DEVELOPMENTAL NEUROPSYCHOLOGY ARTICLES
Developmental neuropsychology articles
Article 1: Early experience and brain development – Johanna Bick and Charles A. Nelson
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Healthy brain development takes place within the context of individual experience. Here, we
describe how certain early experiences are necessary for typical brain development. We present
evidence from multiple studies showing that severe early life neglect leads to alterations in brain
development, which compromises emotional, behavioral, and cognitive functioning. We also show
how early intervention can reverse some of the deleterious effects of neglect on brain development.
We conclude by emphasizing that early interventions that start at the earliest possible point in
human development are most likely to support maximal recovery from early adverse experiences.
INTRODUCTION
Beginning from the moment of birth, healthy brain development requires adequate nurturing
relationships. Caregivers regulate a baby’s physiology by responding to signals of hunger or sickness,
by soothing the baby to sleep, and by insuring proper body temperature through close physical
contact. Caregiving relationships also provide a critical foundation for emotional and cognitive
development. By providing adequate exposure to language, interactive play, and appropriate
emotional feedback, caregivers dynamically support the development of neural circuitry underlying
self-regulation and cognition. Put simply, caregiving quality feeds emotional health and intelligence.
Studies examining children reared in institutional settings show convincingly that sub-par
early experiences have direct and profoundly negative consequences of the developing brain.
Institutional rearing is often characterized by high child-to-caregiver rations and unresponsive, overly
regimented routines. They are deprived of critical opportunities to develop selective attachments
with primary caregivers and are exposed to a reduced range of sensory, linguistic, and cognitive
input.
THE BRAIN DEVELOPS WITHING THE CONTEXT OF EXPERIENCE
The development of the human brain begins within weeks of conception and continues until
late adolescence and early adulthood. It is important to note that the brain continues to adapt and
change in response to experience even into adulthood. Whereas our genes provide essential
information for establishing basic patterns of neuronal growth and connectivity, our individual
experiences can affect gene expression and the trajectory of brain development.
One way to appreciate the influence of life experiences on brain development is to
differentiate between experience-expectant and experience-dependent development. Experience-
expectant development refers to development that occurs in response to certain life experiences
that are typically shared by all members of a species. For example, starting at or before birth, it is
‘expected’ that humans will be exposed to auditory stimuli, patterned light, and opportunities to
move around and manipulate objects. These experiences support the development of neural
pathways associated with hearing, speech and language, vision, and locomotion.
Experience-dependent development, on the other hand, refers to development that occurs
as a result of experiences that vary across individual members of a species. These experiences also
shape development and are part of what makes each individual unique. For example, the learning of
certain skills (such as reading or writing) depends on specific experiences that some individuals may
have access to, while others may not.
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In summary, there are certain experiences that are required for optimal brain development
to support typical physical, cognitive, and emotional functioning. Many of these experiences need to
occur at specific points in development (called ‘sensitive periods’) for humans to develop optimally.
Variations in individual experiences across the lifespan can also shape brain development, but
normative trajectories of brain development can occur without specific exposure to these
experiences.
HOW DO WE STUDY THE EFFECT OF EARLY EXPERIENCE?
Animal research has contributed enormously to our understanding of the impact of early
rearing experiences on brain development. Extreme childhood stressors interfere with healthy brain
development and lead to deficits in cognitive and emotional functioning.
HOW DO WE ASSESS THE IMPACT OF EARLY EXPERIENCE ON BRAIN DEVELOPMENT?
One of the first studies to investigate the influence of early neglect on brain development
utilized positron emission tomography (PET) imaging. PET measures glucose metabolism, a marker of
functional activity in the brain. In this study, brain activity in institutionally reared children was
compared with brain activity in two other groups: the first included non-neglected children with a
neurodevelopmental disorder (epilepsy), and the second included healthy adults. The institutionally
reared children showed significant reductions in levels of glucose metabolism in prefrontal regions
(the orbital frontal gyrus and infralimbic prefrontal cortex), in the medial temporal lobe (amygdala
and hippocampus), in the lateral temporal cortex, and the brainstem and showed patterns of neural
activation that were more similar to the children with neurodevelopmental problems, when
compared with typical adults. Many of these regions that showed reduced activation in the
institutionally reared children are critically involve d in cognition and emotion regulation; therefore,
the authors proposed that these functional alterations underlie common neglect-associated deficits
in social–emotional and cognitive functioning.
More recent studies using magnetic resonance imaging (MRI) have shown that institutionally
reared children exhibit significant reductions in overall brain volume and corresponding decreases in
total and cortical ‘gray matter’ (brain tissue composed of neuronal cell bodies, and other cells known
as glia) and ‘white matter’ brain tissue composed of myelinated axons, which extend from the cell
bodies and support neural transmission across regions of the brain.
TIMING AND DURATION OF ADVERSE EXPERIENCES IMPACTS RECOVERY
The BEIP has demonstrated that early intervention improves brain activity in institutionally reared
children randomized into foster care.
CONCLUSION
Research on institutionally reared children provides clear evidence for the role of early experiences in
shaping brain development. Children who experience substantial neglect, especially during the first
few years, exhibit dramatic alterations in brain development. These alterations are observed both
structurally and functionally. In general, the longer the brain is deprived of ‘expected’ experiences,
the greater the impairment.
Importantly, the brain can recover if children are placed into more nurturing environments
although the patterns of recovery are complex. Some aspects of brain function and structure may be
more responsive to environmental enrichment than others. Similarly, the degree to which children
show remediation in certain neural processes may depend on the timing of the intervention, with
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greater improvements observed for children who receive intervention at the earliest ages. Finally,
some aspects of neural recovery may be immediate, whereas others may take time to emerge.
This body of research has critical implications for social policy and public health. Institutional
neglect is one of many early adverse experiences. Children reared in neglectful or abusive families
face deficits in brain, behavioral, and emotional development. Consistent with the objectives of many
current child welfare legislative acts, many at-risk children are likely to benefit if we prioritize policies
and programs that increase access to prevention and intervention programs. Also, these children
have the greatest chance to benefit from these programs if they begin as early as possible
Article 4: Advancing non-invasive neuromodulation clinical trials in children: Lessons from
perinatal stroke – Adam Kirton
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Abstract
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 trials, 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.
1. First principles of neuromodulation clinical trials
It is highly unlikely that introducing a focal magnetic field or local current into a functional area of
human cortex will magically create new, clinically relevant function. Instead, an endogenous
substrate for neuroplasticity that might be altered by such neuromodulation seems a much more
likely mechanism by which brain stimulation might produce lasting, therapeutic alterations in brain
function. This fundamental tenet also helps correct for the known and large heterogeneity between
subjects inevitably enrolled in such trials. That a TMS measurement as simple as the rest motor
threshold can range from 20 to over 60% of maximum stimulator output across a sample of normal
subjects of the same age and gender points to an even more enormous inter-subject variability in
clinically diseased populations. However, if such subjects share fundamental neuroplasticity
mechanisms within their cortex (e.g. long term potentiation) and are induced to activate them in the
context of desired, functional activity, the potential for neuromodulation is likely greater.
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In a similar context, an informed cortical target for modulation is also essential. Identification of such
functionally relevant cortical regions is often difficult. As outlined below, studies of enhancement of
motor learning with brain stimulation and have often logically targeted the primary motor cortex.
This has logically extended to clinical populations with motor disability, targeting the motor cortex
and related network components in common populations of motor disability such as adult stroke
hemiparesis.1 Importantly, this evolving process has not rested on such simplistic anatomical
localization alone. Instead, neurophysiological models have been developed to first understand what
happens to the system of interest in the disease state. These often include large bodies of evidence
from preclinical animal models combined with human studies using advanced neuroimaging and
other neurophysiology tools. Such an example for perinatal stroke will be presented below.
Such models not only identify potential targets but also a desired direction for change. For example,
the lesioned motor cortex may be underactive while the homologous region of the contralateral,
non-lesioned hemisphere may be relatively overactive. Such a model of “imbalanced
interhemispheric motor inhibition” is probably over simplified but is well supported by large volumes
of neurophysiological evidence and has driven the majority of non-invasive brain stimulation trials in
adult stroke.1, 2 Recent summative evidence of rTMS therapeutic trials highlights this point by
comparing modalities and targets across a wide range of such conditions. 3
Importantly, each these three principles of modulating an informed target in a specific direction
during activation of endogenous plasticity are arguably still not well defined in relatively concrete
examples like adult stroke. In fact, such principles are often not entirely obvious (or even
theoretically well defined) in many other stimulation clinical trials. While such failure should raise
immediate concerns of validity, their presence is relatively sparse in the most defined therapeutic
non-invasive brain stimulation population: adult major depression. High frequency rTMS of the
dominant dorsolateral prefrontal cortex (DPFC) is FDA and Health Canada approved and rapidly
expanding as an insured service. While based on some human evidence of regional dysfunction in
this broad, highly connected area with functional implications for some symptomology, it could be
argued that the ability of depression to satisfy the above criteria is modest at best.
This raises a final principle consideration of disease specificity. As a very common, disabling, and
highly studied disease, major depression carries well-defined diagnostic and classification criteria.
Despite this, there are innumerable factors, both measureable and unknown, that would likely
influence response to neuromodulation. In contrast, autism is a heterogeneous disorder of social and
communication development that is likely due to hundreds of different genetic disorders in addition
to other etiologies. This does not mean that informed, symptom-specific targeting of cortical regions
to enhance other therapies or learning is impossible. However, the breadth of heterogeneity must be
acknowledged and adjusted for whenever possible if meaningful trials are to be designed. Trials of
autism due to one specific mutation bring limitations of recruitment and sample size and are still not
ideal; consider the phenotypic variability of tuberous sclerosis alone. However, striving for disease
specificity whenever possible will likely advance progress in paediatric neuromodulation trials much
faster. Extricating the very specific forms of perinatal stroke from the more complex world
of cerebral palsy for motor learning neuromodulation trials provides a practical example.
2. Perinatal stroke
You will not likely incur a higher period of risk for ischaemic stroke than the week you are born.4 A
term newborn carries a risk >1:3500,5 three-fold higher than a week in the life of a diabetic,
hypertensive, smoking adult and eight-fold above all adults. 6 An additional 50% of perinatal stroke
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presents later in infancy.7 Perinatal stroke is the leading cause of hemiplegic cerebral palsy (HCP) and
most survivors suffer additional neurological sequelae including intellectual disabilities, language
impairments, developmental and behavioural disorders, and epilepsy.8, 9, 10 Frequent occurrence
combined with lifelong morbidity generates large global burdens. Identification of a causative factor
remains elusive in most cases11 and with no means of prevention, perinatal stroke and HCP will
burden thousands of children for decades to come.
Arterial ischaemic strokes (AIS) are large brain injuries secondary to occlusion of major cerebral
arteries. Some present at birth with acute seizures (called symptomatic neonatal AIS) while others
are not recognized until infancy when hemiparesis becomes evident (called arterial presumed
perinatal ischaemic stroke).7, 18, 19, 20 In contrast, periventricular venous infarctions (PVI) are
subcortical white matter lesions acquired well before birth. Secondary to germinal matrix bleeds with
subsequent medullary venous infarction, these lesions occur in utero before 34 weeks gestation.
3. Perinatal stroke outcomes
Neurodevelopmental deficits occur in ∼75% of perinatal stroke
survivors.8, 10, 19, 28, 29, 30, 31, 32, 33, 34 Hemiparetic CP is the most common term-born cerebral
palsy35 and stroke is the leading cause.36, 37 Motor deficits are the most prominent and disabling
symptom, present in 30–60% of acute symptomatic NAIS31, 38, 39 and >80–90% of presumed
perinatal ischaemic strokes including PVI.12, 18, 19, 31 Clinical, laboratory, and EEG variables are
limited in their abilities to predict motor outcome,9, 10, 29, 34, 40 but neuroimaging has improved
the early identification of the most affected children.31, 33, 34, 41, 42, 43, 44 We and others have
described how corticospinal tract diffusion MRI in NAIS45, 46 and structural MRI in PPIS12 can predict
motor outcomes in infancy. This has opened the window for intervention earlier in development.
Deficits in language, vision, cognition, behaviour and epilepsy also occur, present in 20–
60%8, 10, 18, 19, 47, 48, 49 of arterial strokes. The morbidity of perinatal stroke lasts a lifetime,
amplifying the burden on child, family, and society. 50 Physical disability contributes across this realm
of consequences and current interventions have limited efficacy. 51 There is therefore an urgent need
for new treatment strategies founded upon our best possible understanding of
the neurophysiology that underlies the clinical dysfunction.
4. Plastic organization following unilateral perinatal brain injury: an integrated model
In 1936, Kennard described better outcomes in younger primates following unilateral motor cortex
lesions.52 This Kennard principle has fostered efforts to understand and harness age-related plasticity.
Common occurrence and focal injury in an otherwise healthy brain makes perinatal stroke an ideal
human model. Terms like “repair” and “reorganization” imply the existence of inherent restorative
mechanisms that evolutionary models suggest would not exist. 53 Instead, plastic adaptation may
represent alterations of normal, ongoing developmental processes occurring after injury. Elegant
animal work and human studies have solidified a model that creates novel avenues for therapeutic
interventions in hemiparetic CP.54, 55, 56 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 their influence on spinal motor neuron pools (C).
A. The lesioned hemisphere: contralateral projections to the paretic hand. Adult stroke and
animal studies suggest that, on average, motor control in the lesioned hemisphere is
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associated with better function. Enhancing motor control in the lesioned hemisphere should
favour improved function.
B. Role of the unlesioned hemisphere: epilateral projections to the paretic hand. Abnormal
projections from the unlesioned hemisphere to the paretic hand are common in hemiparetic
CP, but inconsistent in their physiology. Ipsilateral projections likely arise from homologous
region of primary motor cortex. Complex cortical motor circuits within and between the
hemispheres also mediate neuroplasticity including interhemispheric inhibition (IHI) and
intracortical inhibitory and facilatory circuits.
C. Synaptic competition model. The target of these developing upper motor neuron systems are
the spinal lower motor neurons, control of which determines function. Continuous
competition between contralateral and ipsilateral corticospinal tract projections to establish
synapses with these cells occurs through development with eventual contralateral
domination and withdrawal of ipsilateral projections.
5. The window of opportunity in developmental neuroplasticity
Modern definitions of CP suggest deficits are static and non-progressive. However, neonates with
stroke usually demonstrate no observable neurological deficits. Plastic motor organisation continues
well beyond adolescence.
6. Therapeutic neuromodulation in hemiparetic CP
6.1 Intensive motor learning, manual therapy
Constraint induced movement therapy (CIMT) promotes functional use of an impaired limb by
constraint of the less-impaired limb coupled with repetitive motor practice. CIMT limitations include
a somewhat invasive nature and the exclusion of bimanual learning. Bimanual approaches can also
improve function in hemiparetic CP trials. Hand-arm Intensive Bimanual Therapy (HABIT) is an
evidence-based, safe, valid, and effective motor learning therapy in children with hemiparetic CP.
Comparison of CIMT and HABIT suggest possible greater achievement of self-directed goals with
HABIT.
How such therapies are delivered has also evolved. Intensive, camp-based models are increasingly
popular, both for psychosocial and programming benefits but also t deliver high doses of structured
motor learning therapy that may optimize use-dependent changes in brain plasticity and function.
Providing such intensive, goal-directed, evidence-based therapy to all participants provides
numerous potential advantages. That all subjects receive individualized, ‘best available’ treatment
facilitates randomization to such additional intervention where there is equipoise regarding efficacy
and minimal, but not zero, risk of adverse events. Limitations include the dosage of therapy achieved
over focused time frames where the optimal number of hours, bot total and divided between
focused and more general training, remain to be determined. The balance of unimanual versus
bimanual and the timing of how the two should be integrated is also imprecise and in need of better
evidence. Lastly, the potential psychological and social benefits of such group-based participation
with grouping of participants by developmental level should not be underestimated. Working
together to achieve personal goals alongside similarly affected, motivated peers likely carries large
psychosocial benefits, the more accurate measurement of which is a goal of future trials.
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6.2 Non-invasive brain stimulation: repetitive transcranial magnetic stimulation (rTMS)
TMS given repeatedly can produce lasting changes in brain function. Limitations of rTMS include very
focal administration and burdensome, immobile hardware that prevents simultaneous rehabilitation
and co-activation of endogenous motor learning systems.
Despite both the high burden of motor disability and greater brain plasticity in children, rTMS studies
have been limited. Evidence from our group and others has shown no adverse effect of non-lesioned
M1 inhibitory rTMS on normal (unaffected) hand function in hemiparetic subjects. The trial provides
class II evidence for rTMS and CIMT enhancement of motor learning therapy while supporting the
overall safety and feasibility of conducting non-invasive stimulation trails in children with perinatal
stroke-induced hemiparesis.
6.1 Non-invasive brain stimulation: transcranial direct current stimulation (tDCS)
tDCS applies scalp electrodes (anode and cathode) to generate weak direct currents that induce
polarity-dependent changes in brain excitability. tDSC induces regional, transient modulation of
resting membrane potential and cortical neuronal excitability. In general, anodal stimulation
increases cortical excitability while cathodal simulation decreases it. tDSC can enhance motor
learning in both animals and healthy adults when administered briefly over the motor cortex.
Recent trials provide Class I evidence that tDCS can enhance motor recovery in adults with chronic
stroke. Though fundamental mechanisms may differ, the same approach outlined above –
stimulating the lesioned, or inhibiting the unlesioned hemisphere, (or both) – appears to enhance
motor function.
In summary, interventions were well tolerated with not serious adverse vents and all safety
outcomes were satisfied. Significant tDCS effects were observed on COPM, but not AHA outcomes,
suggesting possible benefit and providing important data for the execution of a larger, mor definitive
trial.
7. Systematic approach to clinical design: CONSORT
Any trial is only as good as the methods on which it rests. The CONSORT (Consolidated Standards of
Reporting Trials) statement is an evidence-based minimum set of standards for the reporting of
randomized clinical trials. Use of the CONSORT guidelines has been associated with improved
reporting of clinical trials. The outline of the guidelines will be applied below to review several
essential elements of trial design as they relate to non-invasive stimulation trials in children.
7.1 Populations
Where participant populations exist and how they are accessed for recruitment will primarily depend
on the inclusion and exclusion criteria. However, before these criteria are applied, the sample to be
screened should be carefully selected to represent, as best as possible, the population of interest as a
whole. Disease-specificity will be a major determinant of this population.
7.2 Selection criteria
Further reduction of the eligible population for recruitment will occur with application of inclusion
and exclusion criteria. Their selection must rest on the primary research question being asked; if this
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has to be compromised by changing criteria to suit other needs, the question should instead be
changed.
7.3 Randomization
Methods for randomization within clinical trials are complex and beyond the scope of this discussion.
However, several fundamental issues to be considered relate predominantly to trial design and a
priori knowledge of response predictors and other potential confounders. Options including block or
minimized randomization may help ensure balance of treatment allocation across subgroups of
patients. Most forms of randomization can be performed simply using patient codes and computer-
based or online software administered by an unbiased study member such as the statistician.
7.4 Recruitment
Failure to recruit complete samples on time is one of the most common reasons for trials to be
delayed or not completed at all. Estimates of attainable sample sizes must be realistic (i.e.
pessimistic). Hard numbers from established populations are required rather than blind estimates of
prevalence based on published epidemiological data. What may appear as large, easily adequate
number of potential subjects often reduces dramatically when realistic limitations are estimated.
Examples include presence of exclusion criteria, inability to confirm all inclusion criteria, geographical
factors, failure to recruit rates, and attrition with drop-outs possible at all stages.
7.5 Informed consent and assent
Consenting children and parents to novel, experimental trials of brain stimulation requires special
attention. Potential benefits may be easily over-estimated by families of disabled children due to lack
of alternative therapies, being “impressed” by technology, or other reasons. Risk must also be fairly
disclosed based on best available evidence. Theoretical risks must be presented in context with
estimates of relative risk and potential harm.
7.6 Structure and flow
Structuring a complex, multifaceted intervention with numerous requirements for space,
infrastructure, and highly qualified personnel requires organized structure. Balancing focused motor
training with more general and group activities as well as breaks and relaxation can be challenging. It
is essential to include input from experts in paediatric therapy, child life, and subjects and their
families for optimal planning.
7.7 Sham-control and blinding
Effective sham techniques are well established for noninvasive stimulation methods. Modern tDCS
systems can also be programmed to randomize and administer accordingly, allowing the
administrator to remain blinded.
7.8 Analysis and sample size
Statistical analysis will of course depend on the research questions to be addressed. In most
circumstances, analysis will be intention to treat, accounting for all subjects randomized whether
they complete the trial or not.
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8. Outcome measures
Selection of outcome measures is likely one of the most essential components of clinical trial design.
Standardized, unbiased administration and interpretation by qualified experts blinded to treatment
allocation and other clinical information is required but often challenging. Additional issues specific
to considering neurostimulation interventions in children include a relative paucity of validated
measures, heterogeneous populations (e.g. CP versus hemiparetic CP versus perinatal stroke
hemiparesis), and variable effects of age and developmental level to name just a few. However,
these limitations are being overcome through a variety of creative means to facilitate evaluation of
such interventions
8.1 Clinical outcomes: motor function
A rigorous, evidence-based approach to clinical motor outcome selection should be adopted.
Measurement of both uni- and bi-lateral function of both limbs are required for normative data,
evaluation of different clinical functions, and safety (including screening for changes in unaffected
hand function). Testing should be video-taped for quality assurance, inter-rater validation, and
additional offline analysis. Motor outcomes are measured at baseline, and 1 week, 2 months post-
intervention.
With these principles in mind, the following three potential primary outcome measures might be
considered in a clinical trial of intensive motor learning therapy combined with non-invasive brain
stimulation in hemiparetic children.
8.1.1 Primary objective motor outcome: Assisting Hand Assessment (AHA)
This is currently the established standard for the objective quantification of bilateral hand function in
children with hemiparetic CP. One potential limitation of the AHA is a drop in score when new
unimanual functions have not yet been incorporated into the bimanual tasks being measured (i.e.
scores may drop despite new function).
8.1.2 Primary subjective motor outcome: Canadian occupational performance measure (COPM)
Subjective outcome measures are now considered a valid, potentially essential outcome measure in
rehabilitation trials including children with hemiparetic CP. It could be argued that any gains shown in
objective tests of motor function (e.g. strength, dexterity) are meaningless if the patients themselves
have not perceived the achievement of a personal goal or some other personal satisfaction. For these
reasons, individualized, patient-centered, goal directed tools such as the COPM have been developed
and validated.
8.1.3 Noval “real-life, continuous” motor outcome: actigraphic symmetry index (ASI)
No existing motor outcome measure can quantify continuous use of the upper extremities during the
normal activities of real life.
8.2 Safety outcomes
With limited non-invasive neuromodulation data in the developing brain, careful and complete
application of safety outcomes is paramount within clinical trials. Adult guidelines and safety reviews
are available for both TMS and tDCS and are certainly applicable. However, issues unique to children
need to be screened for and rates of tolerability and potential adverse events documented. Safety
can be considered under the following headings:
8.2.1 Serious adverse events
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Typical definitions of SAE are adverse events or reactions that results in death, is life-threatening,
requires hospitalisation or prolongation of existing hospitalisation, results in persistent or significant
disability or incapacity, or is a congenital anomaly or birth defect. Fortunately, SAE reports in non-
invasive brain stimulation have been exceedingly 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, one example is provided by the known control of both upper extremities by the non-
lesioned hemisphere. Subsequently, inhibitory stimulation of the contralesional motor cortex might
include theoretical consideration of reducing hand function in the unaffected hand or in the target
affected hand, particularly in those with prominent ipsilateral corticospinal arrangements. Therefore,
primary safety outcomes in our brain stimulation trials have included regular measures of both
affected and unaffected hand function across time points for each subject and within interim safety
analyses. Any intervention capable of having biological effects must also have the risk of side effects.
8.2.4 Tolerability
A standardized safety and tolerability evaluation for TMS in children has been developed and is easily
adapted for different population and modalities including tDCS.190 Subjects are asked to rank order
their stimulation experience amongst 7 other common childhood experiences.
Optimizing safety requires attention to each of the above issues. Brain stimulation studies in children
should be performed by experienced personnel in a secure environment. Immediate access to
medical care should be available in the unlikely occurrence of a serious adverse event. Written
standardized operating procedures, for both experimental methods and handling adverse events,
should be implemented and staff tested for their familiarity with these
9. Neurophysiological outcomes
Advanced neurotechnologies have greatly advanced the ability to understand developmental
plasticity in real patients. This includes baseline measures to evaluate natural process and how they
relate to function but also the opportunity to explore the potential mechanisms of intervention-
induced change. Combining modern technologies allows the comprehensive, integrated study of
brain structure and function personalized to each individual. Clinically relevant examples of such
integration are increasingly available in adults223 but awaiting full exploration in children.
Summarized here are leading applications of single- and paired-pulse TMS, imaging including task
and resting state fMRI and diffusion tensor imaging (DTI), and robotics
9.1 Transcranial magnetic stimulation (TMS)
TMS is safe and well tolerated in children. Modern technologies include single pulse systems for
excitability and pathways as well as paired-pulse methods capable of probing cortical excitatory,
inhibitory, and other physiological functions. Additional potential TMS neurophysiological outcomes
include: (1) Stimulus response curves (rest and active). Bilateral M1 excitability is quantified by
measuring MEP amplitudes across 5 escalating stimulus intensities such as 100/110/120/
130/140/150% of RMT. (2) Interhemispheric Inhibition (IHI). Bidirectional IHI (lesioned to unlesioned
hemisphere and viceversa) applies stimuli to both M1 in quick succession with methods described
elsewhere. Paired-pulse TMS applies a suprathreshold conditioning stimulus (CS) contralaterally
immediately prior to a test stimulus (TS) with interstimulus intervals of 10 and 40 ms. The decrease in
