmild, transient tinglingoritchingduring thefirstminuteof tDCScurrent escalation.177This

sensation can be mimicked in sham experiments, making tDCS

amenable to blinded, randomized trials.178 A published

consensus statement endorses the ability of tDCS to enhancemotor learning (and other brain functions) in healthy and

diseased adults179 but does not even mention the developing

brain. tDCS can enhance motor learning in both animals and

healthy adults when administered briefly over the motor

cortex.180e183 Adult studies have not only demonstrated

enhancedmotor skill learning with contralateral anodal or ipsi-

lateral cathodal tDCSbut are also elucidating themechanismsof

neuroplasticity involved.180,181 The duration of effect clearly

outlasts tDCS interventionsbyhours todays inadosedependent

fashion, confirming a therapeutic potential.85,86,184e186

Recent trials provide Class I evidence that tDCS canenhance motor recovery in adults with chronic stroke (seeTable 1).2,85e87,187,188 Though fundamental mechanisms maydiffer, the same approach outlined above estimulating thelesioned, or inhibiting the unlesioned hemisphere, (or both)2eappears to enhance motor function. For example, Lindenberget al.2 studied 20 chronic, hemiparetic stroke patients. Fivedays of structured therapy (60min)was combinedwith 30minof bilateral anodal (lesioned M1) and cathodal (non-lesioned

M1) tDCS. Outcomes included validated strokemotor functionmeasures and pre and post-intervention fMRI neurophysi-ology. Collectively, such studies support the feasibility, safety,and potential of our proposed study and provide a solidfoundation for design, stimulation parameters, and outcomemeasures. They also highlight directions for advancement e

Fig. 3 e PLASTIC CHAMPS trial flow and primary results. (Top) Recruited participants have all motor measures and TMSneurophysiology measured at baseline. They then enter a day camp for 10 consecutive weekdays, all receiving intensivemotor learning therapy and randomized to rTMS and CIMT or not. Outcomes are repeated at 1 week and clinical measures at2 and 6 months. (Bottom) Main results demonstrated additive benefits of rTMS and CIMT on AHA scores at 6 months (left)with large and sustained gains in COPM across all treatment groups (right). (Modified from Kirton et al, Neurology 2016).174




Table 1 e Summary of tDCS clinical trials in adult stroke.

Study Stroke population N Site tDCS Training Outcome measures Results summary

Hummel, 200587 Chronic 6 AAS

25 cm2; 1 mA; 20 min JTT practice JTT, TMS JTT improved with AA, outlaststim period. AA increasedcortical excitability


25 cm2; 1 mA; 20 min JTT, pinch force, reactiontime, TMS

Improved JTT, reaction time,and increase corticalexcitability

Fregni, 200589 Chronic 6 AACUS

35 cm2; 1 mA; 20 min JTT practice JTT Improved JTT with AA and CU


25 cm2; 1 mA; 20 Pinch force, reaction time AA shortened reaction time andincreased pinch force relativeto S

Hesse, 2007268 Subacute 10 AA 1.5 mA; 7 min; 30 days Robot FM 3/10 improved in FMBoggio, 2007269 Chronic 9 AA

CUS

5 days JTT Both AA and CU improved JTTcompared to sham

Celnik, 2009270 Chronic 9 AASPNS

49 cm2; 1 mA; 20 min Key stroke tDCS þ PNS improved keystroke accuracy compared tosham conditions or tDCS alone.Maintained 1 and 6 days aftertraining.

Kim 2009271 Subacute 10 AAS

25 cm2; 1 mA; 20 min BBT, finger acceleration AA improved BBT and fingeracceleration to a greater extentthan S. BBT improvementslasted at least 60 min post-stim

Kim 2010272 Subacute 19 AACUS

25 cm2; 2 mA; 20 min; 10days

30 min of OT FM, BI CU led to greater FMimprovements compared to S

Lindenberg 20102 Chronic 20 AA þ CUS

16 cm2; 1.5 mA; 30 min;10 days

PT/OT; 5 days FM; WMFT Real tDCS improved FM andWMFT compared to S.Improvements lasted at least 1week

Mahmoudi 2011195 Subacute to Chronic 10 AA þ CUAACUAA

35 cm2, 1 mA; 20 min JTT Improvements with AA þ CU,AA and CU. No improvementswith AA (extra-ceph) or S

Nair 2011273 Chronic 14 CUS

1 mA; 30 min; 5 days OT for 60 min/day; 5days

ROM, FM, fMRI CU resulted in greaterimprovements in ROM and FMthan sham. Effects lasted atleast one week. Decreased fMRIactivation in contralesionalmotor region

Hesse 2011274 Subacute 96 AACUS

35 cm2; 2 mA; 20 min;daily

20 min robot; 30sessions

FM, muscle strength andtone, BI, BBT

All groups improved, no effectbetween interventions

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Bolognini 2011275 Chronic 14 AA þ CUS

35 cm2; 2 mA; 40 min CIMT 14 days JTT, pinch and gripstrength, MALS, FM, TMS

JTT, strength, MALS, FMimproved with tDCS. Increasedlesioned M1 excitability

Stagg 2012276 Chronic 13 AACUS

35 cm2, 1 mA; 2 min Reaction time AA improved reaction time,and CU to a lesser extentcompared to S.

Lindenberg 2012277 Chronic 10 AA þ CU 1.5 mA; 30 min PT/OT 60 min/day; 10days (re-assess at 5days)

FM, WMFT Larger improvements in thefirst week compared to thesecond week

Takeuchi 2012278 Chronic 27 1 Hz rTMSAArTMS þ AA

25 cm2; 1 mA; 20 min Finger tapping, pinch force,TMS

rTMS-tDCS enhanced pinchforce, but had no effect onfinger tapping. Changes in TCI

Rossi 2013279 Acute 50 AAS

35 cm2; 2 mA; 20 min; 5days

FM, NIHSS Both groups improved, but nodifference between AA and S

Zimerman 2012280 Chronic 12 CUS

25 cm2; 1 mA; 20 min Finger tapping; TMS CU enhance motor skillcompared to S. Correlationbetween SICI andenhancement.

Wu 2013281 Subacute 90 CA (S1)S (S1)

25 cm2; 1.2 mA; 20 min;5x/wk # 4 wk

PT; 30 min twice a day,5x/wk # 4wk

MAS, FM, BI More clinical importantdifferences with active tDCScompared to sham post-treatment and at 4 week followup.

Ochi 2013282 Chronic 18 AACU


Robot-assisted armtraining; 5 days

FM, MAS, MAL Both tDCS conditions improvedFM and MAS, but not MAL

Lefebvre 2013283 Chronic 18 AA þ CUS

35 cm2; 1 mA; 30 min Training circuit task Grip force, PPT, circuit task tDCS enhanced circuit taskonline learning, with retentionat 1 week. Improved PPT scoreswith tDCS

Fusco 2013284 Subacute 9 AA þ CUAACUS

35 cm2; 1.5 mA; 15 min 9-hole peg test; pinch force;grip strength

AA improved 9-hole peg test,CU improved strength. Noimprovements with bilateral.


35 cm2; 1 mA; 20 min Precision grip movements,PPT

Grip and PPT improved withtDCS compared to S

Khedr 2013286 Subacute 40 AACUS


Therapy 1 h after tDCS;30 min

NIHSS, BI, muscle strength;TMS

All groups improved (smallerimprovements in musclestrength). No differencebetween AA and CU, but bothbetter than S. Increased corticalexcitability in lesioned M1

O'Shea 2014287 Chronic 13 AACUAA þ CUS

35 cm2; 1 mA; 20 min Reaction time AA þ CU had no effect onreaction time compared tosham, whereas AA and CU didquicken RT.

(continued on next page)

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Table 1 e (continued )

Study Stroke population N Site tDCS Training Outcome measures Results summary

Giacobbe 2013288 Chronic 12 AAS

2 mA; 20 min 20 min robotic practice Robot; TMS Movement speed improved.Smoothness improved withtDCS. tDCS after practicereduced speed. Increasedcortical excitability

Fusco 2014289 Subacute 16 AAS

? PT ? Both AA and S improveddexterity. No chance in handforce

Lee 2014290 Subacute 59 CUSCU þ training

25 cm2, 2 mA; 20 min; 15days

VR therapy, 30min/day MAS, manual muscle test,manual function test, FM,BBT, BI

Both groups improved manualmuscle and function and FMand BI scores. Change in FMwas higher in CU þ traininggroup

Cha 2014291 Chronic 20 AAS

35 cm2; 1 mA; 20 min; 20days

30 min/day BBT; grip strength; FM Both groups improved outcomescores. tDCS improved BBT andFM more than training alone

Fusco 2014290 Subacute 11 CUS

35 cm2; 1.5 mA; 10 min;10 days (1/day)

45min# 2/day# 10 days 9-hole peg test; pinchstrength, FM, grip strength;BI

No added benefit of CUcompared to S

Au-Yeung 2014292 Chronic 10 AACUS

35 cm2; 1 mA; 20 min; 1day

PPT, pinch strength CU improved PPT, but not pinchstrength. No improvement withAA or S

Gillick 2015293 Congenital hemiparesis 13 AA þ CUS

35 cm2; 0.7 mA; 10 min;

Goh 2015294 Chronic 10 AA5 Hz-rTMS-A

1 mA; 20 min TMS; Trail making test;reaction time; pinch force

Increased cortical excitabilitywith AA. No change in motoroutcomes

Di Lazzaro 2014295 Acute 14; 20 AA þ CUS


CIMT þ therapy; 1.5 hper day

ARAT; 9-hole peg test; gripstrength; MAL; NIHS; TMS

No change in motor outcomes.tDCS reduced IHI imbalance at3 months post stroke.


35 cm2; 1 mA; 30 min Trained circuit task PPT, circuit task Greater improvement in circuittask and PPT with real tDCS.

Sattler 2015297 Acute 20 AA þ PNSS þ PNS

35 cm2, 1.2 mA; 13min; 5days

JTT, 9-hole peg test, gripstrength, FM, hand tapping;TMS

Greater improvements at 2 and4 week follow up with AAcompared to sham.Improvements on secondaryoutcome measures too with AAcompared to S

Cho 201556 Chronic 27 AA 35 cm2; 2 mA; 20 min; 18days (3 # 6weeks)

Mirror therapy or none(control); 18 days (3 # 6weeks)

BBT. FM, JTT, grip strength Control groups improved gripstrength and JTT. Greaterimprovements in BBT and gripstrength with tDCS

Rocha 2016298 Chronic 21 AACUS

35 cm2; 1mA; 13min (forAA) or 9 min (for CU); 3x/wk for 4 wks

CIMT; 6 h/day for 3 wk1 h of PT daily 3x/wk for4 wk

FM, MAL, grip strength Increase in FM for active tDCSgroups. All groups equallyimproved MAL and gripstrength.

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Straudi 2016299 Acute - Chronic 23 AA þ CUS

35 cm2, 1 mA, 30 min; 10days

Robot-assisted therapy;10 days

FM, BBT, MAL Both groups improved FM, butno difference between AA andS. Patients with chronicsubcortical strokes benefitedmore than those with acute andcortical stroke however.

Allman 2016300 Chronic 24 AAS


Motor training; 1hr perday

FM, ARAT, WMFT ARAT WMFT showedimprovements up to 3 monthspost-training with AA

Triccas 2015301 Subacute e Chronic 22 AAS

Cunningham 2015302 Chronic 12 AAS

35 cm2; 1 mA; 30 min perstimulation

CIMT þ therapy;30 min # 2/day x 3/weekfor 5 weeks

FM; 9-hole peg test; TMS tDCS improved motoroutcomes. Increasedexcitability in thecontralesional hemisphere.

Lee 2015303 Chronic 24 AA?S

?? Physical therapy FM Real stimulation plus therapyimproved FM scores to a greaterextent compared to therapyalone

Chen 2016304 Subacute e Chronic 5 AA þ CU 16 cm2; 1.5 mA; 30 min;10 days

1 h OT/day; 10 days FM, rsfMRI FM scores improved. Increasedconnectivity betweenipsilesional M1 andcontralesional PMC

Mortensen 2016305 Chronic 15 AAS

35 cm2; 1.5 mA; 20; 5days

OT; 30 min/day 5 days JTT, grip strength Both groups improved JTT. AAimproved grip strengthcompared to sham (no longerpresent 1wk post). Trend for JTTretention with AA

Legend: AA e anodal stimulation, affected hemisphere, CU e cathodal stimulation, unaffected hemisphere, FM e Fugl-Meyer motor score, AAT e Aachener aphasia test.

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larger, more homogeneous populations, evidence-based

therapy, more integrated neurophysiological outcomes and,of course, studying the more plastic paediatric population.

We recently demonstrated the ability of tDCS to enhancemotor learning in typically developing children. One previousstudy had demonstrated early evidence of safety, tolerability,and neurophysiological effects of brief tDCS applications tomotor cortex in children.189 We conducted a 4 arm, blinded,sham-controlled trial of motor cortex tDCS to enhance motorlearning in children aged 6e18 years.190 Subjects repeatedlyperformed a motor learning task (Purdue Pegboard) with theirleft hand over three days. They were randomly assigned to

receive 20 min of contralateral anodal (1 mA), ipsilateralcathodal (1 or 2 mA) or sham tDCS during the first 20 min.Learning curves were strongly enhanced with active treat-ment with effects retained 6 weeks later and additional gainsin untrained motor function of both hands (Fig. 4). We believethis provides important proof-of-principle evidence toadvance further studies in hemiparetic CP and other diseasepopulations.

Though there ismuchneed for additional investigation, themost informed primary target in hemiparetic children withperinatal stroke currently is the contralesional M1. A cathodal

approach is supportedby theaboveevidence for tDCSeffects innormal children190 and probable effect of the similar approachwith inhibitory rTMS in the same population.172 Stimulationover intact (non-lesioned) brain also maximizes safety withmore predictable distribution of tDCS currents compared tochildren with large arterial lesions.191,192 Methods should bebased in the best accumulated evidence from previous studiesof cathodal tDCS in addition to those cited above includingadultmotor learning,179e181 adult stroke rehabilitation2,86,87,188

and studies of electrode montages in stroke.193 Soft, replace-able 25 cm2 electrodes would typically be placed on clean, dry

areas of the scalp with the cathode placed over the non-lesioned M1. This location would ideally be individualized foreach subject using TMS and/or task fMRI and targeted withneuronavigation.Consistentwithprevious tDCSstrokestudiesexamining electrode placement,193 the reference electrodewould be placed over the contralateral orbit. Using available,programmable, and current-controlled stimulators allowsautomatic ramp up slowly over 30 s to the treatment current,typically 1.0 mA tDCS or shamwould usually be administeredduring the first 20e30 min of motor learning therapy and on adaily basis in a camp-based model. Experienced techniciansshould apply and monitor all systems, being on hand for im-

mediate trouble-shooting. Some tDCS systems can blind theadministrator though it is only essential that cliniciansadministering therapy and those performing the outcomemeasures are blinded to treatment allocation.

We recently completed a phase 1/2, randomized, sham-controlled, double-blind, clinical trial to test whether theaddition of tDCS to intensive motor therapy was associatedwith larger gains in clinical function. Participants completed agoal-directed, peer-supported after school camp model ofmotor learning therapy for 2 weeks, randomized to receivecontralesional, cathodal tDCS (1 mA) or sham during the first

20 min of each day. Primary outcomes were the COPM (sub-jective) and AHA (objective) in addition to multiple safety andtolerabilitymeasures (see discussion below)measured out to 2

months post-intervention. The final results were presented at

the 2016 International Stroke Conference in Los Angeles inFebruary 2016 and is currently submitted for publication. Insummary, interventions were well tolerated with no seriousadverse events and all safety outcomes were satisfied. Sig-nificant tDCS effects were observed on COPM, but not AHAoutcomes, suggesting possible benefit and providing impor-tant data for the execution of a larger, more definitive trial.

7. Systematic approach to clinical trialdesign: CONSORT

Any trial is only as good as the methods on which it rests.Thankfully, the importance of this fundamental concept hasevolved over recent decades to carefully define the essentialcriteria of valid clinical trials and their reporting. The CON-

SORT (ConsolidatedStandardsofReportingTrials) statement isan evidence-basedminimumset of standards for the reportingof randomized clinical trials.194 First initiated in 1996, the cur-rent version was last updated in 2010 and the most up to dateversion including recent modifications are available online.These include a 25 item checklist as well as a template flowdiagram to account for participant movement through a trial.An accompanying “explanation and elaboration” statementfurther defines each element and is available in multiple for-mats.Multiple extensions have also beendeveloped to addressdesigns beyond simple two group parallel designs such as

cluster, non-inferiority, and pragmatic trials.Use of the CONSORT guidelines has been associated with

improved reporting of clinical trials.195 The website receives>17,000 hits per month. More importantly, over 600 journalshave endorsed the CONSORT guidelines. While the primarymotive for applying the CONSORT guidelines should be thebest possible trial, it is fair to say that no future clinical trialwill likely be published in any reputable journal withoutcareful adherence. It is therefore reasonable to suggest thatapplication of the CONSORT guidelines is both an extremelyhelpful and scientifically essential process in the design,

execution, and reporting of any clinical trial. With this inmind, the outline of the guidelines will be applied below toreview several essential elements of trial design as they relateto non-invasive brain stimulation trials in children. Outcomemeasures, the largest single issue, are discussed separatelyfollowing this.

7.1. Populations

Where participant populations exist and how they areaccessed for recruitment will primarily depend on the inclu-sion and exclusion criteria (discussed next). However, beforethese criteria are applied, the sample to be screened should becarefully selected to represent, as best as possible, the popu-lation of interest as a whole. Reductions from the true popu-

lation toward the sample studied will inevitably introduceselection and other biases, the number and calibre of whichdecrease the translatability of any ultimate findings propor-tionately. Therefore, the optimal starting point is a large,complete, population-based sample of subjects with the con-dition of interest. Asmentioned elsewhere, disease-specificity




will be a major determinant of this population. For example,from a population-based sample of cerebral palsy (somethingalready difficult to find), perhaps 30% of these will be hemi-paretic and perhaps 75% of these will have confirmed peri-natal stroke as the cause.

We began building the Alberta Perinatal Stroke Project (APSP)in 2007. This is a large population-based cohort of MRI-

confirmed perinatal stroke consented to research nownumbering nearly 800 subjects all living within the Canadianprovince of Alberta (population of ~4.2 million). This requiredanexhaustive reviewofover 80 ICDcodes, 6000medical charts,structured imaging review, patient contact and inperson clinicassessments. The effort took over 7 years and is still ongoing.

The yield for clinical trials however was immense, providing alarge unbiased sample from which candidates could berandomly recruited, optimizing translatability to the diseasepopulation as awhole. As outlined in the following sections onselection criteria and recruitment, this apparently very largenumber shrinks rapidly as these realities are introduced,further biasing the sample along the way.

7.2. Selection criteria

Further reduction of the eligible population for recruitmentwill occur with application of inclusion and exclusion criteria.Their selection must rest on the primary research question

Fig. 4 e tDCS motor learning trial methods and results. Motor training of the non-dominant hand over 3 days is shown inthe top bars with subjects randomized to 1 of 4 tDCS treatment montages (including sham). Active treatment groupsshowed markedly steeper learner curves (bottom) with sustained effects at 6 weeks. (Modified from Ciechanski and Kirton,Cerebral Cortex 2016).192




being asked; if this has to be compromised by changing

criteria to suit other needs, the question should instead bechanged. Once true to the primary question, additional issuesof confounders, known response predictors, clinical realities(i.e. minimum function levels), clinical significance or need(i.e. maximal function levels), safety, and ability to complymust be considered. Criteria should be strictly quantified orqualified according to established metrics when possible.

The following provides an example of potentially relevantinclusion and exclusion criteria for a combined intensivemotor learning and neurostimulation trial in hemiparetic CP.

7.2.1. Inclusion criteria

1. Symptomatic hemiparetic CP (Paediatric Stroke OutcomeMeasure (PSOM) > 0.5) AND Manual Abilities ClassificationSystem (MACS)196 grade IeIV AND child/parent perceivedlimitations in function)

2. Clinical and MRI-confirmed perinatal stroke syndrome(NAIS, APPIS, PVI)

3. Active wrist extension >20$, finger extension >10$

4. Can lift the affected arm 15 cm above a table surface andgrasp light objects

5. Term birth (>36 weeks) and current age 5e18 years6. Informed consent/assent

7.2.2. Exclusion criteria

1. Other neurological disorder not related to perinatal stroke2. Multifocal stroke3. Severe hemiparesis (no voluntary contraction in paretic

hand, MACS level V)

4. Severe spasticity in the affected limb (Modified AshworthScale >3)

5. Severe developmental delay or other inability to complywith study protocol

6. Unstable epilepsy (>1 seizure/month or >2 medicationchanges last 6 months)

7. Any TMS171 or MRI contraindication including implantedelectronic devices

8. Botox, orthopaedic surgery, or other invasive mechanicaltherapy in past 6 months

9. Constraint, brain stimulation or other modulatory therapy

in past 6 months

7.3. Randomization

Methods for randomization within clinical trials are complexand beyond the scope of this discussion. However, severalfundamental issues to be considered relate predominantly totrial design and a priori knowledge of response predictors andother potential confounders. Options including block orminimized randomization may help ensure balance oftreatment allocation across subgroups of patients. Such

subgroups may be easily defined (e.g. site A versus site B) ormore complicated such as predefined factors known orhighly suspected to be associated with the outcomes of in-terest or potential response to treatment. Examples mightinclude factors such as age, level of baseline disability, orcorticospinal tract arrangement. However, it should be

emphasized that the relationship of these factors to the

ability to respond to an intervention are incompletely, if atall, understood. Therefore, despite these specific consider-ations, it should be remembered that simple randomizationshould usually correct for such differences across treatmentgroups.

Most forms of randomization can be performed simplyusing patient codes and computer-based or online softwareadministered by an unbiased study member such as thestatistician. Concealment of randomization must be assuredand multiple means are available. Development, storage, andbreaking of codes by an unbiased third party may be reason-

able. Treatment administrators can sometimes be automati-cally blinded, such as modern, programmable tDCS systems.Stimulation trials in children are likely moving toward multi-centre studies, introducing additional considerations.Randomization in permuted blocks, with the number ofblocks matching the number of participating sites, mayfacilitate even distribution within sites. Multi-site trials on theother hand, may require a central randomization and treat-ment allocation process. Expertise from experienced clinicaltrialists and statisticians may be particularly helpful.

7.4. Recruitment

Failure to recruit complete samples on time is one of themostcommon reasons for trials to be delayed or not completed atall. Estimates of attainable sample sizes must be realistic (i.e.pessimistic). Hard numbers from established populations arerequired rather than blind estimates of prevalence based onpublished epidemiological data. What may appear as large,easily adequate number of potential subjects often reduces

dramatically when realistic limitations are estimated. Exam-ples include presence of exclusion criteria, inability to confirmall inclusion criteria, geographical factors, failure to recruitrates, and attrition with drop-outs possible at all stages (whomust be included within intention to treat analyses if occursfollowing randomization).

7.5. Informed consent and assent

Consenting children and parents to novel, experimental trialsof brain stimulation requires special attention. Potentialbenefits may be easily over-estimated by families of disabledchildren due to lack of alternative therapies, being“impressed” by technology, or other reasons. Risk must alsobe fairly disclosed based on best available evidence. Our labhas completed nearly 3 million stimulations on over 250childrenwithmany conditions without serious adverse event.This provides direct evidence to families of minimal risk theycan trust however such examples are not always available.Theoretical risks must be presented in context with estimatesof relative risk and potential harm. An ability to understand

randomization may be difficult to communicate and may beforgotten months later when final results are shared withfamilies. Both parents and children, in our experience, maysometimes harbour feelings of disappointment or evenmistrust when discovering they were in the sham group, evenwhen they may have made substantial clinical gains. Honest,




clear, and repeated explanations are all that can reasonably be

offered.

7.6. Structure and flow

Structuring a complex, multifaceted intervention withnumerous requirements for space, infrastructure, and highly

qualified personnel requires organized structure. An exampleof the sequence, timeline and flow of our recently completedcontrolled trial of tDCS in school-aged children is shown inFig. 2. Factors considered include family convenience wheretiming of drop offs and pick-ups, time of year (school yearversus summer), and extracurricular activities may affectcompliance and participation. Including unique activitiesmaydiversify therapy while optimizing fun for participants. Ex-amples in our experience include virtual reality, cooking,therapeutic arts, horticultural therapy, and video gaming (e.g.rockband). Balancing focused motor training with more gen-

eral and group activities as well as breaks and relaxation canbe challenging. It is essential to include input from experts inpaediatric therapy, child life, and subjects and their familiesfor optimal planning.

7.7. Sham-control and blinding

Effective sham techniques are well established for non-invasive stimulation methods. For rTMS, this includesaltering coil direction or use of commercially available shamcoils. For tDCS, devices can often be ramped on for all subjectsto produce the typically transient scalp sensations experi-enced, and then ramped off for the sham group. Such sham-ming has been proven effective,178 including in children.172,190

Cross-over design trials carry a risk of subjects detecting dif-ferences when they switch groups and interventions in naı̈vesubjects only avoid this potential problem. Ideally, all in-

vestigators, those administering treatments, outcome asses-sors, parents and children remain blinded. Thoseadministering tDCSmaynot be if they are otherwise separatedfrom the outcome measures and therapy. Modern tDCS sys-tems can also be programmed to randomize and administeraccordingly, allowing the administrator to remain blinded.

7.8. Analysis and sample size

Statistical analysis will of course depend on the researchquestions to be addressed. In most circumstances, analysiswill be intention to treat, accounting for all subjects ran-domized whether they complete the trial or not. Additionalper protocol analyses may be performed and reported but thisis not usually done in isolation. Collaborator expertise inclinical trials and biostatistical methods are an essentialrequirement. Variables for calculation of sample size shouldbe extrapolated from the most relevant literature. Estimates

are typically based on application of the first order analysismethod to the main hypothesis using the primary outcome.Estimated samples should be comparable or proportional toprevious trials in similar populations.

All studies need to be registered prior to consent of the firstpatient (www.clinicaltrails.gov).

8. Outcome measures

Selection of outcome measures is likely one of the mostessential components of clinical trial design. Standardized,unbiased administration and interpretation by qualified ex-perts blinded to treatment allocation and other clinical in-formation is required but often challenging. Additionalissues specific to considering neurostimulation in-

terventions in children include a relative paucity of vali-dated measures, heterogeneous populations (e.g. CP versushemiparetic CP versus perinatal stroke hemiparesis), andvariable effects of age and developmental level to name justa few. However, these limitations are being overcomethrough a variety of creative means to facilitate evaluationof such interventions. Measures used in similar previoustrials should be considered in anticipation of comparabilityand eventual pooling of data in meta-analyses. At the sametime, careful review of how well certain measures were ableto demonstrate change (or not) and other limitations in

those same trials may be good reasons to consider addi-tional or alternative outcomes. Outcome measures can beconsidered under headings of clinical/functional, safety, andneurophysiological.

8.1. Clinical outcomes: motor function

A rigorous, evidence-based approach to clinical motoroutcome selection should be adopted. Testing should beperformed by a team of experienced experts that may include

paediatric occupational and physical therapists, develop-mental paediatricians, paediatric neurologists and physiat-rists, and clinical trialists. More specific outcomes mayrequire additional expertise such as child psychology re-searchers when considering psychosocial and quality of lifeoutcomes. Multidimensional evaluations should consider thebody structure and function, activity and participation do-mains of the WHO International Classification of Func-tioning, Disability and Health (ICF), considering bothunimanual and bimanual performance.197 Tools with estab-lished clinimetric properties in the population of interest (i.e.

hemiparetic CP) are selected to evaluate diverse upper ex-tremity functions relevant to daily living in children.198,199

Measures need to be both child and family friendlyincluding sensitivity to time and fatigue. Measurement ofboth uni- and bi-lateral function of both limbs are requiredfor normative data, evaluation of different clinical functions,and safety (including screening for changes in unaffectedhand function). Testing should be video-taped for qualityassurance, inter-rater validation, and additional offlineanalysis. Motor outcomes are measured at baseline, and 1week, 2 months post-intervention.

With these principles in mind, the following three po-

tential primary outcome measures might be considered in aclinical trial of intensive motor learning therapy combinedwith non-invasive brain stimulation in hemiparetic chil-dren. An additional list of possible secondary outcomes andtheir supporting evidence and attributes are summarized inTable 2.


http://www.clinicaltrails.gov



Table 2 e Examples of potential functional outcome measures for clinical trials of neuromodulation in hemiparetic CP.

Measure Target Application and evidence-base

Canadian Occupational Performance Measure (COPM) Individual goals for therapy Individualized, family-centred tool identified child and family-perceived difficulties and personalimprovement goals for self-care, productivity (school), and activities. The same experienced OTscreened potential goals with child and parents with consensus defining those goals that were bothfunctionally relevant and reasonably achievable. Scaled scores for performance and satisfaction of eachgoal were obtained (1 lowest, 10 highest). Such subjective, patient-centred measures are increasinglyconsidered essential in paediatric hemiparetic CP trials. The COPM is validated for paediatrichemiparetic CP trials across our age range. Sensitivity to change has been established with an increasein COPM scores of %2 units considered clinically significant.

Assisting Hand Assessment (AHA) Bimanual function The AHA is an established evidence-based standard for the objective quantification of bilateral handfunction in children with hemiparetic CP. Certified occupational therapists administer a structured,play-based assessment of spontaneous bimanual hand use followed by itemized scoring of the video-taped session. This Rasch-built evaluation carries the strongest evidence of inter-rater, intra-rater, andtest-retest reliabilities, test-validity, and responsiveness to change for bimanual tasks in hemiparetic CPchildren within our age range. Sensitivity to change and excellent clinimetric properties have beenestablished in paediatric hemiparetic CP trials. Consistent with validated methods, AHA scores areexpressed as logit units with an increase of %5 units considered clinically significant.

Melbourne Assessment of UnilateralUpper Limb Function (MA)

Unimanual function The MA is a validated, criterion-referenced functional measure designed to detect change inhemiparetic children. Trained therapists evaluate upper extremity motor tasks with performanceranked for each creating a total maximal score of 122 points (reported as percentage). Validation studieshave correlated MA with clinically relevant functional outcomes in school-aged children.

Jebsen Taylor Test of Hand Function (JTTHF) Unimanual function 1. Standardized timed test of unimanual upper extremity functional activities evaluating efficiency ofmovement. Important for comparability as the most common outcome measure used in adult stroketDCS clinical trials and recent paediatric CP studies.

AbilHAND Manual function Designed to assess manual function in children with cerebral palsy, the AbilHAND scores 21 commonmanual activities in children at 3 levels of difficulty with summary logit unit scores. This measure is notspecific to hemiparetic children but has been used in other paediatric CIMT trials.

Grip and pinch strength (GS, PS) Motor function GS is a simple, quick measure of hand motor function quantifiable with a dynamometer employed inmany paediatric hemiparetic CP and adult rTMS stroke trials. Unaffected hand GS and PS are alsopotential safety outcomes.

Box and blocks (BB) Dexterity This test of unimanual dexterity will be applied on both sides as in previously reported paediatric CIMTtrials. Assessment of the unaffected limb provides a safety measure (described above).

Purdue pegboard test (PPT) Dexterity 2. Performed bilaterally to measure manual dexterity and is commonly used in paediatric CIMT studies,and was the primary outcome in our healthy tDCS motor learning trial in children.

Paediatric Motor Activity Log (PMAL) Daily activity 3. Commonly used in hemiparetic CP studies with test-retest stability and sensitivity to change.Completed by parents.

PedsQL Cerebral Palsy Module (3.0) Quality of Life Condition specific and validated, age-adjusted child and parental reports assessed domains of dailyactivities, school activities, movement/balance, pain/hurt, fatigue, eating activities, and speech/communication.

APSP Parental Outcome Measure (POM) Parental psychology Measures adverse parental psychological outcomes in parents of children with perinatal strokeincluding unique symptoms of maternal guilt and blame.

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8.1.1. Primary objective motor outcome: Assisting HandAssessment (AHA)

This is currently the established standard for the objectivequantification of bilateral hand function in children withhemipareticCP.199ARasch-built evaluation, theAHAcarriesthe strongest evidence of inter-rater, intra-rater, and test-retest reliabilities, test-validity, and responsiveness tochange for bimanual tasks in hemiparetic school-agedchildren.199e204 Sensitivity to change and excellent clini-

metric properties have been established in multiple pedi-atricHCPclinical trials.120,144,205e207Onepotential limitationof theAHAisadrop inscorewhennewunimanual functionshave not yet been incorporated into the bimanual tasksbeingmeasured (i.e. scoresmay drop despite new function).Our trained therapistshave successfullyexecuted>200AHAmeasurements within multiple clinical trials172 with excel-lent compliance and robust data.

8.1.2. Primary subjective motor outcome: Canadianoccupational performance measure (COPM)

Subjective outcome measures are now considered a valid,potentially essential outcome measure in rehabilitationtrials including children with hemiparetic CP.51,208 It couldbe argued that any gains shown in objective tests of motorfunction (e.g. strength, dexterity) are meaningless if thepatients themselves have not perceived the achievementof a personal goal or some other personal satisfaction. Forthese reasons, individualized, patient-centered, goaldirected tools such as the COPM have been developed andvalidated. Applied by an experienced pediatric OT incombinationwith child and parents, the COPM can identify

child and family-perceived difficulties in categories of self-care, productivity (school), and activities.209e213 Validatedfor both school-aged children214,215 and pediatric hemi-paretic CP trials,208,214,216e218 the COPM has been a robustmeasure in our previous perinatal stroke trials.172 We havealso recently characterized how COPM goals are set in thispopulation and their relationship to success in suchinterventional trials (Haspels et al., 2016, unpublisheddata).

8.1.3. Novel “real-life, continuous” motor outcome:actigraphic symmetry index (ASI)

No existing motor outcome measure can quantify contin-uous use of the upper extremities during the normal ac-tivities of real life. We recently proposed to overcome thislimitation using actigraphy. Lightweight wrist accelerom-eters can constantly measure and store subtle movements(e.g. fitbit). Such systems can also track movements indisabled persons including those with CP.219 In upcoming

trials, we will use the Actiwatch2 system to record meanmovements every 15 seconds for 48 hour epochs of time(baseline, 2 months, 6 months) as well as continuously

during the 2 week intervention phase. Importantly, we will

do this bilaterally (2 watches), allowing the generation of asymmetry index between the affected and unaffectedlimbs. Our preliminary data has established the feasibilityand accuracy of these methods in school-aged children(Cole et al., unpublished data).

Many additional clinical outcome measures can beconsidered depending on the nature of the trial. Examples,including their supporting evidence and primary targets, aresummarized in Table 2.

8.2. Safety outcomes

With limited non-invasive neuromodulation data in thedeveloping brain, careful and complete application of safetyoutcomes is paramount within clinical trials. Adult guidelinesand safety reviews are available for both TMS171 and tDCS175

and are certainly applicable. However, issues unique to chil-

dren need to be screened for and rates of tolerability and po-tential adverse events documented. Safety issues should beidentified a priori by experienced investigators but also atarms-length by a data safety and monitoring board (DSMB).Interim safety analyses may be incorporated into trial designat set time points (e.g. after certain numbers of subjects havecompleted outcomes). These analyses, as well as any seriousadverse events, should be reviewed by the DSMB and insti-tutional ethics boards requirements according to established,pre-defined protocols.

Safety can be considered under the following headings.

8.2.1. Serious adverse events

Typical definitions of SAE are adverse events or reactionsthat results in death, is life-threatening, requires hospi-talisation or prolongation of existing hospitalisation, re-sults in persistent or significant disability or incapacity, oris a congenital anomaly or birth defect. Fortunately, SAEreports in non-invasive brain stimulation have beenexceedingly rare across decades of use.

8.2.2. Function-specific adverse effects

Unique undesired outcomes may occur in specific studies.In the case of modulation trials for hemiparetic CP, oneexample is provided by the known control of both upperextremities by the non-lesioned hemisphere. Subse-quently, inhibitory stimulation of the contralesional motorcortex might include theoretical consideration of reducinghand function in the unaffected hand or in the target

affected hand, particularly in those with prominent ipsi-lateral corticospinal arrangements. Therefore, primarysafety outcomes in our brain stimulation trials haveincluded regular measures of both affected and unaffectedhand function across time points for each subject andwithin interim safety analyses.




8.2.3. Side effects

Any intervention capable of having biological effects mustalso have the risk of side effects. Extrapolating from themuch larger volume of evidence from the adult brainstimulation world and published guidelines,171 a reason-able list of side effects to be specifically screened for can begenerated. These include feelings of headache or neck painwith TMS with the addition of itching or burning sensa-tions for tDCS. However, symptoms specific to young age

groupsmay exist, such as TMS-induced vasovagal syncopein adolescents.220,221 Each anticipated subjective symptomcan be screened for and quantified including scale severity,duration, need for treatment, etc using a simple form.Screening and documentation should be repeated overtime to assess for persistence or tolerance.

8.2.4. Tolerability

A standardized safety and tolerability evaluation for TMS

in children has been developed63,222 and is easily adaptedfor different population and modalities including tDCS.190

Subjects are asked to rank order their stimulation experi-ence amongst 7 other common childhood experiences.

Optimizing safety requires attention to each of the aboveissues. Brain stimulation studies in children should be per-formed by experienced personnel in a secure environment.Immediate access to medical care should be available in theunlikely occurrence of a serious adverse event. Written stan-dardized operating procedures, for both experimentalmethods and handling adverse events, should be imple-

mented and staff tested for their familiarity with these.Our single centre experience has administered nearly 3

million stimulations to over 280 children in the past 8 years.Ages ranged from 8months to 19 years (median 11.2) with thevast majority being school-aged. The most common condi-tions were perinatal stroke/cerebral palsy (70), mild traumaticbrain injury (TBI, 68), or typically developing (53). Multi-disciplinary neurophysiological studies included single- andpaired-pulse TMS methods. Therapeutic clinical trials usedrepetitive TMS (rTMS) and anodal/cathodal motor cortextDCS. Prospectively collected safety and tolerability data on all

subjects included the paediatric TMS safety and tolerabilitymeasure, child and parental interviews, and data safety andmonitoring boards. There were no serious adverse events.Tolerability between TMS (402,680 stimulations) and rTMS(2.1million stimulations) was comparable and rated similar toa long car ride. Although >100 had brain injuries and/or epi-lepsy, no seizures occurred. Headache following a TMSneurophysiology protocol was more common in perinatalstroke (40%) than typically developing (13%) participants butwas mild and self-limiting. Mild neck pain with was relativelycommon but comparable between perinatal stroke (22%),

depression (19%), and TBI (19%). Tolerability improved overtime with rates of headache, neck pain, and unpleasanttingling decreasing by >50% at repeat testing. Of 51 children

receiving tDCS, scalp itching in 55% was mild, transient, and

comparable to shamwith no drop-outs. Neither low frequencyrTMS or cathodal tDCS of the non-lesioned hemispheredecreased function of either hand in children with hemi-paretic cerebral palsy.We believe this data supports that brainstimulation is safe and well tolerated in children.

9. Neurophysiological outcomes

Advanced neurotechnologies have greatly advanced the abil-ity to understand developmental plasticity in real patients.This includes baseline measures to evaluate natural processand how they relate to function but also the opportunity toexplore the potential mechanisms of intervention-inducedchange. Combining modern technologies allows the compre-hensive, integrated study of brain structure and function

personalized to each individual. Clinically relevant examples ofsuch integration are increasingly available in adults223 butawaiting full exploration in children. Summarized here areleading applications of single- and paired-pulse TMS, imagingincluding task and resting state fMRI and diffusion tensorimaging (DTI), and robotics.

9.1. Transcranial magnetic stimulation (TMS)

First described in 1985,224 most TMS studies are publishedsince 2008 but only <3% include children. Focused magneticfields applied across neuronal membranes result in focaldepolarisations of human cortex according to Faraday's Law.With narrow spatial resolution, TMS can affect discrete

functional areas,225 offering non-invasive, painless mappingof motor systems.67,76,77,226 Tools relevant to the current studyinclude “single-pulse” measurements such as motor evokedpotentials (MEP) which quantify motor pathway neurophysi-ology from cortex to muscle. Motor thresholds and stim-uluseresponse curves reflect corticospinalexcitability.72,222,227 Paired-pulse TMS employs multiplestimuli to elucidate interactions between different brainareas.90,92,225,228e232 TMS is safe and well tolerated in chil-dren,162,222,233 supported by animal studies106,151,234e238 andpublished guidelines.171 Application is safe in adult

stroke85e87,148,149,160,161,166,228 and supported by our safetywork in children with stroke.66,72,81,220 TMS-related seizureshave not been described in children162 including administra-tion over seizure foci.239,240

Modern technologies include single pulse systems forexcitability and pathways as well as paired-pulse methodscapable of probing cortical excitatory, inhibitory, and otherphysiological functions. Neuronavigation systems such asBrainsight (Rogue Research, Montreal) allow real time co-registration of coil location with individual subject MRI inthree dimensions, including overlay of functional imagingtargets. We have successfully demonstrated each of these

methods in children with stroke.99 Single pulse TMS candetermine bilateral M1 excitability.99,241 Motor evoked poten-tials are recorded from hand muscle, often the first dorsalinterosseous (FDI), bilaterally. The motor “hotspot” is definedover M1 as the area producing consistent, high amplitudeMEP. Resting motor threshold (RMT) is then defined as the




stimulator intensity required to produce MEP % 50 mV in 5/10

trials. Our studies63,78 suggest stroke side MEP are obtainablein >80% of subjects. Activated motor thresholds are also ob-tained during ~20% of maximal FDI activation via visualfeedback. Motor maps can also be created in the lesioned andunlesioned hemisphere. We recently added a TMS Roboticsystem (Axilum, Strasbourg) that should greatly facilitateexecution of such outcomes.

Additional potential TMS neurophysiological outcomesinclude: (1) Stimulus response curves (rest and active). BilateralM1 excitability is quantified by measuring MEP amplitudesacross 5 escalating stimulus intensities such as 100/110/120/

130/140/150% of RMT. (2) Interhemispheric Inhibition (IHI). Bidi-rectional IHI (lesioned to unlesioned hemisphere and vice-versa) applies stimuli to both M1 in quick succession withmethods described elsewhere.63,90,96,242e244 Paired-pulse TMSapplies a suprathreshold conditioning stimulus (CS) con-tralaterally immediately prior to a test stimulus (TS) withinterstimulus intervals of 10 and 40 ms. The decrease in TSMEP quantifies IHI. (3) Short interval intracortical inhibition (SICI).M1 SICI can be determined according to established paired-pulse methods.91,245 For example, after suprathreshold CS,SICI effects are typically seenwith an interstimulus interval of

2 ms. These and other TMS measures of cortical neurophysi-ology can define baseline function as well as changes occur-ring secondary to interventions.

9.2. Functional MR (fMRI) and the resting state (rsfMRI)

Functional MRI extrapolates regional brain activity fromchanges in blood oxygen-dependent signal. Two fMRI mo-

dalities have provided valuable insight to motor physiology,development, and stroke recovery. Task-dependent fMRIcompares regional activity between on and off states duringperformed motor tasks. Task fMRI has established funda-mental principles of development and stroke recoveryincluding the roles of each hemisphere (above). Small hemi-paretic CP studies have demonstrated similar utility andsupport ourmodel. However, task fMRI only studies individualbrain areas rather than the integrated neural networks.

“A connectivity-based system perspective is much closer to theneurobiology underlying brain physiology compared to analyzing

anatomically segregated regions (i.e. traditional fMRI).”246 Restingstate fMRI (rsfMRI) is a recent advance that facilitates suchnetwork analysis.247 Simple acquisition of fMRI data duringpatient rest can be analyzed by both exploratory andhypothesis-driven methods to create models of functionaland effective network connectivity.246,248 Such rsfMRI ap-proaches now provide invaluable insight to brain plasticitymechanisms in adult stroke.246,249,250 Resting state motornetworks are measurable in young children251 but are rela-tively unstudied in perinatal stroke. The stark contrast pro-vided by arterial (cortical lesions at term) and PVI (preterm,subcortical) creates an ideal human model to explore motor

network development after perinatal brain injury. Further-more, changes in functional networks likely represent anessential measure of intervention-induced plasticity.Recently, such approaches have been validated in adultswhere change induced by brain stimulation interventionsmay be demonstrated using rsfMRI.223,252

9.3. Diffusion tensor imaging (DTI)

Diffusion MRI acquires microscopic information on structuralbrain connections. DTI measures preferential water moleculediffusion (Brownian motion) along axonal axes, providingunique structural and physiological information in thedeveloping and diseased brain.253 DTI non-invasively mea-sures neural fibre composition, integrity, and orientationwhile tractography creates three dimensional reconstructionsof large white matter tracts.254 DTI can evaluate the motor

system including corticospinal tract integrity.257 In adultstroke, corticospinal tract DTI measures correlate with motoroutcomes.258,259 DTI utility has been demonstrated acrossnumerous childhood neurological disorders257 and can besynergistically integrated with fMRI and TMS to createcomprehensive, in vivo models of brain structure and func-tion.86 Perinatal stroke DTI studies are few260 though CP ap-plications261,262 support feasibility. We recently demonstratedour ability to evaluate corticospinal tract integrity in perinatalstroke using DTI.263

9.4. Robotics

Robots have further advanced the ability to measure complexclinical function indisabledpatients.Robotic technologiessuchas the KINARM (Kinesiological Instrument for Normal andAltered Reaching Movement) can assess limb movements atthe shoulder and elbow. Unique advantages complimentary totheabovemodalitiesareconferred. Forexample,positionsenseis probably a major contributor to disability in hemipareticpatients. However, a lack of objective measures of such func-tion has limited study. Using KINARM, the characteristics of

positionsensesdysfunctionare increasinglywell characterizedin adult stroke18,19 We have shown that the samemethods arewell tolerated by children where a standardized, validatedassessment of sensorimotor function can include two tasksthat specifically target proprioception. Position sense can bemeasured using a positionmatching task; the robot moves theaffected arm to random spatial locations and the subject thenattempts to mirror match the positions with the unaffectedarm. To measure kinaesthesia; the robot moves the affectedarm. Subjects are required to move the good arm to matchspeed, amplitude and direction. Both tasks are completed first

with vision occluded and again without the blindfold to deter-mine their ability to compensate with vision. Using thesemethods, we recently demonstrated the common occurrenceof such deficits in children with perinatal stroke and their as-sociation with clinical function.264 Such robotic outcomes willbe available tool in identifying new modulation targets andassessing outcomes from the interventional trials tat result.

10. Future directions

The translational pipeline from proof of principle through thephases of early stage clinical trials to the accumulation ofmultiple, positive, multicentre fully powered trials must beconsidered. The prolonged nature, and associated high costs,are likely comparable to drug development in some regardsthough potentially more economical. For example, rTMS for




adult major depression has driven the field of therapeutic

non-invasive neuromodulation. Despite many positive ran-domized controlled trials spanning more than a decade, theintervention is only just now becoming an insured service inmany developed countries. The extremely common occur-rence, poor response rates to current medications, anddisabling nature of major depression have likely driven thisprocess relatively quickly. In comparison, treating differentforms of cerebral palsy in children may not carry the sameweight, further slowing the process. This should notdiscourage effort but is a considered reason to optimize thedesign, exaction, and progress of early clinical trials.

The economics of such interventions in children have notbeen studied and remain difficult to estimate with such alimited number of trials to date. However, camp-basedintensive motor learning is both a likely prerequisite forneuromodulation in children with motor disability as well asbeing an expensive, resource-intensive endeavour. Full dayprograms may be required to reach adequate dosing. Highlyqualified personnel are many for such programs, includingskilled therapists to both deliver treatment and administeroutcomes. We have tried to mitigate some of these costs withafter-school therapy programs and incorporating student

therapists to administer therapy under the guidance of moreexperienced therapists. Home-based therapy programs areincreasing in popularity for these reasons and may becomefeasible as portable, simple stimulation devices are developed.Such tDCS systems are already being designed includingpatient-friendly operation and ability for remote program-ming and monitoring by study investigators. However, homeprograms may risk removing the substantial psychosocialbenefits young people may receive from participating in campbased programs. These issues will need to be carefullyweighed in the design of future trials.

Neuromodulation trials in children with cerebral palsybring the possibility of precision medicine to paediatricrehabilitation. While predictors of response to such in-terventions have not yet beenwell defined, there is little doubtthat individual factors such as age, baseline disability, lesiontype or location, and corticospinal tract arrangement likelyplay a role.265 A recent review suggested a possible systematicapproach to classify hemiparetic children based on clinical(e.g. mirrormovements), TMS (corticospinal tract orientation),and imaging (corticospinal tract integrity) variables.266 Theseare logical steps that are yet to be validated but carry the po-tential to bring personalized medicine to the rehabilitation of

children with hemiparetic CP.

Conflict of interest

None.

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http://dx.doi.org/10.3109/09638288.2015.1055379



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