Cerebral Plasticity: Windows of Opportunity in The Developing Brain

e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 2 3 e4 8
Official Journal of the European Paediatric Neurology Society
Review article
Cerebral plasticity: Windows of opportunity in the

developing brain
Fatima Yousif Ismail a,b,*, Ali Fatemi c, Michael V. Johnston c

a
Department of neurology and developmental medicine, The Kennedy Krieger Institute, Johns Hopkins Medical
Institutions, MD, USA
b
Department of pediatrics, College of Medicine and Health Sciences, United Arab Emirates University, Al- Ain, UAE
c
Departments of Neurology and Pediatrics, The Kennedy Krieger Institute, and Johns Hopkins University School of
Medicine, MD, USA
abstract
Keywords: Background: Neuroplasticity refers to the inherently dynamic biological capacity of the
Neurodevelopment central nervous system (CNS) to undergo maturation, change structurally and functionally
Synaptic plasticity in response to experience and to adapt following injury. This malleability is achieved by
Neuromodulation modulating subsets of genetic, molecular and cellular mechanisms that influence the dy-
Critical period namics of synaptic connections and neural circuitry formation culminating in gain or loss
Sensitive period of behavior or function. Neuroplasticity in the healthy developing brain exhibits a heter-
Transcranial magnetic stimulation ochronus cortex-specific developmental profile and is heightened during “critical and
sensitive periods” of pre and postnatal brain development that enable the construction and
consolidation of experience-dependent structural and functional brain connections.
Purpose: In this review, our primary goal is to highlight the essential role of neuroplasticity
in brain development, and to draw attention to the complex relationship between different
levels of the developing nervous system that are subjected to plasticity in health and
disease. Another goal of this review is to explore the relationship between plasticity re-
sponses of the developing brain and how they are influenced by critical and sensitive
periods of brain development. Finally, we aim to motivate researchers in the pediatric
neuromodulation field to build on the current knowledge of normal and abnormal neu-
roplasticity, especially synaptic plasticity, and their dependence on “critical or sensitive
periods” of neural development to inform the design, timing and sequencing of neuro-
modulatory interventions in order to enhance and optimize their translational applications
in childhood disorders of the brain.
Methods: literature review.
Results: We discuss in details five patterns of neuroplasticity expressed by the developing
brain: 1) developmental plasticity which is further classified into normal and impaired
developmental plasticity as seen in syndromic autism spectrum disorders, 2) adaptive
(experience-dependent) plasticity following intense motor skill training, 3) reactive plas-
ticity to pre and post natal CNS injury or sensory deprivation, 4) excessive plasticity (loss of
* Corresponding author. The Kennedy Krieger Institute, Johns Hopkins Medical Institutions, MD, USA.
E-mail address: [email protected] (F.Y. Ismail).
http://dx.doi.org/10.1016/j.ejpn.2016.07.007
1090-3798/© 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
24 e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 2 3 e4 8
homeostatic regulation) as seen in dystonia and refractory epilepsy, 6) and finally, plas-
ticity as the brain's “Achilles tendon” which induces brain vulnerability under certain
conditions such as hypoxic ischemic encephalopathy and epileptic encephalopathy syn-
dromes. We then explore the unique feature of “time-sensitive heightened plasticity re-
sponses” in the developing brain in the in the context of neuromodulation.
Conclusion: The different patterns of neuroplasticity and the unique feature of heightened
plasticity during critical and sensitive periods are important concepts for researchers and
clinicians in the field of pediatric neurology and neurodevelopmental disabilities. These
concepts need to be examined systematically in the context of pediatric neuromodulation. We
propose that critical and sensitive periods of brain development in health and disease can
create “windows of opportunity” for neuromodulatory interventions that are not commonly
seen in adult brain and probably augment plasticity responses and improve clinical outcomes.
© 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights
reserved.
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2. Patterns of neuroplasticity in the developing brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.1. Developmental plasticity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.1.1. Normal developmental plasticity: from neurons to networks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.1.2. Impaired developmental plasticity: plasticity stunted by genetic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
2.2. Adaptive plasticity: reorganization that promotes or improves adaptive function . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.3. Reactive plasticity following sensory deprivation or CNS insult . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.4. Excessive/destabilizing plasticity (reorganization that escapes homeostatic regulation) . . . . . . . . . . . . . . . . . . . . . . . 32
2.4.1. Dystonic disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.4.2. Epileptogenesis: a form of excessive uncontrolled plasticity? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.5. Plasticity as the brain's “Achilles Heel” rendering it more vulnerable to injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.5.1. Hypoxic ischemic encephalopathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.5.2. Epileptic encephalopathy syndromes (EES) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3. Critical/sensitive periods in the developing brain: potential windows of opportunity for neuromodulatory interventions? 37
3.1. What we know about critical and sensitive periods in the developing brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.2. Can we clinically identify the timing of critical or sensitive periods of networks plasticity? . . . . . . . . . . . . . . . . . . . 37
3.3. Can the onset, duration and closure of critical or sensitive periods be modified? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.4. Would manipulating the critical period have short or long-term impact, given the time-dependent
hetero-synchronous pattern of brain development? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.5. Are the critical and sensitive periods in disorders of abnormal synaptic plasticity different? . . . . . . . . . . . . . . . . . . 39
4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
1. Introduction achieved by modulating subsets of genetic, molecular and

cellular mechanisms that influence the dynamics of synaptic
When it comes to the development of the young brain, “The connections and neural circuitry formation culminating in
only constant is change”, Heraclitus of Ephesus a Greek philoso- gain or loss of behavior or function.1 The endpoint of plas-
pher (c.535 BC e 475 BC). Neuroplasticity is a complex process ticity, however, is not always beneficial and can lead to sig-
that is heightened during time-sensitive periods of pre and nificant maladaptive outcomes depending on the nature and
postnatal brain development and continues, albeit to a lesser extent of the neuropathogenic process, the stage of neuro-
degree, throughout adolescence and adulthood. Neuro- development during which it occurs as well as the integrity of
plasticity refers to the inherently dynamic biological capacity homeostatic regulatory mechanisms.2
of the central nervous system (CNS) to undergo maturation, Patterns of abnormal neuroplasticity have been recently
change structurally and functionally in response to experi- recognized as core pathologies in many congenital and ac-
ence and to adapt following injury. This malleability is quired pediatric disorders of CNS such as neonatal hypoxic
e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 2 3 e4 8 25
ischemic encephalopathy, cerebral palsy, epilepsy and Neurogenesis is most prominent during early fetal devel-
epileptic encephalopathies, dystonia, intellectual disabilities, opment. This is followed by robust synaptogenesis that starts
autism spectrum disorders (ASD) and neuropsychiatric dis- as early as 27 weeks post gestational age and intensifies over
orders such as attention deficit hyperactivity disorder the first 2 years of life following a heterochronus cortex-
(ADHD)3 and schizophrenia.4,5 Hence, the potential of modu- specific maturational pattern.1 For example, in the auditory
lating abnormal plasticity patterns in childhood disorders of cortex, maximum synaptogenesis occurs at around 3 months
the brain is gaining momentum in translational pediatric of age, while it peaks at 18 months of age in the prefrontal
neuromodulation research. cortex.7 Similarly, excessive activity-dependent synaptic
In this article, we will 1) Review the different patterns of pruning is completed earlier in the auditory cortex while it
neuroplasticity in the young brain under normal and continues in prefrontal cortex until mid-adolescence.7
abnormal conditions. 2) Explore the unique feature of “critical On a molecular level, CNS receptors undergo major alter-
and sensitive periods” that govern the temporal and spatial ations to achieve adult-like pattern and are thought to regu-
profile of neuroplasticity in the developing brain. Finally, 3) late the critical and sensitive periods of development. GABAA,
discuss the importance of considering critical or sensitive NMDA and AMPA receptors follow a sequential expression in
periods of brain development when devising neuro- the developing brain that subsequently allows GABAergic in-
modulatory interventions for children. terneurons to develop, mature, connect and generate patterns
before the pyramidal cells.8 Similarly, NMDA receptors
develop before AMPA receptors providing the basic platform
for neuronal communication and networks formation, and
2. Patterns of neuroplasticity in the
finally AMPA receptors develop at the appropriate time for
developing brain
experience-dependent long term potentiation (LTP) and long
term depression (LTD) plasticity.8 This sequential expression
The young brain harbors a repertoire of neuroplasticity re-
is not mutually exclusive.
sponses that are not commonly seen in its adult counterpart.
Moreover, crucial developmental alterations occur on a
This feature allows the young brain to appropriately develop
CNS-wide scale in which glutamate and GABA receptors switch
and unceasingly adapt as mentioned earlier. Attempting to
their subunits composition triggering a cascade of intracellular
classify the patterns of neuroplasticity in the young brain is a
and synaptic events that renders the developing brain more
challenging task given the multifaceted and interwoven
susceptible to perturbation. For example, the embryonic brain
manifestations of these patterns in health and disease. Fig. 1
is abundant with two major types of glutamate receptors sub-
summarizes our proposed classification of neuroplasticity in
units, GluN2B and GluN2D. The composition of NMDAR sub-
pediatrics with selected examples of each pattern.
units undergoes modification during the first few weeks of life.
While these patterns are compartmentalized into boxes for
The prenatally dominant GluN2B subunit switches to GluN2A
the ease of the discussion, it is important to note that these
subunit during a time window that coincides physiologically
patterns overlap and are not mutually exclusive.
with the critical periods for synaptic maturation and change in
electrophysiological properties leading to circuit formation,
2.1. Developmental plasticity and acquisition of learning abilities. This developmental switch
curbs premature synaptic maturation suggesting its crucial role
2.1.1. Normal developmental plasticity: from neurons to in neural activation and experience-dependent synaptic plas-
networks ticity.9 GABA receptors undergo a similar “switch” in function
Developmental neuroplasticity is a complex genetically during early post-natal life (as discussed later).
encoded, time-dependent and sequenced maturational pro- Structurally, age- and sex-related changes in brain volume
cess that is closely regulated by intrinsic homeostatic mech- in relation to head circumference,10 cortical thickness and
anisms and is influenced by extrinsic environmental surface area, cortical, subcortical and cerebellar anatomy11
experiences. Developmental neuroplasticity is an inclusive have been extensively described. Microstructural changes at
term that involves fundamental changes in neurogenesis, the level of individual white matter tracts using DTI technique
neuronal cell migration, synapse formation and structural have also shown spatially variable age- and tract-specific
and functional neuronal networks specialization leading to maturation.12 The dynamic mapping of human cortical
behavioral acquisition of motor and non-motor develop- development has been postulated to temporally reflect
mental milestones and adaptation to a constantly changing changes at the level of synaptogenesis and synaptic pruning.13
environment through learning and memory. Several mecha- On a network level, resting state functional MRI (rsfMRI)
nisms contribute to the intricate balance between neural studies in infants and young children have shown age-related
plasticity and homeostasis in the developing brain allowing a developmental pattern of brain functional architecture. Gao
reasonably functional “not too rigid and not too flexible” de- and coworkers examined rsfMRI in 143 subjects during the
gree of synapses and networks stability.4 first 2 years of life. Scans demonstrated established primary
From a biological perspective, neurogenesis, synapto- networks resembling adult-like pattern in neonates with
genesis and synaptic pruning represent the building blocks for minimal inter-subject variability, while higher-order large-
CNS plasticity. These biological processes are subjected to scale association networks showed age- and sex-dependent
genetically programmed, time-limited periods, called the maturational profile with increased connectivity and syn-
critical or sensitive periods during which the brain is most chronization at 2 years of age and more inter-subject vari-
amenable to change.6 ability.14 The same research group looked at genetic
NeuroplasƟcity
Excessive/ CNS
Developmental AdapƟve ReacƟve destabilizing vulnerability
Normal Impaired Experience- Post sensory Dystonia HIE

Post injury
dependent deprivaƟon
Epileptogenesis EES
Neurogenesis RS Hemi- Amblyopia
spherectomy
Synaptogenesis/ FXS
pruning
Perinatal insult Deafness
TSC
Networks formaƟon
NF-1
Electrophysiolo-gical
changes
AS
Behavior PMS
Fig. 1 e Patterns of neuroplasticity in the developing brain. RS: Rett Syndrome; FXS: Fragile X Syndrome, TSC: Tuberous
Sclerosis Syndrome; NF-1: Neurofibromatosis Syndrome; AS: Angelman Syndrome; PMS: Phelan-McDermid Syndrome. HIE:
Hypoxic Ischemic Encephalopathy; EES: Epileptic Encephalopathy Syndromes.
influences on networks formation between singletons, In vivo characterization of age-specific typical and atypical
monozygotic and dizygotic twins and found that there was developmental trajectory of motor cortex electrophysiology in
age-dependent and region-specific trend of increasing inter- children has been identified using transcranial magnetic
subject variability with decreasing genetic sharing magni- stimulation (TMS). Patterns of age-related changes in motor
tude. In other words, monozygotic twins showed more threshold, silent period latency and duration, central motor
decreased inter-subject variability more than dizygotic twins conduction time, interhemispheric inhibition/facilitation and
and singletons15 pointing towards inherent genetic influences transcallosal inhibition have been reported in healthy chil-
on network connections and susceptibility to experience- dren and correlated with developmental trajectory of motor
dependent plasticity. behavior (reviewed in17,18). Although limited by number of
The observation of heterochronus cortex-specific matura- studies and protocol designs, the dynamics of age-specific
tion has also been supported by PET studies of cerebral neuronal network oscillations involved in cognitive process-
glucose metabolism that showed distinctive age-dependent ing in the developing brain using Magnetoencephalography
metabolic patterns. For example, during the neonatal period, (MEG) have been mapped in typical and atypical brain
glucose metabolism is most apparent in sensorimotor cortex, development.19
cingulate and mesial temporal cortex, thalamus, basal To summarize, the substrates of developmental neuro-
ganglia, brainstem and cerebellar vermis. At around 2e3 plasticity span across molecular alterations, cellular adapta-
months of age, heightened glucose metabolism shifts to pa- tions, cortical electrophysiological changes and structural and
rietal, occipital and temporal cortices, basal ganglia and functional neuronal networks assembly and are expressed
cerebellar hemispheres. Increased glucose metabolism of vigorously during time-sensitive periods of brain develop-
frontal cortex emerges at around 8 months of age. Moreover, ment (Fig. 2).
regional cerebral rates of glucose utilization at birth undergo a
two-fold increase compared to adult brain until 4e5 years of 2.1.2. Impaired developmental plasticity: plasticity stunted
age. This rate plateaus until 9e10 years of age and starts to by genetic disorders
decline to adult rate by 16e18 years of age.16 The results of Pathological states can disturb normal developmental ho-
these studies suggest that intrinsic factors “create the back- meostasis and/or induce aberrant developmental neuro-
bone” for primary functional networks formation while large- plasticity contributing to abnormal neurophysiological and
scale association networks are more subjected to the influ- behavioral phenotype. Distinct abnormal “plasticity patterns”
ence of environmental input and experience. More impor- have been implicated in many neurological disorders of
tantly, both primary and large-scale association networks childhood. For example, abnormal dendritic spine structural
seem to show a time-sensitive “readiness” to maturation into plasticity has been implicated in Rett syndrome, intellectual
adult-like patterns. disabilities and epilepsy.20 Disorders of over- or under-
Behavior
Networks
Synaptogenesis Synapse Signaling

Pruning cascades
StabilizaƟon
Prerequisites Open CriƟcal and SensiƟve Periods Prerequisites Closed
GeneƟc Molding and EpigeneƟc ModulaƟon
Normal Development
Fig. 2 e The time-sensitivity and multi-level integration of neuroplasticity in the young brain. Neuroplasticity encompasses
alterations beyond the level of the synapse and attention must be drawn to the complex relationship between different
levels of the developing nervous system that are subjected to plasticity. A dysfunction of plasticity at one level translates to
“upstream” and “downstream” levels. Similarly, a neuromodulatory intervention at one level would be expected to induce
upstream and downstream changes. Thus, the outcomes of neuromodulation should be examines across as many levels as
possible to develop distinctive profile pattern for certain disorders or intervention tools.
pruning of the synapse have been described as basic etiologies cytotoxic levels of glutamate that interfere with normal
for certain neurobehavioral disorders such adolescence-onset neuronal transmission and activity-dependent neuronal
schizophrenia.21,22 Data from genetic association studies plasticity required for learning and memory.
revealed that many developmental disorders of cognition From a neurophysiological point of view, impaired activity-
share structural or functional pathology of glutamatergic dependent LTP and absent LTD activities have been described
synapses that occur during critical periods for synaptogenesis in MeCP2-null mouse models of Rett syndrome.26 Neuropath-
and pruning23 and continue beyond those critical periods ological studies in young patients with Rett syndrome showed
leading to dysfunctional activity-dependent plasticity by increases in glutamate to cytotoxic levels with concomitant
impairing LTP and LTD. In this section we will discuss few up-regulation of NMDA receptor density compared to age
examples of neurodevelopmental and neurological disorders matched controls. On the other hand, older patients with Rett
associated with impaired developmental synaptic plasticity syndrome (10 years of age) showed abnormally low glutamate
or abnormal synaptic homeostasis. Table 1 summarizes the levels compared to age matched controls.27
multi-level manifestation (from genes to cortical electro- Conventional and advanced neuroimaging studies have
physiology) of abnormal plasticity mechanisms in selected provided invaluable insight into structural and functional
genetic disorders of brain development. changes in patients with Rett. For example, diffusion tensor
imaging (DTI) revealed selective abnormalities in white matter
2.1.2.1. Rett syndrome. Patients with Rett syndrome tend to tracts of corpus callosum, internal capsule, and frontal white
follow a normal developmental trajectory for the first few matter while limbic system and cerebellar tracts were
months of life, but then developmentally regress and exhibit spared.28 Moreover, selective vulnerability of frontal brain
seizures, intellectual disability, stereotypic movements, regions as evident by neuronal and glial biomarkers of injury
abnormal breathing, dysautonomia, dystonia and ataxia. Ac- has been confirmed by magnetic resonance spectroscopy
quired microcephaly is common and reflects brain growth (MRS) and increases in glucose uptake has been demonstrated
deceleration during the period of maximal synapse prolifera- by positron emission tomography (PET) studies likely related
tion. This is supported by neuropathological studies that to increased glutamate cycling in the synapses.29
showed reduced gray matter and closely packed neurons Finally, using single-pulse TMS, in vivo characterization of
secondary to arrested ongoing synaptic formation and matu- cortico-spinal hyperexcitability as evident by short central
ration and disrupted axono-dendritic formation.24,25 motor conduction time in young patients with Rett syndrome
Abnormal neuronal homeostatic synaptic scaling in which has been reported,30 which can be explained by increased
there is an increase in glutamate signaling and inappropriate glutamate level and greater synaptic density for excitatory
increase, rather than decrease, in glutamate receptors leading inputs as mentioned earlier. These findings correlate with the
to “synaptic overshoot” has been observed in patients with clinical observation that seizures are more common in
Rett syndrome as a result of MeCP2 mutations. This abnormal younger patients due to excessive glutamate. Studies corre-
homeostatic synaptic scaling predisposes the young brain to lating in vivo cortical hyperexcitability or other measures of
Table 1 e Abnormal developmental plasticity in selected genetic disorders: from genes to cortical electrophysiology. RS:
Rett Syndrome; FXS: Fragile X Syndrome, TSC: Tuberous Sclerosis Syndrome; AS: Angelman Syndrome; PMS: Phelan-
McDermid Syndrome; NF-1: Neurofibromatosis Syndrome; DYT1: Early onset generalized torsion dystonia. LTP: long term
potentiation; LTD: long term depression; CMCT: Central motor conduction time; TBS: Theta Burst Stimulation; ICI:
Intracortical Inhibition; SP: Silent Period; RI: Reciprocal inhibition.
Disorder/gene defect Impaired plasticity Excitatory/Inhibitory Clinical cortical
mechanisms imbalance electrophysiology and
plasticity by TMS
RS/MeCP2 Abnormal homeostatic synaptic ↑↑ Glutamate and NMDAR ↓ CMCT29
scaling density,26 impaired LTP, absent
LTD25
FXS/FMR1 Delayed maturation and Impaired Late-phase LTP and Impaired LTP/LTD-like plasticity
stabilization of dendritic plasticity dysregulation of mGluR- after TBS.36
and increased spine density.31 dependent LTD,33 downregulation Reduced/absent GABA-A mediated
of GAB-A receptors35 parameters in asymptomatic
carriers37
TSC/TSC 1 and 2 Defective dendritic spine pruning Abnormally increased LTP and No available data*
and increase spine density43 impaired mGluR-mediated LTD43
AS/UBE3A Restricted dendritic spines growth Impaired AMPA-mediated No available data*
and maturation and reduced plasticity,50 upregulation of
synaptic density mGLuRS-mediated LTD51
PMS/SHANK3 Decrease membrane expression of Impaired activity-dependent LTP40 No available data*
AMPA and NMDA receptors40
NF-1 Reduced spine density,63 Abnormal Abnormal increase in presynaptic Abnormal GABA mediated
morphology of synapses64 GABA release of inhibitory neurons inhibition during motor learning67
leading to impaired LTP65
DYT1/TOR1A Defective cerebellar Abnormally increased LTP and Cortical hyperexcitability, Reduced
synaptogenesis111 failure to induce LTD114 ICI, SP and Rl.120 Exaggerated
LTP122 and LTD responses121
*
No data was available at the time of literature search.
intracortical inhibition or excitation to behavioral phenotype machinery in neurons, depresses long-term storage of spatial
in Rett syndrome are lacking. memories, limits hippocampal late-phase LTP and decreases de
With better understanding of the pathological and molec- novo GluA2 (regulatory AMPA receptor subunit) synthesis in
ular mechanisms underlying CNS dysfunction in Rett syn- mice. Disruption of FMRP leads to decreased stimulation-
drome, numerous strategies targeting MeCP2 gene and its induced postsynaptic mRNA translation and internalization
downstream signaling pathways have shown promising re- of AMPA receptors causing dysregulation of mGluR-dependent
sults in pre-clinical studies.31 LTD.34 This might partially explain defective learning and
memory in patients with FXS. Moreover, synaptic hyper-
2.1.2.2. Fragile X. FXS is an X-linked neurobehavioral disorder excitability has been reported in FXS secondary to defective
that is considered to be a common form of intellectual presynaptic control of calcium influx and activity-dependent
disability (ID) with high comorbidity of autism and epilepsy. neurotransmitter release,35 and altered expression of critical
Children with FXS additionally exhibit symptoms of obsessive- components of GABAergic synapses including down-
compulsive disorders, anxiety, hyperactivity and abnormal regulation of GABA-A receptor subunits in cortex and hippo-
motor learning. The pathology is linked to epigenetic silencing campus, decreased GABA synthesis in cortex and Amygdala
of FMR1 gene via pathogenic Cytosine, Guanine, Guanine (CGG) and decreased GABA receptor clustering in cortex,36 possibly
trinucleotide expansion (>200 repetition), resulting in loss of explaining the high preponderance of epilepsy in this patient
the postsynaptic mRNA-binding protein (FMR protein) leading population.
to excessive protein synthesis and delayed maturation and In-vivo study of motor cortex plasticity using TMS in 2
stabilization of activity-dependent dendritic spine plasticity patients with FXS, showed abnormal LTP and LTD-like activity
and increased synaptic density.32 Abnormal activity- following Theta burst stimulation.37 Interestingly, another
dependent up-regulation of matrix metalloproteinase-9 TMS study examined motor cortical plasticity in 13 asymp-
mRNA at synapses has also been described in FMR1 knockout tomatic women with FMR1 premutation (<200 CGG repeat)
mouse models of FXS. Moreover, altered spatiotemporal found abnormally reduced or absent GABA-A mediated plas-
expression of BDNF and TrkB leading to impaired plasticity and ticity parameters such as short intracortical inhibition, short
circuit dysfunction have been reported.33 A study by Cook and afferent inhibition and cerebellar inhibition.38
coworkers has shown that Fragile X Related Protein 1 (FXR1P), Research in FXS focusing on rescuing the FMR1 phenotype
an RNA-binding protein that regulates translation of mRNA in is on a surge. Hagerman and Polussa have recently published a
non-neuronal cells and co-localizes with translational review on the many promising treatments in FXR.39 For
example, Acaprosate (partial mGLUR5 antagonist), Minocy- rescuing TSC phenotype. Currently, there is active recruit-
cline (an antibiotic that reduces the abnormally high levels of ment to phase 2 and 3 clinical trials lead by Utrecht University
Matrix Metalloproteinase 9 in FXS), lovastatin (an HMGA-Co using Everolimus in children with autism and TSC
reductase inhibitor that lowered excessive extra cellular re- (Clinicaltrials.gov; NCT01730209).
ceptor kinase-mediated protein synthesis and blocked
mGluR5-mediated epileptiform bursting), and sertraline (an 2.1.2.4. Angelman syndrome (AS). Angelman syndrome is a
SSRI that promotes neurogenesis and corrects the reduced neurobehavioral disorder characterized by global develop-
levels of BDNF seen in FXS) are all pharmaco- mental delay, lack of speech, intellectual disability, happy
neuromodulatroy approaches that have shown improve- demeanor, sleep disorder, epilepsy, abnormal voluntary
ment in behavioral phenotype in individuals with FXS. movements and autistic behaviors.50 The genetic etiology for
AS is depressed expression of ubiquitin protein ligase E3A
2.1.2.3. Tuberous sclerosis complex (TSC). Tuberous sclerosis (UBE3A) gene (chromosome 15) that is maternally inherited.
complex (TSC) is an autosomal dominant monogenic disorder The paternal copy of UBE3A is silenced, thus neurons depend
characterized by multi-organ hamartomatous lesions with entirely on expression of maternal UBE3A. The UBE3A gene
invariable involvement of CNS. Patients with TSC are known encodes for E3 ubiquitin ligase that facilitates selective syn-
to express significant epilepsy, Intellectual Disability (ID) and aptic protein degradation by tagging substrate proteins Arc
autism comorbidities.40 The pathoegenetic profile of TSC is and Ephexin-5 with ubiquitin. Abnormal E3 ubiquitin
localized to 2 genes TSC1 (encoding for hamartin; at 9q34) and expression leads to accumulation of Arc and Ephexin-5. High
TSC2 (encoding for tuberin; at 19p13.3) that form intracellular levels of Ephexin-5 limit dendritic spine growth and matura-
complex that inhibits protein translation by antagonizing tion. On the other hand, accumulation of Arc mediates inap-
phosphoinositide 3-kinase-mammalian target of Rapamycin propriate internalization of glutamate-mediated AMPA
(P13K-mTOR) signaling pathway.41 Abnormal hyper- receptors in response to experience-dependent stimulation.51
activation of mTOR signaling pathway caused by these ge- Abnormal up-regulation of mGLuR5-mediated LTD has also
netic defects has been implicated in dysregulation of cell been reported in animal models of AS.52 This translates to
proliferation and growth causing widespread hamartomas. impaired synaptic formation and reduced synaptic density
Moreover, on a neuronal level, impaired neurogenesis, syn- leading to dysfunction of activity-dependent synaptic plas-
aptic excitability and epileptogenesis have been described.42 It ticity and “rigid” network modulation.
is thought that mTOR signaling pathways play a vital role in The abnormal voluntary movements seen in AS patients
reducing inhibitory synapses onto excitatory neurons creating resemble, to a large degree, motor symptoms of Parkinson's
a positive feedback loop.43 disease (PD) reflecting abnormal dopamine signaling. Riddy
Although FXS and TSC share some features of impaired and coworkers reported pathway-specific dopaminergic ef-
plasticity such as defective dendritic spine pruning leading to fects of UBE3A loss in the mouse model of AS. More specif-
abnormal age-dependent increases in dendritic spine density, ically, dopamine release was increased in the nucleus
mTOR, unlike FMRP, causes down-regulation of activity- accumbens of the mesolimbic dopaminergic pathway while it
dependent protein synthesis leading to increased LTP and was decreased in dorsal striatum of the nigrostriatal dopa-
impaired mGluR-mediated LTD44 leading to excitatory/inhib- minergic pathway possibly explaining the resemblance to the
itory synaptic imbalance promoting hyper-excitability and PD motor phenotype.53 These results prompted emergence of
defective activity-dependent modulation of cortical circuits. clinical trials that used L-Dopa as a mode of therapy for
Cortical hyperexcitability and abnormal connectivity maps movement disorders and development in patients with AS
predisposing to epilepsy in TSC is supported by in vivo ex- (clinicaltirals.gov; NCT01281475, data in progress).
periments using TMS. D'Argenzio and coworkers demon- There is a well recognized high preponderance of epilepsy
strated abnormally amplified excitatory connectivity in in patients with AS, a majority of cases with onset less than 3
parieto-motor axonal tracts in adult TSC patients that were years of age.54 While the exact mechanisms of generalized or
not on antiepileptic medications (AED) compared to TSC pa- focal epilepsy in AS patients are not yet well described,
tients on AED and healthy controls.45 excitatory/inhibitory imbalance driven by UBE3A deficiency is
As previously mentioned, patients with tuberous sclerosis thought to be a common converging mechanistic pathway.
have a high propensity to epilepsy. Animal models of TSC1 Judson and coworkers conducted a recent study using
haplo-insufficiency exhibit age-dependent expression of epi- “neuron-type-specific manipulations of maternal UBE3A
lepsy that closely mimics the phenotype seen in TSC patients. expression to demonstrate that GABAergic UBE3A loss is suf-
. Early control of seizures with vigabatrin improves long term ficient to yield Angelman syndrome-like EEG abnormalities,
outcome in children with TSC.46,47 Vigabatrin is a GABA enhancement in seizure susceptibility, and atypical clathrin-
agonist and partial mTOR inhibitor that reduces mTOR coated vesicle accumulations within presynaptic terminals”.
pathway activation.48 Preventative antiepileptic therapy of These effects of UBEA3 were not observed when glutamatergic
infants with tuberous sclerosis complex and high risk of epi- neurons were manipulated using the same protocol.55
lepsy markedly improves their neurodevelopmental outcome Silva-Santos and Colleagues have conducted a systematic
and reduces the incidence of drug-resistant seizures. This study in which they reinstated UBE3A at different ages of
implicates the role of the mTOR pathway in the pathogenesis development in murine model of AS. They have shown that
of epilepsy in this patient population.49 there was a neurodevelopmental window-specific rescue of
Based on these mechanisms of impaired plasticity, many phenotype upon restoration of UBE3A. While hippocampal
studies have investigated the role of mTOR inhibitors in synaptic plasticity was rescued upon UBE3A restoration at any
age, restoration of UBE3A in adolescent mice restored motor Currently, Phase 2 clinical trial using IGF-1 in patients with
phenotype only. Moreover, anxiety, repetitive behavior and PMS is being conducted (clinicaltrials.gov; NCT01525901).
epilepsy were rescued only during early developmental rein-
statement of UBEA3.56 These results signify developmental 2.1.2.6. Neurofibromatosis type 1. NF1 is an autosomal domi-
critical periods as important determinants of response to nant monogenic neurocutanous disorder of variable pheno-
therapeutic interventions. typic expression. Clinical features include Cafe -au-lait
Multiple clinical trials focusing on different therapeutic macules, cutaneous and plexiform neurofibromas, axillary or
targets have been pursued in AS. For interested readers, Tan inguinal freckling, Lisch-nodules, optic pathway gliomas and
and Bird have published a comprehensive review of all mo- osseous lesions. Significant numbers of NF-1 patients have
lecular targets involved in current trials of AS neurocognitive deficits and learning disabilities. NF-1 is
pharmacotherapy.57 caused by loss of function mutations in the NF-1 gene (tumor
suppressor gene located at Chromosome 17) that encodes
2.1.2.5. Phelan-McDermid Syndrome (PMS). PMS is a neuro- neurofibromin. Lack of neurofibromin leads to hyper-
behavioral disorder that encompasses macrocephaly, activation of Ras pathway as well as other downstream
neonatal hypotonia, delayed development, speech impair- signaling pathways leading to dysregulation of cellular pro-
ment, intellectual disability, and epilepsy and autistic behav- liferation and tumor formation.63 On a neuronal level, neu-
iors. PMS is caused by deletions of SHANK3 gene on rofibromin, via two separate pathways (Protein Kinase A-
chromosome 22, which encodes postsynaptic SHANK3 scaf- Enabled/Vasodilator-stimulated Phosphorylation and Valosin
folding proteins at the post synaptic density (PSD: a protein Containing Protein), regulates filopodia and spine formation
dense specialization of the post-synaptic membrane). in dendrites and its deficiency leads to reduced spine
Although SHANK 3 proteins are widely expressed in the CNS, density.64
there seem to be preferential high levels of expression in the In a mouse model of NF-1, Armstrong and coworkers re-
cortex, hippocampus, striatum and the cerebellum.58 ported normal ultra-structural synaptic morphology and
SHANK3 proteins are major scaffolding proteins at the postsynaptic density of CAI hippocampal cells. However, an
PSD. They interlink membrane cell-adhesions molecules abnormal lower degree of curvature in concave synapses
(presynaptic Neurexin and post synaptic Neuroligin), post- compared to controls was observed suggesting a morpholog-
synaptic AMPA and NMDA receptors and actin- ical basis for abnormal plasticity.65 Physiologically, lack of
cytoskeletons. SHANK3 also mediates mGluR5 signaling via Neurofibromin results in increased presynaptic GABA release
Homer 1b/c to PSD. This extensive multifaceted role of (via enhancement of ERK-synapsin I dependent pathway),
SHANK3 allows modulation and maturation of dendritic which subsequently interferes with hippocampal LTP and
spine morphology, size and signaling, glutamate-mediated learning. These results were seen in inhibitory neurons but
AMPA and NMDA receptor trafficking.41 not excitatory neurons or astrocytes.66 At the level of inhibi-
On a physiological level, this leads to decreased membrane tory interneurons, loss of NF-1 leads to increased interneuron
expression of AMPA and NMDA receptors leading to impaired excitability secondary to attenuation of hyperpolarization-
LTP and ultimately impaired activity-dependent synaptic activated cyclic nucleotide-gated channel 1 (HCN1), which is
plasticity. thought to contribute to cognitive dysfunction seen in NF-1
There are currently few potential targets for PMS. In mouse subjects.67
model of SHANK3 mutation in which exon 11 was deleted, Employing paired-pulse TMS, Zimmerman and coworkers
mGluR5 agonist (3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl) reported abnormally reduced task related short intracortical
benzamide) reduced functional and behavioral deficits.59 inhibition during motor skill learning in NF-1 asymptomatic,
Recently recognized for it's for its role in synaptic plasticity, adult patients with normal Intelligence Quotient (IQ)
Insulin-like growth factor-1 (IGF-1) has been shown to restore compared to matched controls reflecting impaired GABA-
AMPA signaling and motor deficits in SHANK3 mouse models mediated intracortical circuits.68
of PMS.60 Using functional neurons derived from induced Therapeutic interventions for NF-1 are based on selective
pluripotent stem cells (iPSC) from patients with PMS, Shche- targets. For example, antagonizing abnormally increased
glovitov and coworkers have shown direct evidence of GABA-A in a mouse model of NF-1 results in rescuing spatial
defective excitatory, but not inhibitory, synaptic transmission learning defects.66 Lovastatin, an HMG CoA reductase inhibitor
secondary to reduced SHANK3 expression that was corrected has been shown to restore LTP deficits and improve the neu-
by restoration of SHANK3 or treating neurons with Insulin- rocognitive profile in the mouse model of NF-1.69 Additionally,
like growth factor-1 (IGF-1). Intriguingly, IGF-1 corrected syn- using TMS-derived parameters, Lovastatin showed in vivo ev-
aptic transmission by promoting mature SHANK3-indepen- idence of restoration of abnormal intracortical inhibition and
dent PSD95-NMDA excitatory synapses.61 synaptic plasticity and behavioral improvement in Test of
Kolevzon and colleagues have conducted a pilot, placebo- Attentional Performance (TAP) in placebo-controlled, double
controlled double-blinded crossover trial of IGF-1 in children blind, randomized trials in 11 adult patients with NF-1.70
with PMS aged 5e15 years. IGF-1 was administered for 3 Active clinical trials using lovastatin and Lamotrigine
months with 3 months of placebo in random order separated (HCN-1 agonist) as therapeutic interventions to rescue the
by one month of washout period. They found that the treated neurocognitive profile in NF-1patients are being conducted
group showed significant improvement in social impairment (clinicaltrials.gov; Lovastatin; NCT00853580, Lamotrigine;
and restrictive behaviors.62 NCT02256124).
2.2. Adaptive plasticity: reorganization that promotes or is well established that infants born with bilateral congenital
improves adaptive function deafness undergo auditory cortex reorganization and visual
cross-modal compensatory plasticity.81 This cross modal
The long standing notion that the developing brain has an plasticity can be reversed by cochlear implants as reported in
intrinsically greater capacity for plasticity compared to the a case study by Sharma and coworkers.82 Neurobiological and
adult brain stems from many clinical observations pertaining physiological evidence of cortical reorganization of V1 area in
to children's enhanced capacity for learning and memory as the visual cortex following monocular sensory deprivation
evident by their ability to learn a second language more effi- has also been established. A clinically relevant phenomenon
ciently,71,72 easy acquisition of complex motor skills as seen in is amblyopia, which is an impairment of vision secondary to
early musical practice73 and capacity to recover from major abnormal binocular visual input during early development
brain injuries as exemplified by the capacity to recover gross which forces the brain to “disregard” the input from the
motor skills after hemispherectomy.74 affected eye thus causing monocular visual impairment
Experience-dependent structural synaptic plasticity is (amblyopia) if untreated in a timely fashion.83
abundant in the developing brain and is thought to represent Probably the most dramatic example of reactive plasticity
the neurobiological substrate for learning and memory for- in young brain is observed in pediatric patients following
mation. It is sub-served by integrated mechanisms involving hemispherectomy for intractable seizures. In patients who
axonal and dendritic spine growth and bouton formation, underwent hemispherectomy, studies have shown age-
dendrites sprouting and synapse formation and elimination. related correlation between functional recovery and age at
There is mounting evidence that such activities are cell- surgery where younger patients do better than older patients.
specific and take place in motor, somatosensory and visual The mechanisms of reactive and, in majority of cases adap-
cortices.75 Moreover, changes in glutamate-mediated NMDA tive, plasticity in the motor circuits involve intra-cortical and
and AMPA receptors support Long Term Potentiation (LTP), inter-cortical re-organization and development of ipsilateral
which is associated with memory formation and consolida- corticospinal projections that is speculated to be a result of
tion that has been shown to be enhanced in immature brain.76 inter-hemispheric imbalance.84 Interestingly, motor function
New learning is stored in synaptic networks that are dynamic recovery also varied based on the ontogeny of the epilepto-
over time, even in adults, with old synapses being replaced by genic disorder. In a study by van der Kolk and coworkers, the
newer ones, allowing some memories to be forgotten and new pattern of long-term motor function recovery after hemi-
ones acquired based on experience. In a study by Schanck and spherectomy in 35 children differed between children with
coworkers examining cortical thickness in relation with intelli- developmental etiology and those with stable acquired or
gence in 504 subjects, ranging in age between 9 and 60 years, has progressive etiologies.85 Heterogeneity in outcomes might be
found that cortical thinning was associated with higher intelli- related to differences in “plasticity capacity” in which children
gence at younger age. This association was reversed in young with developmental etiologies have inherently dysfunctional
adults where higher intelligence correlated with increase in plasticity mechanisms compared to children with acquired
cortical thickness which was most evident in the left superior stable or progressive etiologies.
frontal cortex, superior motor area, Rolandic operculum, insula Post-hemispherectomy plasticity is not confined to motor
and (pre)cuneus. This age-dependent structural plasticity of circuits. There is strong evidence for re-organization of
cortical thickness is thought to serve as a mediator for receptive and expressive language even with left sided
intelligence-dependent neural development.77 In other words, hemispherectomy86 also reshaping of somatosensory tracts,87
changes in cortex structure are never completed, and continue visual88 and auditory circuits.89 An intriguing observation
to evolve depending on intelligence.78 here is that there seems to be a distinctive “plasticity capacity”
Skilled learning in the form of musical training has been for different brain regions following hemispherectomy. For
shown to induce structural plasticity in the young and even the example, while language and gross motor recovery is more
old brain. Musical practice in childhood leads to more robust prevalent among subjects, fine motor control and speech re-
brainstem auditory signal to noise ratios of music signal covery is subtle regardless of age at or side of surgery.90,85
compared to noise.73 Moreover, string playing and age at Current efforts are being made to evaluate the preoperative
playing correlated with expansion of cortical representation of use of TMS in guiding epilepsy and tumor resection surgeries.
fingers in the contralateral hemisphere.79 In a study that Although limited, data comparing navigated TMS to the gold
examined gray matter volume (GMV) in the pars orpecularis standard electrical cortical stimulation found no differences
and pars triangularis of Broca's area in orchestral musicians in accuracy of motor mapping.91 Moreover, compared to fMRI,
compared to non-musicians as depicted by Voxel-Based pre-operative mapping of CST projections (unilateral vs.
Morphometric analysis showed that there was an increase in bilateral) using TMS was more correctly predictive of hand
GMV that correlated with years of musical performance argu- motor outcomes after hemispherectomy.92
ably representing use-dependent structural plasticity in Another common and important example of reactive
response to intensive audio-motor skill acquisition.80 plasticity is cortical reorganization following perinatal brain
insult. Interestingly, the pattern of brain injury following
2.3. Reactive plasticity following sensory deprivation or perinatal brain insult differs depending on the timing of insult
CNS insult in relation to post conception age, the stage of neuro-
development during which the insult occurs and the integrity
An important form of plasticity is activity-dependent plas- of plasticity mechanisms.2 The corticospinal tract shows an
ticity following chronic sensory deprivation or brain injury. It early maturation profile during the third trimester of
pregnancy making it selectively vulnerable to perinatal in- DTI and decrease in interhemispheric inhibition using TMS
juries.93 The developmental stage-dependent heightened attributed to impaired motor control and increase in motor
vulnerability of certain brain areas to insult is well reported. In movements in the context of structurally normal CSTs.104 Its
the premature infant (less than 34 weeks of gestation), the is therefore, important to consider all “players” of sensori-
periventricular white matter injury in the form of periven- motor system maturation and their dependence on critical
tricular leukomalacia and hemorrhage is the most common and sensitive periods of development (proposed to be between
MRI finding, while in mature infants, evidence of basal 6 and 12 months postnatal) when devising a neuromodulation
ganglia; cortical-subcortical damage and focal cortical infarcts intervention in the form of behavioral or stimulation-based
were more common.94 These time-sensitive selective injury therapies (Fig. 3).
patterns establish the pathological variations of cerebral palsy
(CP) in children, alongside cortical malformations and genetic 2.4. Excessive/destabilizing plasticity (reorganization
syndromes. that escapes homeostatic regulation)
So, how does early brain insult affect corticospinal tract
development in CP and what plasticity mechanisms are 2.4.1. Dystonic disorders
implicated in “overcoming” the insult? To better understand Dystonia is a movement disorder that is characterized by
this, we need to take a closer look at normal motor develop- intermittent or sustained co-activation of agonist and antago-
ment. It has been well characterized by many animal and nist muscles causing abnormal movements or postures.
human studies that development of motor cortex is driven by Phenomenological description and etiological classification of
genetically programmed axon guidance molecules/ligands dystonia of childhood have been described.105 Early dystonia,
(EphA4/EphrinB3) and is refined by activity-dependent plas- such as dystonic cerebral palsy, has a particularly severe
ticity during critical periods of pre and perinatal life.95 Early in impact on the lives of children, interfering with normal activity
development, the motor cortex sends bilateral projections to and participation.106 In line with our main goal of discussing
the spinal motor neurons and a subsequent activity- prominent plasticity related disorders, we will discuss two
dependent synaptic competition between the two pro- examples of dystonia related to excessive (destabilizing) plas-
jections on alpha motor neurons ends up with near-total ticity 1) focal dystonia related to intensive motor training (task-
retraction of the ipsilateral projections and strengthening of specific dystonia) and 2) primary monogenetic dystonia (DYT1).
contralateral projections.93
Numerous studies have shown that timing of insult in 2.4.1.1. Focal task-specific dystonia. As mentioned earlier,
relation to gestational age and phase of corticospinal tract adaptive experience-dependent plasticity in the form of so-
development as well as the location and structural charac- matosensory cortical representation and changes in grey
teristics of the lesion can influence the pattern of CST pro- matter thickness is well described in healthy musicians.73
jections and therefore the motor outcome.93,96,97,98 This time- Intriguingly, in 1e2% of professional musicians, a patholog-
sensitive capacity to re-organize can also be seen in basal ical phenomenon develops in which the same motor task can
ganglia,99 transcallosal motor fibers,100 thalamo-cortical cause undesirable activation of adjacent muscles leading to
afferent projections,98 language and visual system.101 dystonia. Musician's dystonia provides an interesting example
For example, as studied by Staudt and colleagues, early in which intensive and repetitive practice causes, at some
unilateral lesions (occurring before completion of competi- point and in certain individuals, exaggerated plastic response
tive elimination of ipsilateral CST fibers) triggers plastic in the form of distorted reorganization of motor and so-
reorganization of the CST in which ipsilateral fibers from the matosensory cortical maps and loss of normal GABA-
healthy hemisphere strongly compete and eliminate CST mediated intracortical inhibition (Reviewed in107). Another
from damaged hemisphere resulting in bilateral control of clue perhaps is the observation that elderly people have larger
movements by the healthy hemisphere. This bilateral control cortical maps when performing motor tasks, similar to the
results in less functional use of the paretic hand and devel- motor mapping in young children, reflecting less precise
opment of mirror movements, which are considered mal- function, in contrast to young adults who exhibited more
adaptive. However, if the unilateral lesion occurs after focused cortical maps.108
competitive elimination of ipsilateral fibers, no reorganiza- Few studies looked at a possible genetic basis for musi-
tion takes place and useful hand functions cannot be cian's dystonia and found that in some family members of
retrieved.102 affected individuals, other forms of dystonia or movement
In addition to CST maldevelopment, studies of children disorders were present suggesting a familial etiology.109 In a
with Hemiparetic CP have shown that lesions of thalamcort- genome-wide association study, a possible risk variant at the
ical projections in children with PVL correlated more with arylsulfatase G locus was idntientifed.110
severity of motor dysfunction than with lesions of cortico- It is intriguing to note that task-specific dystonia is almost
spinal tract, suggesting that thalamo-cortical projections never reported in children. Whether abnormal excessive
might be a reasonable neuromodulation target to improve plasticity in musician or writer's dystonia is a result of decay
motor symptoms in unilateral CP.103 Moreover, Friel and co- in age-dependent homeostatic mechanisms regulating adap-
workers have also suggested the important role of the rubro- tive cortical plasticity in genetically susceptible individuals is
spinal tract and inhibitory spinal interneurons in determining a question worth investigating.
the overall functional outcome after unilateral brain lesions in
CP95. In a study of children with bilateral CP, authors reported 2.4.1.2. Genetic dystonia. Early-onset generalized torsion
impairment of transcallosal motor fiber microstructure using dystonia (DYT1) is an autosomal dominant movement
Transcallosal
Basal Ganglia
motor fibers
Thalamo-
Supplementary corƟcal
motor areas projecƟons
Contralateral Rubrospinal
CST tract
Motor-sensory Inhibitory
Ipsilateral CST impairment in spinal
CP interneurons
Fig. 3 e Potential targets that have been shown to contribute to motor-sensory impairment in patients with cerebral palsy.
With advances in understanding the inter-related and time-dependent nature of plasticity in cortical and subcortical
networks during motor-sensory development, is it time to adopt a multi-modal (behavioral, pharmacological or
stimulation-based), multi-targeted neuromodulatory approach to improve behavioral outcomes? CST: corticospinal tract;
CP: cerebral palsy.
disorder most commonly caused by GAG base-pair deletion in both LTP and LTD as a cause for hyperexcitability at the level
the TOR1A gene coding for torsinA protein. TorsinA is distrib- of the synapse.
uted in many cortical and subcortical regions. It is highly Intriguingly, only 30e40% of DYT1 mutation carriers
expressed in the dopaminergic neurons of the substantia nigra develop dystonia. So, what triggers the clinical onset of motor
pars compacta. It has been implicated in many cellular pro- symptoms in DYT1 mutation carriers? Asymptomatic carriers
cesses including intracellular signaling and synaptic vesicle of the DYT1 mutation have shown an array of subclinical
fusion.111 Children with DYT1 exhibit symptoms of sustained microstructural abnormalities in basal ganglia size118 and
muscle contractions, postures, and/or involuntary supplementary motor area119 as well as impaired motor
movements. sequence learning caused by abnormal motor circuit devel-
Animal models of dystonia have provided significant opment.120 Cortical electrophysiological studies have pro-
insight into the effect of DYT1 mutations on synaptic plas- vided interesting insight into functional consequences of
ticity. Evidence for defective cerebellar synaptogenesis DYT1 mutations. For instance, Edwards and colleagues have
(reduction of inhibitory input as well as unbalanced excitatory showed cortical hyperexcitability in adult patients with DYT1
innervation to Purkinje cells), during critical periods of brain mutation as evident by reduced intracortical inhibition (ICI)
development,112 abnormal cerebello-thalamo-cortical and silent period (SP) and absent presynaptic phase of spinal
pathway113 and abnormal time window for synaptic integra- reciprocal inhibition (RI) compared to controls. On the other
tion between thalamo-striatal and corticospinal inputs114 has hand, non-manifesting DYT1 mutation carriers showed
been reported. Moreover, abnormal increase in LTP and failure reduced ICI and SP but normal spinal reciprocal inhibition that
to induce LTD in cortico-striatal pathways, while hippocam- was similar to controls suggesting that clinical expression of
pal synaptic activity and plasticity was unaffected empha- dystonia involves widespread changes in cortical/subcortical
sizes the region-specific expression of synaptic plasticity and particularly spinal networks.121
deficits in this disorder.115 Evidence of dysfunctional cholin- Studies utilizing plasticity-induction protocols via repeti-
ergic transmission116 and imbalanced striatal dopaminergic/ tive TMS (rTMS) looked into aberrant plasticity in symptom-
cholinergic signaling during a susceptible period of post natal atic and non-symptomatic DYT1 mutation carriers.
development has also been described.117 The constellation of Edwards and colleagues used continuous theta burst
these findings suggests disruptive homeostatic regulation of stimulation cTBS (an inhibitory protocol that induces LTD-like
plasticity) and reported in-vivo evidence of abnormally exag- To cap, there is persuasive evidence that homeostatic
gerated and prolonged LTD-like plasticity in adult patients mechanisms that regulate cortical excitability levels within a
with DYT1 mutation compared to asymptomatic DYT1 car- normal dynamic range are impaired in Musician's dystonia
riers and controls,122 which suggests loss of homeostatic and DYT-1 dystonia. Therapeutic modalities applied during
regulation of plasticity. Interestingly, in the same study, critical periods of susceptibility might prevent or reverse the
asymptomatic DYT1 mutation carriers did not show LTD-like exaggerated synaptic response in this type of distorted
plastic response to the same stimulation protocol. While this plasticity.
study did not use a stimulatory protocol to study LTP-like re-
sponses for safety reasons, other studies of primary general- 2.4.2. Epileptogenesis: a form of excessive uncontrolled
ized dystonias have reported exaggerated LTP-like plasticity plasticity?
compared to controls.123,124 Epileptogenesis is a well investigated phenomenon in epilepsy
Based on these findings, its likely that loss of homeostatic research.138 It basically refers to the cascade of alerted mo-
synaptic regulation is the “tipping point” that leads to an lecular and cellular signaling, synaptic transmission and
abnormally intense response to excitatory or inhibitory network rewiring that turn a seizure-naı̈ve circuit into a self-
“plasticity induction” stimuli which increases the risk of sufficient generator of spontaneous recurrent seizures139
developing clinical dystonia in DYT1 mutation carriers. resulting in development of the epileptic condition or pro-
In regards to applying this to pediatric patients with DYT1 gression of epilepsy after it is established.140 Many factors
mutations two major points need to be carefully studied. First, have been described as epileptogenic insults including trau-
is there a critical period during which the developing nervous matic brain injury, focal cortical dysplasia, tumors, CNS in-
system is most susceptible loss of torsinA function as depicted fections, hypoxic-anoxic injury, prolonged febrile seizures and
by the susceptibility of cerebellar synaptogenesis in animal even status epileptics. However, there is increased recognition
model of DYT1 mutation dystonia? of genetic and epigenetic etiologies that govern epilepto-
Second, can we identify this period clinically using a multi- genesis as exemplified by epileptic genetic syndromes.141
modal approach to study the development of abnormal cir- Clinically, the hallmark of defining an epileptogenic disorder
cuits via fMRI and DTI studies and TMS-induced parameters of is the latent period between the insult and the emergence of
cortical plasticity in motor and somatosensory areas? If so, first unprovoked seizures. In other words, the time required
can these protocols be employed as screening methods in turning a naive circuit into an epileptogenic one. Although
high-risk populations? difficult to characterize in patients, animal models of epilepsy
Therapeutic interventions for DYT1 dystonia include have provided valuable insight into this phase. This phase en-
pharmacological modulation using anti-cholinergic drugs that compasses significant changes including neuroinflammation,
restore aberrant cholinergic transmission,125 though these neurodegeneration, gliosis, neurogenesis and abnormal axonal
and other drugs may not be as well tolerated in dystonic sprouting, and alerted gene expression and epigenetic regula-
children as previously thought,126 restoration of motor inhi- tion.141,142 Subsequently, the induction mechanisms for
bition using inhibitory TMS stimulation of dorsolateral pre- epileptogenic transformation include altered excitatory/inhib-
frontal cortex127,128 and deep brain stimulation (DBS) of the itory balance of neural excitability favoring depolarization
Globus Pallidus internus (GPi). through formation of new excitatory glutamatergic synapsis
GPi DBS is an established symptomatic treatment in chil- and weakening of inhibitory tonic input due to loss of
dren and adults with DYT1 dystonia that aims at ameliorating GABAergic synapses culminating in decreased seizure
the progressive nature of the symptoms early in the disease threshold. Moreover, persistent increases in intracellular
course (Level B evidence).129 DBS has shown successfully chloride concentration [Cl-] favors a depolarization (rather than
sustained outcomes in improving dystonia and movement hyperpolarization) state of GABAergic neurons facilitating
clinical scales130,131 though improvements with DBS may be generation of seizures.138,143 Finally, significant structural re-
inversely related to the proportion of life lived with dystonia in organization of networks takes place during seizures leading
primary and secondary dystonias.132 More modest benefits of to formation of aberrant networks that are consolidated by
DBS in dystonic CP, the subject of considerable interest, have altered molecular and cellular changes of synaptic trans-
also been reported (133e136). mission and interference with local and large-scale network
The physiological basis of clinical improvement after DBS connectivity by recurrent seizures possibly contributing to
in DYT1 patients is not fully understood. Using paired-pulse seizure progression and refractoriness as well as develop-
TMS in DYT1 patients after DBS of GPi, LTP-like motor cortex mental comorbidities such as psychiatric disorders and the
plasticity was reduced when DBS was ON, but not when DBS learning disability notoriously common in this population.
was OFF, which correlated with clinical improvement in Latency period between the onset of CNS insult and first
dystonia.124 These findings suggest that DBS stimulation of unprovoked recurrent seizures has been a rich area for
GPi “neutralizes”, to a certain degree, the excessive LTP-like research (Fig. 4). Targeting the different elements involved
cortical plasticity observed in patients with dystonia. It also during this phase is thought to prevent epileptogenesis. It is
emphasizes the complex interaction between sub-cortical worth noting that the latency period differs between patients
modulation of neural activity and its effect on cortical (genetic molding and epigenetic modulation), nature of CNS
plasticity. Moreover, selective cholinergic antagonism (anti- insult (TBI vs. febrile seizures vs. hypoxic ischemic insult) and
M1 muscarinic receptors) has been shown to rescue age at insult144 (probably related to sensitive and critical pe-
abnormal synaptic plasticity in mouse model of DYT1 riods of brain development and maturation of homeostatic
dystonia.137 regulatory mechanisms of plasticity). It is, therefore, clinically
Refractory
Epilepsy
GeneƟc EpilepƟc Syndromes

malformaƟon/dysplasia, stroke) or
CNS Insult (tumor,
Aberrant Networks
Loss of homeostasis?
E/I Abnormal
imbalance Signaling
First
Seizure
InflammaƟon, degeneraƟon, gliosis,
disturbed synapƟc transmission, etc.
Latent Period IIP IIP IIP Refractory Epilepsy
SensiƟve or criƟcal period(s) for progressive epileptogenesis? Too late to intervene?
GeneƟc Molding and EpigeneƟc ModulaƟon
Fig. 4 e Epileptogenesis: questions to ponder. Is there a critical or sensitive period(s) during which a naı̈ve circuit turns into
an epileptogenic one after CNS insult or genetically-induced dysregulation of synaptic plasticity? Is this period temporally
equivalent to the clinically observed latent period? Should neuromodulatory interventions focus on the studying and
modulating circuits’ plasticity during the latent period to delay or reverse refractory epileptogenesis? E/I: Excitatory/
Inhibitory balance; IIP: Inter-ictal period.
challenging to time the initiation and duration of anti- Despite its widespread trophic role in CNS plasticity,9 and
epileptogenic therapeutic interventions without deeper un- potential role in ischemia tolerance (ischemic precondition-
derstanding of the primers, modifiers and regulators of brain ing),149 glutamate mediated excitotoxicity is a well-accepted
plasticity response to an insult.145 mechanistic pathway for neuronal damage in HIE along-side
Due to the deleterious downstream effects of epilepto- ischemia-induced inflammation, mitochondrial damage, and
genesis, researchers are on a quest to identify biomarkers that oxidative stress.150 Abnormal overactivity of glutamate re-
can reliably measure aspects of epileptogenesis for diagnosis ceptors (AMPA, NMDA and mGluR) following hypoxic-
and treatment follow-up. Currently, few biomarkers are being ischemic insult sparks an immediate and latent cascade of
investigated clinically including hippocampal structural and extracellular and intracellular events leading to altered
functional changes on MRI/PET imaging, pathological high neurotransmission and synaptic dysfunction, oligodendrocyte
frequency oscillations on MEG, cortical excitability using TMS. damage and neuronal death leading to abnormal “sculpting”
In theory, identifying patients who are at high risk for re- of motor and sensory pathways.9,147,148,151 Moreover, HIE can
fractory epilepsy and measuring the success of anti- impair epigenetic regulators of neuronal and vascular devel-
epileptogenesis treatments can objectively be evaluated opment of the brain leading to abnormal plasticity, distorted
using these biomarkers.140 neuro-vascular coupling and brain maldevelopment.152
Evidence for age-dependent selective vulnerability of excit-
2.5. Plasticity as the brain's “Achilles Heel” rendering it atory glutamate-containing neurotransmitter circuits to
more vulnerable to injury hypoxic-ischemic insult in newborns is well estab-
lished.153,151,154,155 The classically affected regions in the
2.5.1. Hypoxic ischemic encephalopathy neonatal brain are peri-rolandic area, posterior putamen and
We have discussed earlier some of the molecular and cellular venterolateral thalamus, which are connected by glutamate-
mechanisms that augment and enhance the developing containing neuronal pathways. Increased glutamate-
brain's capacity for plasticity allowing maturation and devel- mediated activity in these pathways may be associated with
opment. These same mechanisms can become the brain's seizures and abnormal EEG activity noted in infants with HIE.146
“Achilles heels” in the face of a brain energy crisis, as it is the Rescuing the young brain from hypoxic-ischemic insults by
case in hypoxic ischemic encephalopathy (HIE).146 mitigating mechanisms responsible for excitotoxicity, inflam-
Neonatal HIE is characterized by excessive neuronal exci- mation and apoptosis constitute a major line of research in
tation that translates clinically into clinical and subclinical neonatology and neonatal neurology. For detailed review see.148
seizures, abnormal background EEG activity, neurological
impairments including cerebral palsy, epilepsy, and cognitive 2.5.2. Epileptic encephalopathy syndromes (EES)
impairments. The pathophysiology of neonatal HIE is Epileptic encephalopathy “is an electroclinical syndrome
complicated, clinical care is multifaceted and is well reviewed associated with a high probability of encephalopathic features
in the literature (see147,148). that present or worsen after the onset of epilepsy … Inherent
in the concept of epileptic encephalopathy is the notion that render the brain pro-epileptic.162,163 Therefore, the rising
suppression of epileptic activity may improve cognition and concern that modifying GABA with anti-epileptic medication
behavior … The source of an apparent encephalopathy … may in the neonatal period might interfere with normal synaptic
be the product of the underlying cause, the result of epileptic and network plasticity, thus creating “aberrant circuits” that
process, or a combination of both.”156 might contribute to epileptogenesis and spread of seizures is
Epileptic encephalopathies are more common and severe legitimate.8 Second, blocking glutamate receptors before the
in infancy and childhood. EES are classified according to age of “maturation” of GABA into its inhibitory role leads to seizures
onset into 3 groups: Neonatal (Early myoclonic encephalopa- with burst suppression (re-emergence of GDP-like activity)
thy, Ohtahara syndrome), infantile (Epilepsy of infancy with and disorders of glutamate receptor transport leads to
migrating focal seizures, West syndrome and Dravet syn- epileptic encephalopathy with burst suppression.138 Third,
drome) and childhood EE (Lennox-Gastaut syndrome, the GABA excitatory/inhibitory switch seems to be regulated
Epileptic encephalopathy with continuous spike-and-wake by the developmental expression of NKCC1 and KCC2 co-
during sleep and Landau-Kleffner syndrome).156 Although transporters, which have been shown to be disturbed in
EES have distinctive semiology and electrographic signatures, many neurological disorders such as infantile epilepsies, and
they share features of pharmaco-resistance and severe HIE.164 These models of CNS dysfunction have shown to be
cognitive and behavioral disturbances. associated with abnormal excitatory GABA activity, probably
In this section, we will focus on two important plasticity- contributing to susceptibility to seizures.
related concepts. First, the concept of ‘heightened” vulnera-
bility of the developing brain to seizures and second is the 2.5.2.2. The impact of seizures on mechanisms of neural
impact of seizures on mechanisms of neural development and development and plasticity. A closer look into the genetic,
plasticity leading to cognitive impairment. molecular and cellular mechanisms in epileptogenesis and
excitatory/inhibitory imbalance in EES reveals a considerable
2.5.2.1. The basis of heightened vulnerability to seizures in the overlap with aberrant mechanisms involved in developmental
developing brain. As mentioned earlier, the immature brain neuroplasticity and homeostasis as discussed earlier. Thus, it is
undergoes dynamically complex and variable expression of not surprising that certain EES “go hand in hand” with long-
excitatory and inhibitory neurotransmitters and receptors in term cognitive impairments and learning disabilities espe-
different brain regions and at distinctive windows of cially when occurring early in life. With advances in genetic
development.157,158 sequencing and analysis, different genes have been implicated
Unlike adult neurons, the immature neurons depolarize, in the pathogenesis of early-onset EES including, but not
rather than hyperpolarize, in response to GABAA activation. limited to, STXBP1, ARX, SLC25A22, KCNQ2, CDKL5, SCN1A, and
This is because immature neurons have a high concentration PCDH19.165 Interestingly, some of these genes have also been
of intracellular CL-at resting state mediated by high expres- associated with neurodevelopmental disorders.
sion of NKCC1 (CL-importer) and low expression of KCC2 (CL- The cellular and molecular pathological underpinning of
exporter).159 Activation of GABAA receptors mediates efflux of comorbid susceptibility to ASD, ID and epilepsy is yet to be
CL-to extracellular space leading to depolarization of post- fully understood. The significant phenotypic and genetic
synaptic potential, which then activates voltage-gated sodium overlap between ASD, ID and epilepsy has been established
and calcium channels initiating an action potential and with the help of clinical and genetic association studies
allowing calcium influx that triggers a wide range of intra- reflecting shared abnormal neuroplasticity mediated by ge-
cellular signaling cascades. Moreover, GABAA activation leads netic and epigenetic faulty machinery at the level of the syn-
to co-activation of glutamatergic receptors via removing the apse.166 Animal and patient-derived iPSC studies of single
NMDA blockade exerted by Mgþ. The synergistic excitatory gene syndromes associated with intellectual disability and
effect of GABA and glutamate generates “primitive currents” autism have successfully recapitulated synaptic pathway
called giant depolarizing potentials (GDP)160 that dominate dysregulation that culminates in defective synaptic develop-
brain activity at this developmental stage and is believed to ment, signaling and plasticity.167
mediate neuronal assembly, synaptogenesis and formation of West syndrome is considered one of the most common
functional units. GDP are characterized by recurrent bursts causes of infantile epileptic encephalopathies. It is composed
with large polysynaptic currents founding the basis for of a triad of infantile flexion or extension spasms, character-
immature brain hyperexcitability. The action of GABA istic EEG findings (Hypsarrhythmia) and neurodevelopmental
changes from excitatory at the onset of GDP to inhibitory at disabilities. Structural and metabolic causes and genetic pre-
peak of GDP leading to hyperpolarization as a way of pre- dispositions have been described. It is thought that severe and
venting epileptiform synchronization.161 Furthermore, to persistence epilepsy in patients with West syndrome con-
counterbalance GABA-mediated GDP hyperexcitability, tributes to poor cognitive profile. Hence, early and aggressive
glutamate transporters control glutamate concentration until treatment has been advocated.
GABAA switches to its inhibitory adult-pattern. Once GDP Multiple models of genetic and acquired infantile spasms
dissipate, generation of experience-dependent NMDA and (IS) have been developed to provide insight into the basic
AMPA mediated patterns of plasticity commence.8 neuropathological mechanisms of seizures and cognitive
There are many clinical correlations that can be inferred impairment. These models are thoroughly reviewed by Auvin
from the developmental switch of receptor activity and co- and colleagues.168 We will focus on two models that have clear
transporter expression. First, GABA plays a major role in association with aberrant plasticity machinery, the acute
early brain development and immature GABAergic synapses NMDA model and the chronic mTOR model. In the NMDA
model of IS, various aspects of the disease were successfully does not remediate the abnormal circuits. Subsequently, with
recapitulated including the semiology of acute seizures, ictal better understanding of developmental neurobiology, the
EEG profile of periods of suppression mixed with ictal activity of broader concept of sensitive periods emerged and was defined
serrated waves and high-voltage chaotic EEG activity169 as well as the time window(s) during which the effect of experience on brain
as long-term cognitive deficits in areas of spatial learning and development is unusually profound and can strongly modulate the
memory.170 Moreover, chronic IS model signified the role of neural circuits.
mTOR and ARX pathways in the pathogenesis of IS and were In an attempt to explain the concept from a network
linked to patients with epileptic encephalopathies and IS.171 perspective, it has been proposed that the neural circuits,
On a structural level, although temporal lobe volume was during critical periods, are committed to a single pattern of
unchanged, Fosi and colleagues have shown impaired func- connectivity that is largely established by the genetic blue-
tional networking and altered white matter development of print and that pattern is consolidated by the presence of a
the temporal lobe in patients with infantile spasms compared preferred stimulus, so the absence of that stimulus leads to
to age matched controls.172 permanently abnormal connections (no alternatives avail-
Meta-analysis of NDD outcomes of infantile spasms, shorter able, as exemplified by Hubel and Wiesel experiments174,175).
lead-time to treatment was associated with better neuro- On the other hand, during sensitive periods, the neural circuits
developmental outcome.173 This suggests that NDD outcomes are highly “motivated to change” and have genetically-
are not entirely related to seizure control and abnormal plas- encoded multiple potential connection patterns to select
ticity beyond seizures contributed to cognitive impairment. from and can commit to one pattern or the other based on the
stimulus. So in the absence of the preferred stimulus, the
network is still “open for change” once the stimulus is rein-
3. Critical/sensitive periods in the troduced, although this capacity decreases with age. There-
developing brain: potential windows of fore, all critical periods are sensitive periods but not all
opportunity for neuromodulatory interventions? sensitive periods are critical periods. For insightful reading,
please refer to Knudsen (2004).176 It is important to note that
While the field of neuromodulation is showing promising critical and sensitive periods are not absolute and differ in
technical, diagnostic and therapeutic advances in adult dis- their temporal and spatial profile between neural subtypes,
orders of the brain, its application in pediatric neurological networks and regions177 and even behavioral phenotypes.
and neurodevelopmental disorders is still in infancy. A Therefore, the precise definition of critical and sensitive
growing number of pediatric case studies and clinical trials periods in neural development is important for researchers in
are emerging with the hope to establish the evidence of sup- the field of developmental neuroscience as they represent
port needed to carry wide-scale clinical applications. interlinked yet different heightened capacities for the time
The apparatus of neuromodulation is diverse and the course of susceptibility to change. The term ‘critical period’ has
cortical, subcortical and spinal targets vary depending on the been described at multiple levels and in different regions of
primary pathological process and downstream effects on the the nervous system. For example, there are critical periods for
neural networks, pathways and synapses. In our opinion, neurogenesis and cell migration during which an insult to the
neuromodulation that alters mechanisms of neuroplasticity is brain can lead to malformations. Similarly, critical periods for
an inclusive term that should include behavior, pharmacolog- synaptic plasticity, experience dependent local and large scale
ical, electrical and biological approaches (Fig. 5). Each one of network wiring, and even the onset of the spectrum of higher
these approaches interacts preferentially with multiple com- cognitive functions and behaviors have been described.178
ponents (or levels) of plasticity in the young brain, probably The question that is important for those in neuro-
influencing different regulatory mechanisms, and ultimately modulation research to consider is which definition of ‘critical
yielding different effects on behavioral outcome (Fig. 6). and sensitive periods’ should they adopt and consider as refer-
We think that the basis of these interactions in the young ence for timing of interventions and assessment of outcomes.
brain is the temporal and spatial profile of critical and sensi- Should the definition of critical and sensitive periods be based
tive periods that orchestrate neuronal and network responses on periods of heightened synaptogenesis and pruning, low-
during development. So, how can critical or sensitive periods level or large level network formation, clinical behavior or a
of neuronal development be utilized in neuromodulation constellation of these? To help answer these questions we will
research? discuss four important (proof of concept) points regarding the
critical and sensitive periods of brain development in the
3.1. What we know about critical and sensitive periods context of neuromodulation.
in the developing brain
3.2. Can we clinically identify the timing of critical or
The original description of critical periods came from the sensitive periods of networks plasticity?
1960e70s experiments of early monocular deprivation in kit-
tens by Nobel Prize Laureates Hubel and Wiesel. They showed As alluded to earlier, the onset and closure of these periods is
that visual deprivation during a certain time window of young not absolute. To answer this question, we need to look at the
brain development leads to alteration in visual cortex net- plethora of data emerging from studies of ocular dominance
works.174,175 They deemed that visual experience during that plasticity, which is, by far, the most well-studied model of
period is “critical” for normal neural circuit development and critical periods in animal models and humans. We now know
that restoration of normal visual experience after that period that there are chains of events that dictate the onset of the
Behavioral Pharmacological Electrical Cell-based

MagneƟc Field
NeuromodulaƟon NeuromodulaƟon NeuromodulaƟon NeuromodulaƟon
• Training-based • CNS acƟve • DBS • rTMS • Stem cell

physical therapy medicaƟons • NIBS • Constant transplant
• CIMT • Nano- (rTMS/tDCS) magneƟc fields
• CogniƟve technology • Spinal cord
• Neuro feedback sƟmulaƟon
• VNS
Fig. 5 e The spectrum of neuromodulation techniques. CIMT: Constraint-induced movement therapy; DBS; deep brain
stimulation; NIBS: non-invasive brain stimulation; rTMS: repetitive transcranial magnetic stimulation; tDCS: transcranial
direct current stimulation; VNS: vagal nerve stimulation.
Fig. 6 e When devising a neuromodulatory intervention, researchers are encouraged to consider the relationship between
the time-sensitivity and multi-level integration of neuroplasticity in the young brain and the potential upstream and
downstream effects of neuromodulation. For example, in order for a rTMS protocol to induce long lasting changes in a
specific motor behavior, the timing of application should be based on the temporal and spatial profile of normal CST motor
development and the other components of the motor system (depicted in Fig. 3). Applying rTMS that targets synaptic
plasticity during the critical or sensitive periods of motor development might increase the susceptibility of downstream
(signaling cascades, epigenetic modulations and gene expression) and upstream (networks and behavior) targets to change
following neuromodulation yielding a more sustainable results.
critical period in the visual cortex including a shift in excit- neuroimaging techniques, we are closer than ever to precisely
atory/inhibitory balance in neuronal circuits mediated by decode online the “language of neural communication” via
development of GABAergic parvalbumin-expressing in- means of EEG/MEG, resting state and functional connectivity
terneurons, activity-dependent expression of brain-derived fMRI and PET.
neurotrophic factor (BNDF) and its upregulation by IGF-1 and For example, in the visual cortex, since the onset critical
enhancement of retinal-based transcription factor OTX2, to periods is attributed to a shift in excitatory/inhibitory balance
name a few. The shift to a predominantly inhibitory activity where GABA-mediated activity predominates, following GABA
culminates in consolidating the neuronal circuits by curtailing activity might be a reasonable approach. Using [11c]flumaze-
the development of new synapses and pruning existing ones. nil PET imaging to study GABAA receptor ontogeny in the
On the other hand, the events regulating the closure of the cortex, Chugani and colleagues reported age-related changes
visual critical period is less clear. For detailed review please in volume of distribution of flumazenil in newborns in which
refer to.179,180 low receptor binding was found in visual cortex,181 only to
So, can the onset of a critical or sensitive period be “traced” increase to its highest value at 2 years of age and then
clinically? With advances in electrophysiological and decrease by almost 50% in adults, probably reflecting the
differences in synaptic plasticity.182 Another study showed a disorders. For example, therapeutic modalities targeting
direct link between [11c]flumazenil PET activity and gamma neutralization of Nogo-A receptor, a regulatory transmembrane
oscillations detected by MEG in the V1 region of the cortex.183 protein that is strongly expressed by the developing brain to
Therefore, it is theoretically plausible, using different real- promote destabilization of synapses, and thought to be related
time imaging and electrophysiological modalities, to “trace” to “closing” of critical periods governing plasticity of ocular
the activity of GABAergic synaptic plasticity in the visual dominance columns, have shown promising results in
cortex to determine its temporal profile. enhancing axonal growth and synaptogenesis after injury in
So, by parallel, can TMS be used to evaluate the timing of the animal models of stroke and spinal cord lesions.190
critical period? In other words, can we monitor the onset and It is thus intriguing to explore whether the timing of the
closure of the critical period by measuring visual cortex excit- critical period can be modulated non-invasively using NIBS.
ability as a function of shift in excitatory/inhibitory balance? For instance, can a TMS or transcranial direct current stimu-
Finally, it is thought that the type of the neural circuit (low- lation (tDCS) protocol applied over the visual cortex extend or
level or high level, single or parallel processing) dictates the prolong the critical period for ocular dominance, lending more
degree of plasticity or stability in response to perturbation time for amblyopia interventions to take place? Well, studies
during sensitive or critical periods of development. For in adults with amblyopia have shown a relatively long lasting
example, Harrison and colleagues pointed out that it is un- improvement (up to 2.5 months) in amblyopic eye contrast
likely to have one period of deafness beyond which cochlear sensitivity and visual evoked potentials following repetitive
implants for congenitally deaf children is of no value at all. TMS or tDCS stimulation (reviewed in191). However, studies in
Their stems from studies that showed different “cut-off” ages the pediatric population are lacking likely due relative success
or sensitive periods for simple and difficult auditory compre- of early interventions before the closure of the critical period
hension task performance after cochlear implant, empha- for ocular dominance.
sizing the different developmental dynamics (of neural
circuits) involved in a given measured behavioral outcome 3.4. Would manipulating the critical period have short
(simple and complex hearing task).184 or long-term impact, given the time-dependent hetero-
See also Jiang and Driver; Hudson et al. (EJPN special edi- synchronous pattern of brain development?
tion neuromodulation).
While this question remains unanswered due to insufficient
3.3. Can the onset, duration and closure of critical or data, some speculations are worthy of discussion. Studies of
sensitive periods be modified? children with early sensory impairment during critical periods
of brain development have shown a clear interdependent
Again, studies of visual cortex plasticity are very informative relationship between functional maturation of different brain
in this regard. In Amblyopia, restoring binocular vision is regions. For example, it is well demonstrated in children with
more successful if treatment is initiated before the “closure” profound deafness that if they had cochlear implant before
of the visual critical period which translates clinically to 7 the age of 5, their speech production and perception is better
years of age.185 than those who had the implant at an older age192 (Jiang and
Research employing induction of epigenetic regulators Driver 2016; Hudson et al., 2016: EJPN Special Edition). Simi-
such as environmental enrichment186 and pharmacological larly, individuals with early visual impairment had abnormal
treatments,187 and cell-based therapies to modulate critical visuo-tactile integration in the somatosensory cortex indi-
periods of visual cortex plasticity are holding great promise. cating altered neurophysiological processing.193 These results
In a recently published study, the onset of the critical period suggest that early intervention to remediate abnormal sen-
of visual cortex plasticity can be delayed by preventing sory input before a “cut-off age” is likely to improve outcomes,
maturation of GABA neurons or knocking out GABA syn- depending on the outcome measured.
thetic enzyme, while it can be brought forward by benzo- Hensch and Bilimoria had recently published a compre-
diazepine (GABA agonists).188 Another recent study by Davis hensive review about manipulating critical periods for brain
and coworkers showed that transplantation of embryonic development, and proposed that disruption of a critical period
inhibitory neurons into V1 region of the cortices of adult by a disease process or abnormal experience in one region
mice with visual impairment secondary to monocular might interrupt normal synchronization between critical pe-
deprivation at a young age had “re-opened” the critical riods across connected brain regions. By the same token,
period of ocular dominance plasticity and yielded physio- abnormal shortening or extension in duration of one critical
logical response as shown by visual evoked potentials as period may prematurely accelerate or stall the onset of others,
well as behavioral improvement in visual perception.189 respectively.179 So what researcher need to think about is
More interestingly, the transplanted embryonic inhibitory “should plasticity interventions in early brain development
neurons mediated plasticity during a certain time frame “emulate” the physiological duration and natural sequence of
that corresponded to the peak critical period for fetal donors critical periods of development in the young brain?”
regardless of the age of the recipient animal. This might
point towards intrinsic and environment-dependent epige- 3.5. Are the critical and sensitive periods in disorders of
netic mechanisms that regulate the plasticity-induction abnormal synaptic plasticity different?
properties of fetal interneurons.
The concept of “re-opening” the critical period for neural It is important to mention that experience-dependent plas-
plasticity has also been investigated in some neurological ticity during critical or sensitive periods have been largely
described in relation to sensory experiences (e.g. vision,185 the disorders of abnormal plasticity machinery for different
hearing194) and cognitive processing (e.g. language195) in in- circuits of interest (auditory, language, higher cognitive
dividuals with presumed normal “plasticity machinery”. In functions and behavior).
other words, the competency of plasticity to occur during By the same token, how is the critical period for sensori-
critical or sensitive periods is present but the phenotype is motor cortex development affected by perinatal brain injury?
altered due to abnormal external stimulus, or lack thereof. A flurry of studies have examined motor cortex plasticity in
Based on that, the question is “in patients with abnormal infants with early unilateral brain lesions and identified pat-
plasticity machinery such as abnormal excitatory synaptic terns of neuroplasticity that are dependent on timing of injury
scaling (Rett syndrome) or abnormal dendritic spine forma- and are relevant to clinical outcomes as discussed earlier.96
tion/elimination (Fragile X syndrome) or impaired synaptic One interesting observation is the emergence and elimina-
formation (Angelman syndrome), can critical or sensitive pe- tion of ipsilateral connections to the spinal cord. While these
riods occur? If so, is their temporal or spatial profile different?” ipsilateral connections naturally involute, to a certain degree,
It was suggested by Knudsen, which remains to be experi- if the injury happens prior to that then these connections get
mentally validated, that there are three prerequisites for the “reinforced” and serve to optimize hand function. Conversely,
onset of a sensitive (including critical) period in the developing it the injury occurs after major ipsilateral tracts are elimi-
brain that include 1) reliable and precise input to the circuit to nated, the presence of these ipsilateral tracts can hinder
allow execution of its function, 2) adequate information pro- functional outcomes depending on competing with the
cessing through proper network structures that involve both remaining tracts of the contralateral side for spinal connec-
excitatory and inhibitory connections, and 3) the presence of tions. Therefore, can the period of ipsilateral CST elimination
activated mechanisms that enable plasticity including but not be considered a “critical period” for motor development after
limited to synapse formation, pruning and network consoli- perinatal brain injury? If we agree to this, then should neu-
dation mechanisms.176 It is therefore conceivable that romodulatory interventions be “customized and timed” based
abnormal plasticity mechanisms can result in abnormal on the presence and functionality of ipsilateral CST pro-
timing, duration and strength of critical and sensitive periods. jections at the time of diagnosis?
In an attempt to characterize changes in critical periods of Since the onset of motor symptoms in CP can be visible
ocular dominance in disorders of abnormal plasticity such as before 6 months of age and the diagnosis is usually confirmed
syndromic autism, researchers have studied animal models of at 13e19 months of age,197 timely interventions before “closing
Rett, fragile X and Angelman syndromes. of critical period” for CST neural activity-based refinement
Using MeCP2-null mice, Krishnan and coworkers have should be carefully examined and applied to restore motor
demonstrated “precocious onset and closure” of ocular function in children with CP. The working hypothesis of neu-
dominance plasticity and deficient binocular visual function romodulation in hemiplegic CP, for example, is derived from
compared to age matched wild type mice that was strongly studies of adult stroke patients and is based on the assumption
related to accelerated maturation of parvalbumin inhibitory that activating the damaged CST and silencing the healthy
interneurons as demonstrated by enhanced GABAergic ac- ipsilateral CST will “rebalance” the competition between the
tivity via elevated GABA synthetic enzymes, vesicular GABA two hemispheres towards restoring CST connections from the
transporter, perineuronal nets, and enhanced GABA trans- damaged hemisphere in an attempt to improve motor
mission among Parvalbumin interneurons. Moreover, they outcome. Many clinical trails are evaluating different activity-
have shown that reduction of (GAD67), a rate-limiting GABA based neuromodulation tools to achieve this target. Intensive
synthetic enzyme, rescued the precocious opening of the bimanual therapy, constraint induced movement therapy of
ocular dominance critical period in MeCP2-null mice.196 Given the healthy upper limb, stimulatory TMS/tDCS on the
the ubiquitous presence and function of GABAergic in- damaged hemisphere and inhibitory TMS/tDCS on the healthy
terneurons in the nervous system, the mechanisms underly- hemisphere have been reported in children with unilateral CP
ing ocular dominance precocious critical period in MECP2- with variable degrees of success. Readers are referred to a
deficient microcircuits may be generalized to other sensory recent review of non-invasive neurorehabilitation in-
modalities or cortical functions. terventions in children with unilateral CP.198 While this
Inferred from this line of evidence, Le Blanc and Fagiolini approach has been widely adopted in many trials of TMS- and
proposed that “alteration of the expression and/or timing of behavioral based therapies in stroke patients, the generalized
critical period circuit refinement in primary sensory brain applicability to young children with hemiplegic CP should be
areas may significantly contribute to autistic phenotypes, carefully scrutinized in the light of the critical period of motor
including cognitive and behavioral impairments”.23 development after perinatal brain injury.
It is therefore important to note that, for the sake of timing
the application of neuromodulatory interventions, critical
periods in disorders of “abnormal plasticity machinery” such 4. Concluding remarks
as Rett syndrome, are not a mere function of time per se, but
rather a manifestation of the “readiness” of neural circuits to In this article, we attempted to draw attention to the dynamic,
get activated, modulated and consolidated by extrinsic stim- multifaceted and most importantly, time-sensitive features of
ulation, which may or may not overlap with the temporal neuroplasticity in pediatric brain development in health and
profile of critical periods described in normal development. disease.
Thus, it is crucial to attempt and plot and profile the onset, We have probably posed more questions than answers, but
closure, duration and peak of critical and sensitive periods in we think it is a reflection of the major strides we need to make
in our understanding of young brain plasticity. We strongly

believe that being mindful of and capitalizing on the Acknowledgement
mounting knowledge of critical and sensitive periods of brain
maturation and development can propel the field of pediatric We thank Milos Ljubisavljevic for his valuable insight that
neuromodulation forward as they present unique and prom- assisted the editing of this manuscript.
ising windows of opportunities to study and intervene. It is
foreseeable in the near future that we can identify which and
references
when neurological disorders are more “amenable” to
neuroplasticity-informed interventions based on a deeper
understanding of developmentally-controlled and time-
1. Johnston MV, Ishida A, Ishida WN, Matsushita HB,
sensitive mechanisms of neuroplasticity. This might be the Nishimura A, Tsuji M. Plasticity and injury in the developing
first step in changing our neuromodulation approach for pe- brain. Brain Dev 2009;31(1):1e10. http://dx.doi.org/10.1016/
diatric brain disorders into time-sensitive, disease-specific j.braindev.2008.03.014.
and mechanism based interventions encapsulating the 2. Dennis M, Spiegler BJ, Juranek JJ, Bigler ED, Snead OC,
concept of precision neuromodulation. Fletcher JM. Age, plasticity, and homeostasis in childhood
brain disorders. Neurosci Biobehav Rev 2013;37(10):2760e73.
http://dx.doi.org/10.1016/j.neubiorev.2013.09.010.
3. Kasparek T, Theiner P, Filova A. Neurobiology of ADHD from
Brief summary for journal use childhood to adulthood: findings of imaging methods. J Atten
Disord 2013;20(10):1e13. http://dx.doi.org/10.1177/
1087054713505322.
In this article, the authors attempt to draw the attention 4. Johnston MV. Clinical disorders of brain plasticity. Brain Dev
of researchers and clinicians in the field of pediatric 2004;26(2):73e80. http://dx.doi.org/10.1016/S0387-7604(03)
neurology and neurodevelopmental disabilities who are 00102-5.
interested in exploring the arena of neuromodulation to 5. Dennis M, Spiegler BJ, Simic N, Sinopoli KJ, Wilkinson A,
the crucial role of “critical and sensitive periods” of Yeates KO, et al. Functional plasticity in childhood brain
disorders: when, what, how, and Whom to Assess.
neurodevelopment that control and shape the neuro-
Neuropsychol Rev 2014;24(4):389e408. http://dx.doi.org/
plasticity potential of the developing brain. This unique
10.1007/s11065-014-9261-x.
feature has not yet been examined in the context of 6. Meredith RM. Sensitive and critical periods during
neuromodulation in pediatrics and might open “win- neurotypical and aberrant neurodevelopment: a framework
dows of opportunity” to intervene that are not seen in for neurodevelopmental disorders. Neurosci Biobehav Rev
adult brain. Thus, the authors encourage the pediatric 2015;50:180e8. http://dx.doi.org/10.1016/
neuromodulation community to capitalize on the j.neubiorev.2014.12.001.
7. Huttenlocher PR, Dabholkar AS. Regional Differences in
mounting experimental and clinical knowledge of tem-
Synaptogenesis in Human Cerebral Cortex. J Comp Neurol
poral and spatial characteristics of these periods when
1997;178:167e78.
choosing and devising a neuromodulatory intervention 8. Ben-Ari Y, Khazipov R, Leinekugel X, Caillard O, Gaiarsa J-L.
for pediatric disorders of the brain. Finally, they hy- GABAA, NMDA and AMPA receptors: a developmentally
pothesize that modulating critical and sensitive periods regulated “menagee atrois”. Trends Neurosci 1997;20(11):523e9.
in disorders of impaired plasticity or after brain injury or 9. Paoletti P, Bellone C, Zhou Q. NMDA receptor subunit
sensory deprivation can maximize the impact of the diversity: impact on receptor properties, synaptic plasticity
and disease. Nat Rev Neurosci 2013;14(6):383e400. http://
neuromodulatory interventions and improve clinical
dx.doi.org/10.1038/nrn3504.
outcomes of interest. 10. Bartholomeusz HH, Courchesne E, Karns CM. Relationship
between head circumference and brain volume in healthy
normal toddllers, children, and adults. Neuropediatrics
‘What this paper adds’ 2002;33:232e8.
11. Sussman D, Leung RC, Chakravarty MM, Lerch JP, Taylor MJ.
The unique feature of heightened plasticity during crit- Developing human brain: age-related changes in cortical,
subcortical, and cerebellar anatomy. Brain Behav 2016;457.
ical and sensitive periods of brain development has not
http://dx.doi.org/10.1002/brb3.457. n/a e n/a.
been examined systematically yet in the context of 12. Chen Z, Zhang H, Yushkevich PA, Liu M, Beaulieu C.
neuromodulation in pediatrics. The authors promote Maturation along white matter tracts in human brain using
that critical and sensitive periods of brain development a diffusion tensor surface model tract-specific analysis. Front
in health and disease can create “windows of opportu- Neuroanat 2016;10(February):1e18. http://dx.doi.org/10.3389/
nity” for neuromodulatory interventions that are not fnana.2016.00009.
13. Gogtay N, Giedd J, Lusk L, Hayashi KM, Greenstein D,
commonly seen in adult brain.
Vaituzis AC, et al. Dynamic mapping of human cortical
development during childhood through early adulthood.
Proc Natl Acad Sci 2004;101(21):8174e9.
14. Gao W, Alcauter S, Smith JK, Gilmore JH, Lin W.
Development of human brain cortical network architecture
during infancy. Brain Struct Funct 2014:1e14. http://
Conflict of interest dx.doi.org/10.1007/s00429-014-0710-3.
15. Gao W, Elton A, Zhu H, Alcauter S, Smith JK, Gilmore JH,
The authors report no conflict of interest. et al. Intersubject variability of and genetic effects on the
brain's functional connectivity during infancy. J Neurosci translation. Cell Rep 2014;9(4):1402e16. http://dx.doi.org/
2014;34(34):11288e96. http://dx.doi.org/10.1523/ 10.1016/j.celrep.2014.10.028.FXR1P.
JNEUROSCI.5072-13.2014. 35. Zakharenko SS, Klyachko VA. NIH Public Access77; 2014.
16. Chugani HT. A critical period of brain development: studies of p. 696e711. http://dx.doi.org/10.1016/
cerebral glucose utilization with PET. Prev Med Balt j.neuron.2012.12.018.FMRP. 4.
1998;27(27):184e8. http://dx.doi.org/10.1006/pmed.1998.0274. 36. Paluszkiewicz SM, Martin BS, Huntsman MM. Fragile X
17. Garvey MA, Mall V. Transcranial magnetic stimulation in syndrome: the GABAergic system and circuit dysfunction.
children. Clin Neurophysiol 2008;119(5):973e84. http:// Dev Neurosci 2011;33(5):349e64. http://dx.doi.org/10.1159/
dx.doi.org/10.1016/j.clinph.2007.11.048. 000329420.
18. Garvey MA, Gilbert DL. Transcranial magnetic stimulation in 37. Oberman L, Ifert-Miller F, Najib U, Bashir S, Woollacott I,
children. Eur J Paediatr Neurol 2004;8(1):7e19. http:// Gonzalez-Heydrich J, et al. Transcranial magnetic
dx.doi.org/10.1016/j.ejpn.2003.11.002. stimulation provides means to assess cortical plasticity
19. Taylor MJ, Doesburg SM, Pang EW. Neuromagnetic vistas and excitability in humans with fragile X syndrome and
into typical and atypical development of frontal lobe autism spectrum disorder. Front Synaptic Neurosci
functions. Front Hum Neurosci 2014;8(June):1e12. http:// 2010;2(JUN):1e8. http://dx.doi.org/10.3389/
dx.doi.org/10.3389/fnhum.2014.00453. fnsyn.2010.00026.
20. Phillips M, Pozzo-Miller L. Dendritic spine dysgenesis in 38. Conde V, Palomar FJ, Lama MJ, Martı́nez R, Carrillo F,
autism related disorders. Neurosci Lett 2014;601:30e40. Pintado E, et al. Abnormal GABA-mediated and cerebellar
http://dx.doi.org/10.1016/j.neulet.2015.01.011. inhibition in women with the fragile X premutation. J
21. Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Neurophysiol 2013;109(5):1315e22. http://dx.doi.org/10.1152/
Kamitaki N, et al. Schizophrenia risk from complex variation jn.00730.2012.
of complement component 4. Nature 2016;530:177e83. 39. Hagerman RJ, Polussa J. Treatment of the psychiatric
http://dx.doi.org/10.1038/nature16549. problems associated with fragile X syndrome. Curr Opin
22. Lewis DA, Jill G. Dendritic Spine Pathology in Schizophrenia. Psychiatry 2015;28(2):107e12. http://dx.doi.org/10.1097/
Neuroscience 2011;18(11):1492e501. http://dx.doi.org/10.1016/ YCO.0000000000000131.
j.str.2010.08.012.Structure. 40. Curatolo P, Moavero R, Roberto D, Graziola F. Genotype/
23. Fagiolini M, Leblanc JJ. Autism: a critical period disorder? Phenotype correlations in tuberous sclerosis complex. Semin
Neural Plast 2011:2011. http://dx.doi.org/10.1155/2011/921680. Pediatr Neurol 2015;22(4):259e73. http://dx.doi.org/10.1016/
24. Armstrong DD. Original article Neuropathology of Rett j.spen.2015.10.002.
Syndrome. J Child Neurol n.d.:747e754. 41. Volk L, Chiu S-L, Sharma K, Huganir RL. Glutamate synapses
25. Ronnett GV, Leopold D, Cai X, Hoffbuhr KC, Moses L, in human cognitive disorders. Annu Rev Neurosci
Hoffman EP, et al. Olfactory biopsies demonstrate a defect in 2015;38(1):127e49. http://dx.doi.org/10.1146/annurev-neuro-
neuronal development in Rett's syndrome. Ann Neurol 071714-033821.
2003;54(2):206e18. http://dx.doi.org/10.1002/ana.10633. 42. Tee AR, Sampson JR, Pal DK, Bateman JM. The role of mTOR
26. Asaka Y, Jugloff DGM, Zhang L, Eubanks JH, Fitzsimonds RM. signalling in neurogenesis, insights from tuberous sclerosis
Hippocampal synaptic plasticity is impaired in the Mecp2- complex. Semin Cell Dev Biol 2016;52:12e20. http://dx.doi.org/
null mouse model of Rett syndrome. Neurobiol Dis 10.1016/j.semcdb.2016.01.040.
2006;21(1):217e27. http://dx.doi.org/10.1016/ 43. Bateup HS, Johnson CA, Denefrio CL, Saulnier JL, Sabatini BL.
j.nbd.2005.07.005. Hyperexcitability in mouse models of Tuberous Sclerosis.
27. Blue ME, Naidu S, Johnston MV. Altered development of Neuron 2013;78(3):510e22. http://dx.doi.org/10.1016/
glutamate and GABA receptors in the basal ganglia of girls j.neuron.2013.03.017.Excitatory/inhibitory.
with Rett syndrome. Exp Neurol 1999;156(2):345e52. http:// 44. Auerbach BD, Osterweil EK, Bear MF. NIH Public Access480;
dx.doi.org/10.1006/exnr.1999.7030. 2012. p. 63e8. http://dx.doi.org/10.1038/
28. Arif M, Genila B, A-Lai Z, Izlem I. White matter impairment nature10658.Mutations. 7375.
in Rett syndrome: diffusion tensor imaging study with 45. D'Argenzio L, Koch G, Bombardieri R, Mori F, Moavero R,
clinical correlations. AJNR Am J Neuroradiol 2010;31(2):295e9. Centonze D, et al. Abnormal parieto-motor connectivity in
http://dx.doi.org/10.1016/j.surg.2006.10.010.Use. tuberous sclerosis complex. Epilepsy Res 2009;87(1):102e5.
29. Naidu S, Kaufmann WE, Abrams MT, Pearlson GD, http://dx.doi.org/10.1016/j.eplepsyres.2009.07.009.
Lanham DC, Fredericksen KA, et al. Neuroimaging studies in 46. Cusmai R, Moavero R, Bombardieri R, Vigevano F, Curatolo P.
Rett syndrome. Brain Dev 2001;23(Suppl. 1):S62e71. Long-term neurological outcome in children with early-
S0387760401003813. onset epilepsy associated with tuberous sclerosis. Epilepsy
30. Eyre A, Kerr AM, Miller S, Sullivan MCO, Ramesh V. Behav 2011;22(4):735e9. http://dx.doi.org/10.1016/
Projections to the upper limb in subjects with RettIeH. j.yebeh.2011.08.037.
I J Neurol Neurosurg Psychiatry 1990;53:874e9. 47. Bombardieri R, Pinci M, Moavero R, Cerminara C, Curatolo P.
31. Katz DM, Bird A, Coenraads M, Gray SJ, Menon DU, Early control of seizures improves long-term outcome in
Philpot BD, et al. Rett syndrome: Crossing the threshold to children with tuberous sclerosis complex. Eur J Paediatr
clinical translation. Trends Neurosci 2016;39(2):100e13. http:// Neurol 2010;14(2):146e9. http://dx.doi.org/10.1016/
dx.doi.org/10.1016/j.tins.2015.12.008. j.ejpn.2009.03.003.
32. He CX, Portera-Cailliau C. The trouble with spines in fragile 48. Zhang B, McDaniel SS, Rensing NR, Wong M. Vigabatrin
X syndrome: density, maturity and plasticity. Neuroscience inhibits seizures and mTOR pathway activation in a mouse
2013;251:120e8. http://dx.doi.org/10.1016/ model of tuberous sclerosis complex. PLoS One 2013;8(2).
j.neuroscience.2012.03.049. http://dx.doi.org/10.1371/journal.pone.0057445.
33. Castren ML, Castren E. BDNF in fragile X syndrome. 49. Jozwiak S, Kotulska K, Domariska-Pakiela D, Lojszczyk B,
Neuropharmacology 2014;76(Pt C):729e36. http://dx.doi.org/ Syczewska M, Chmielewski D, et al. Antiepileptic treatment
10.1016/j.neuropharm.2013.05.018. before the onset of seizures reduces epilepsy severity and
34. Cook D, Nuro E, Jones EV, Altimimi HF, Farmer WT, risk of mental retardation in infants with tuberous sclerosis
Gandin V, et al. FXR1P limits long-term memory, long- complex. Eur J Paediatr Neurol 2011;15(5):424e31. http://
lasting synaptic potentiation, and de novo GluA2 dx.doi.org/10.1016/j.ejpn.2011.03.010.
50. Bird LM. Angelman syndrome: review of clinical and 66. Cui Y, Costa RM, Murphy GG, Elgersma Y, Zhu YHD, et al.
molecular aspects. Appl Clin Genet 2014;7:93e104. http:// Release and Learning135; October 2009. p. 549e60. http://
dx.doi.org/10.2147/TACG.S57386. dx.doi.org/10.1016/j.cell.2008.09.060.Neurofibromin. 3.
51. Stellacci F, Mortensen A. Angelman syndrome connections 67. Omrani A, van der Vaart T, Mientjes E, van Woerden GM,
Model's reputation restored. Nature 2010;5:8e9. Hojjati MR, Li KW, et al. HCN channels are a novel
52. Pignatelli M, Piccinin S, Molinaro G, Di Menna L, Riozzi B, therapeutic target for cognitive dysfunction in
Cannella M, et al. Changes in mGlu5 receptor-dependent Neurofibromatosis type 1. Mol Psychiatry
synaptic plasticity and coupling to homer proteins in the 2015;20(11):1311e21.
hippocampus of Ube3A hemizygous mice modeling 68. Zimerman M, Wessel MJ, Timmermann JE, Granstro € m S,
angelman syndrome. J Neurosci 2014;34(13):4558e66. http:// Gerloff C, Mautner VF, et al. Impairment of procedural learning
dx.doi.org/10.1523/JNEUROSCI.1846-13.2014. and motor intracortical inhibition in neurofibromatosis type 1
53. Riday TT, Dankoski EC, Krouse MC, Fish EW, Walsh PL, patients. EBioMedicine 2015;2(10):1430e7. http://dx.doi.org/
Han JE, et al. Pathway-specific dopaminergic deficits in a 10.1016/j.ebiom.2015.08.036.
mouse model of Angelman syndrome. J Clin Invest 69. Li W, Cui Y, Kushner SA, Brown RAM, Jentsch JD,
2012;122(12):4544e54. http://dx.doi.org/10.1172/JCI61888. Frankland PW, et al. The HMG-CoA reductase inhibitor
54. Thibert RL, Larson AM, Hsieh DT, Raby AR, Thiele EA. lovastatin reverses the learning and attention deficits in a
Neurologic manifestations of Angelman syndrome. Pediatr mouse model of Neurofibromatosis Type 1. Curr Biol
Neurol 2013;48(4):271e9. 2005;15(21):1961e7. http://dx.doi.org/10.1016/
55. Judson MC, Wallace ML, Sidorov MS, Burette AC, Gu B, van j.cub.2005.09.043.
Woerden GM, et al. GABAergic neuron-specific loss of Ube3a 70. Mainberger F, Jung NH, Zenker M, Wahlla € nder U,
causes angelman syndrome-like EEG abnormalities and Freudenberg L, Langer S, et al. Lovastatin improves impaired
enhances seizure susceptibility. Neuron 2016:1e14. http:// synaptic plasticity and phasic alertness in patients with
dx.doi.org/10.1016/j.neuron.2016.02.040. neurofibromatosis type 1. BMC Neurol 2013;13:131. http://
56. Silva-Santos S, Van Woerden GM, Bruinsma CF, Mientjes E. dx.doi.org/10.1186/1471-2377-13-131.
Ube3a reinstatement identifies distinct treatment windows 71. Klein D, Mok K, Chen JK, Watkins KE. Age of language
in Angelman syndrome model mice. J Clin Invest learning shapes brain structure: a cortical thickness study
2015;125(5):2069e76. http://dx.doi.org/10.1172/ of bilingual and monolingual individuals. Brain Lang
JCI80554DS1. 2014;131:20e4. http://dx.doi.org/10.1016/
57. Tan W-H, Bird LM. Pharmacological therapies for Angelman j.bandl.2013.05.014.
syndrome. Wien Med Wochenschr 2016:1e14. http:// 72. Li P, Legault J, Litcofsky KA. Neuroplasticity as a function of
dx.doi.org/10.1007/s10354-015-0408-z. second language learning: anatomical changes in the
58. Harony-Nicolas H, De Rubeis S, Kolevzon A, Buxbaum JD. human brain. Cortex 2014;58:301e24. http://dx.doi.org/
Phelan McDermid syndrome: from genetic discoveries to 10.1016/j.cortex.2014.05.001.
animal models and treatment. J Child Neurol 73. Barrett KC, Ashley R, Strait DL, Kraus N. Art and science:
2015;30(14):1861e70. http://dx.doi.org/10.1177/ how musical training shapes the brain. Front Psychol
0883073815600872. 2013;4(October):1e13. http://dx.doi.org/10.3389/
59. Vicidomini C, Ponzoni L, Lim D, Schmeisser MJ, Reim D, fpsyg.2013.00713.
Morello N, et al. Pharmacological enhancement of mGlu5 74. Kastrup O, Leonhardt G, Kurthen M, Hufnagel A. Cortical
receptors rescues behavioral deficits in SHANK3 knock-out motor reorganization following early brain damage and
mice. Mol Psychiatry August 2015;2016:1e14. http:// hemispherectomy demonstrated by transcranial magnetic
dx.doi.org/10.1038/mp.2016.30. stimulation. Clin Neurophysiol 2000;111(8):1346e52. http://
60. Bozdagi O, Tavassoli T, Buxbaum JD. Insulin-like growth dx.doi.org/10.1016/S1388-2457(00)00339-4.
factor-1 rescues synaptic and motor deficits in a mouse 75. Holtmaat A, Svoboda K. Experience-dependent structural
model of autism and developmental delay. Mol Autism synaptic plasticity in the mammalian brain. Nat Rev Neurosci
2013;4(1):9. http://dx.doi.org/10.1186/2040-2392-4-9. 2009;10(9):647e58. http://dx.doi.org/10.1038/nrn2721.
61. Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, 76. Crair MC, Malenka RC. A critical period for long term
Shu R, Sebastiano V, et al. SHANK3 and IGF1 restore synaptic potentiation at the thalamocortical synapses. Lett Nat
deficits in neurons from 22q13 deletion syndrome patients. 1995;375:325e8.
Nature 2013;503(7475):267e71. http://dx.doi.org/10.1038/ 77. Schnack HG, Van Haren NEM, Brouwer RM, Evans A,
nature12618. Durston S, Boomsma DI, et al. Changes in thickness and
62. Kolevzon A, Bush L, Wang AT, Halpern D, Frank Y, surface area of the human cortex and their relationship with
Grodberg D, et al. A pilot controlled trial of insulin-like intelligence. Cereb Cortex 2015;25(6):1608e17. http://
growth factor-1 in children with Phelan-McDermid dx.doi.org/10.1093/cercor/bht357.
syndrome. Mol Autism 2014;5(1):54. http://dx.doi.org/10.1186/ 78. Shaw P, Greenstein D, Lerch J, Clasen L, Lenroot R, Gogtay N,
2040-2392-5-54. et al. Intellectual ability and cortical development in
63. Shofty B, Constantini S, Ben-Shachar S. Advances in Molecular children and adolescents. Nature 2006;440(7084):676e9.
Diagnosis of Neuro fibromatosis Type 11; 2015. p. 234e9. http:// http://dx.doi.org/10.1038/nature04513.
dx.doi.org/10.1016/j.spen.2015.10.007. 79. Elbert T, Pantev C, Wienbruch C, Rockstroh B, Taub E.
64. Hu H-T, Shih P-Y, Shih Y-T, Hsueh Y-P. The involvement of Increased cortical representation of the fingers of the left
neuron-specific factors in dendritic spinogenesis: molecular hand in string players. In: Elbert Thomas, Pantev Christo,
regulation and association with neurological disorders. Wienbruch Christian, Rockstroh Brigitte, Edward, editors.
Neural Plast 2016;2016:1e10. http://dx.doi.org/10.1155/2016/ American Association for the Advancement of Science Stabl270;
5136286. 2016. p. 305e7. 5234.
65. Armstrong BC, Le Boutillier JC, Petit TL. Ultrastructural 80. Abdul-Kareem IA, Stancak A, Parkes LM, Sluming V.
synaptic changes associated with neurofibromatosis type 1: Increased gray matter volume of left pars opercularis in
a quantitative analysis of hippocampal region CA1 in a Nf1 male orchestral musicians correlate positively with years of
þ/- mouse model. Synapse 2012;66(3):246e55. http:// musical performance. J Magn Reson Imaging 2011;33(1):24e32.
dx.doi.org/10.1002/syn.21507. http://dx.doi.org/10.1002/jmri.22391.
81. Campbell J, Sharma A. Visual cross-modal re-organization in 97. Staudt M. Reorganization after pre- and perinatal brain
children with cochlear implants. PLoS One lesions. J Anat 2010;217(4):469e74. http://dx.doi.org/10.1111/
2016;11(1):e0147793. http://dx.doi.org/10.1371/ j.1469-7580.2010.01262.x.
journal.pone.0147793. 98. Staudt M. Brain plasticity following early life brain injury:
82. Sharma A, Glick H, Campbell J. Cortical plasticity and insights from neuroimaging. Semin Perinatol
reorganization in pediatric single-sided deafness pre-and 2010;34(1):87e92. http://dx.doi.org/10.1053/
postcochlear implantation: a case study. Otol 2016:26e34. j.semperi.2009.10.009.
http://dx.doi.org/10.1097/MAO.0000000000000904. 99. Juenger H, Grodd W, Kra € geloh-Mann I, Staudt M. (Re-)
83. Wong AMF. New concepts concerning the neural organization of basal ganglia in congenital hemiparesis
mechanisms of amblyopia and their clinical implications. with ipsilateral cortico-spinal projections. Neuropediatrics
Can J Ophthalmol 2012;47(5):399e409. http://dx.doi.org/ 2008;39(5):252e8. http://dx.doi.org/10.1055/s-0029-
10.1016/j.jcjo.2012.05.002. 1202284.
84. Umeda T, Funakoshi K. Reorganization of motor circuits 100. Juenger H, Koerte IK, Muehlmann M, Mayinger M, Mall V, Kr??
after neonatal hemidecortication. Neurosci Res geloh-Mann I, et al. Microstructure of transcallosal motor
2014;78(1):30e7. http://dx.doi.org/10.1016/ fibers reflects type of cortical (re-)organization in congenital
j.neures.2013.08.011. hemiparesis. Eur J Paediatr Neurol 2014;18(6):691e7. http://
85. van der Kolk NM, Boshuisen K, van Empelen R, Koudijs SM, dx.doi.org/10.1016/j.ejpn.2014.05.006.
Staudt M, van Rijen PC, et al. Etiology-specific differences in 101. Fiori S, Guzzetta A. Plasticity following early-life brain
motor function after hemispherectomy. Epilepsy Res injury: insights from quantitative MRI. Semin Perinatol
2013;103(2e3):221e30. http://dx.doi.org/10.1016/ 2015;39(2):141e6. http://dx.doi.org/10.1053/
j.eplepsyres.2012.08.007. j.semperi.2015.01.007.
86. Hertz-Pannier L, Chiron C, Jambaque I, Renaux-Kieffer V, 102. Staudt Martin, Gerloff Christian, Grodd Wolfgang,
Van de Moortele P-F, Delalande O, et al. Late plasticity for Holthausen Hans, Niemann Gerhard, Kra € geloh-
language in a child's non-dominant hemisphere: a pre- and Mann Ingeborg. Reorganization in congenital hemiparesis
post-surgery fMRI study. Brain 2002;125(Pt 2):361e72. http:// acquired at different gestational ages. Ann Neurol
dx.doi.org/10.1093/brain/awf020. 2004;56(6):854e63. http://dx.doi.org/10.1002/ana.10145.
87. Graveline CJ, Mikulis DJ, Crawley AP, Hwang PA. 103. Hoon AH, Stashinko EE, Nagae LM, Lin DDM, Keller J,
Regionalized sensorimotor plasticity after hemispherectomy Bastian A, et al. Sensory and motor deficits in children with
fMRI evaluation. Pediatr Neurol 1998;19(5):337e42. http:// cerebral palsy born preterm correlate with diffusion tensor
dx.doi.org/10.1016/S0887-8994(98)00082-4. imaging abnormalities in thalamocortical pathways. Dev
88. Werth R. Cerebral blindness and plasticity of the visual Med Child Neurol 2009;51(9):697e704. http://dx.doi.org/
system in children. A review of visual capacities in patients 10.1111/j.1469-8749.2009.03306.x.
with occipital lesions, hemispherectomy or 104. Koerte I, Pelavin P, Kirmess B, Fuchs T, Laubender RP,
hydranencephaly. Restor Neurol Neurosci Borggraefe I, et al. NIH Public Access 2012;53(2):179e86. http://
2008;26(4e5):377e89. dx.doi.org/10.1111/j.1469-8749.2010.03840.x.Anisotropy.
89. Yao N, Qiao H, Li P, Liu Y, Wu L, Deng X, et al. Ipsilateral and 105. van Egmond ME, Kuiper A, Eggink H, Sinke RJ, Brouwer OF,
contralateral auditory brainstem response reorganization in Verschuuren-Bemelmans CC, et al. Dystonia in children and
hemispherectomized patients. Neural Plast 2013;2013:1e10. adolescents: a systematic review and a new diagnostic
90. Liegeois F, Morgan AT, Stewart LH, Helen Cross J, Vogel AP, algorithm. J Neurol Neurosurg Psychiatry 2015;86(7):774e81.
Vargha-Khadem F. Speech and oral motor profile after http://dx.doi.org/10.1136/jnnp-2014-309106.
childhood hemispherectomy. Brain Lang 2010;114(2):126e34. 106. Lin J-P, Lumsden DE, Gimeno H, Kaminska M. The impact
http://dx.doi.org/10.1016/j.bandl.2009.12.004. and prognosis for dystonia in childhood including dystonic
91. Picht T, Schmidt S, Brandt S, Frey D, Hannula H, cerebral palsy: a clinical and demographic tertiary cohort
Neuvonen T, et al. Preoperative functional mapping for study. J Neurol Neurosurg Psychiatry 2014:1e6. http://
rolandic brain tumor surgery: comparison of navigated dx.doi.org/10.1136/jnnp-2013-307041.
transcranial magnetic stimulation to direct cortical 107. Sussman J. Musician's dystonia. Pract Neurol
stimulation. Neurosurgery 2011;69(3):581e8. http:// 2015;15(4):317e22. http://dx.doi.org/10.1136/practneurol-
dx.doi.org/10.1227/NEU.0b013e3182181b89. 2015-001148.
92. Zsoter A, Pieper T, Kudernatsch M, Staudt M. Predicting 108. Graziadio S, Basu A, Tomasevic L, Zappasodi F, Tecchio F,
hand function after hemispherotomy: TMS versus fMRI in Eyre JA. Developmental tuning and decay in senescence of
hemispheric polymicrogyria. Epilepsia 2012;53(6):98e101. oscillations linking the corticospinal system. J Neurosci
http://dx.doi.org/10.1111/j.1528-1167.2012.03452.x. 2010;30(10):3663e74. http://dx.doi.org/10.1523/
93. Eyre JA. Corticospinal tract development and its plasticity JNEUROSCI.5621-09.2010.
after perinatal injury. Neurosci Biobehav Rev 109. Schmidt A, Jabusch H, Altenmüller E, Hagenah J,
2007;31(8):1136e49. http://dx.doi.org/10.1016/ Brüggemann N, Lohmann K, et al. Etiology of musician’s
j.neubiorev.2007.05.011. dystonia familial or environmental? Neurology
94. Bax M, Tydeman C, Flodmark O. Clinical and MRI correlates 2009;72:1248e54. http://dx.doi.org/10.1212/
of cerebral palsy: the european cerebral palsy study. JAMA 01.wnl.0000345670.63363.d1.
2006;296(13):1602e8. http://dx.doi.org/10.1001/ 110. Lohmann K, Schmidt A, Schillert A, Winkler S, Albanese A,
jama.296.13.1602. Baas F, et al. Genome-wide association study in musician's
95. Friel KM, Williams PTJ a, Serradj N, Chakrabarty S, Martin JH. dystonia: a risk variant at the arylsulfatase G locus? Mov
Activity-based therapies for repair of the corticospinal Disord 2014;29(7):921e7. http://dx.doi.org/10.1002/
system injured during development. Front Neurol 2014;5:229. mds.25791.
http://dx.doi.org/10.3389/fneur.2014.00229. November. 111. Granata A, Warner TT. The role of torsinA in dystonia. Eur J
€ geloh-Mann I.
96. Staudt M, Grodd W, Gerloff C, Erb M, Stitz J, Kra Neurol 2010;17(SUPPL. 1):81e7. http://dx.doi.org/10.1111/
Two types of ipsilateral reorganization in congenital j.1468-1331.2010.03057.x.
hemiparesis: a TMS and fMRI study. Brain 2002;125:2222e37. 112. Vanni V, Puglisi F, Bonsi P, Ponterio G, Maltese M, Pisani A,
http://dx.doi.org/10.1093/brain/awf227. et al. Cerebellar synaptogenesis is compromised in mouse
models of DYT1 dystonia. Exp Neurol 2015;271:457e67. http:// 127. Huang YZ, Edwards MJ, Bhatia KP, Rothwell JC. One-Hz
dx.doi.org/10.1016/j.expneurol.2015.07.005. repetitive transcranial magnetic stimulation of the premotor
113. Ulug AM, Vo A, Argyelan M, Tanabe L, Schiffer WK, Dewey S, cortex alters reciprocal inhibition in DYT1 dystonia. Mov
et al. Cerebellothalamocortical pathway abnormalities in Disord 2004;19(1):54e9. http://dx.doi.org/10.1002/mds.10627.
torsinA DYT1 knock-in mice. Proc Natl Acad Sci U. S. A 128. Huang YZ, Rothwell JC, Lu CS, Wang J, Chen RS. Restoration
2011;108(16):6638e43. http://dx.doi.org/10.1073/ of motor inhibition through an abnormal premotor-motor
pnas.1016445108. connection in dystonia. Mov Disord 2010;25(6):696e703.
114. Sciamanna G, Tassone A, Mandolesi G, Puglisi F, Ponterio G, http://dx.doi.org/10.1002/mds.22814.
Martella G, et al. Cholinergic dysfunction alters synaptic 129. Fox MD, Alterman RL. Deep brain stimulation for torsion
integration between Thalamostriatal and Corticostriatal dystonia. JAMA Neurol 2015;72(6):713e9. http://dx.doi.org/
inputs in DYT1 dystonia. J Neurosci 2012;32(35):11991e2004. 10.1016/B978-0-12-374248-3.00046-X.
http://dx.doi.org/10.1523/JNEUROSCI.0041-12.2012. 130. Marks W, Bailey L, Reed M, Pomykal A, Mercer M,
115. Martella G, Maltese M, Nistic R, Schirinzi T, Madeo G, Macomber D, et al. Pallidal stimulation in children:
Sciamanna G, et al. Regional specificity of synaptic plasticity comparison between cerebral palsy and DYT1 dystonia. J
deficits in a knock-in mouse model of DYT1 dystonia. Child Neurol 2013;28(7):840e8. http://dx.doi.org/10.1177/
Neurobiol Dis 2014;65:124e32. http://dx.doi.org/10.1016/ 0883073813488674.
j.nbd.2014.01.016. 131. Alterman RL, Tagliati M. Deep brain stimulation for torsion
116. Martella G, Tassone A, Sciamanna G, Platania P, Cuomo D, dystonia in children. Childs Nerv Syst 2007;23(9):1033e40.
Viscomi MT, et al. Impairment of bidirectional synaptic http://dx.doi.org/10.1007/s00381-007-0382-x.
plasticity in the striatum of a mouse model of DYT1 132. Lumsden DE, Kaminska M, Gimeno H, Tustin K, Baker L,
dystonia: role of endogenous acetylcholine. Brain Perides S, et al. Proportion of life lived with dystonia
2009;132(9):2336e49. http://dx.doi.org/10.1093/brain/ inversely correlates with response to pallidal deep brain
awp194. stimulation in both primary and secondary childhood
117. Sciamanna G, Tassone A, Martella G, Mandolesi G, Puglisi F, dystonia. Dev Med Child Neurol 2013;55(6):567e74. http://
Cuomo D, et al. Developmental profile of the aberrant dx.doi.org/10.1111/dmcn.12117.
dopamine D2 receptor response in striatal cholinergic 133. Vidailhet M, Yelnik J, Lagrange C, Fraix V, Grabli D, Thobois S,
interneurons in DYT1 dystonia. PLoS One 2011;6(9). http:// et al. Bilateral pallidal deep brain stimulation for the treatment
dx.doi.org/10.1371/journal.pone.0024261. of patients with dystonia-choreoathetosis cerebral palsy: a
118. Draganski B, Schneider SA, Fiorio M, Klo € ppel S, Gambarin M, prospective pilot study. Lancet Neurol 2009;8(8):709e17. http://
Tinazzi M, et al. Genotype-phenotype interactions in dx.doi.org/10.1016/S1474-4422(09)70151-6.
primary dystonias revealed by differential changes in brain 134. Marks W, Honeycutt J, Acosta Jr F, Reed MM, Bailey L,
structure. Neuroimage 2009;47(4):1141e7. http://dx.doi.org/ Pomykal A, et al. Dystonia due to cerebral palsy responds to
10.1016/j.neuroimage.2009.03.057. deep brain stimulation of the globus pallidus internus. Mov
119. Carbon M, Kingsley PB, Su S, Smith GS, Spetsieris P, Disord 2011;26(9):1748e51. http://dx.doi.org/10.1002/
Bressman S, et al. Microstructural white matter changes in mds.23690.
carriers of the DYT1 gene mutation. Ann Neurol 135. Koy A, Hellmich M, Pauls KAM, Marks W, Lin JP, Fricke O,
2004;56(2):283e6. http://dx.doi.org/10.1002/ana.20177. et al. Effects of deep brain stimulation in dyskinetic cerebral
120. Carbon M, Argyelan M, Ghilardi MF, Mattis P, Dhawan V, palsy: a meta-analysis. Mov Disord 2013;28(5):647e54. http://
Bressman S, et al. Impaired sequence learning in dystonia dx.doi.org/10.1002/mds.25339.
mutation carriers: a genotypic effect. Brain 136. Romito LM, Zorzi G, Marras CE, Franzini A, Nardocci N,
2011;134(5):1416e27. http://dx.doi.org/10.1093/brain/awr060. Albanese A. Pallidal stimulation for acquired dystonia due to
121. Edwards MJ, Huang YZ, Wood NW, Rothwell JC, Bhatia KP. cerebral palsy: beyond 5 years. Eur J Neurol 2015;22(3). http://
Different patterns of electrophysiological deficits in dx.doi.org/10.1111/ene.12596. 426ee32.
manifesting and non-manifesting carriers of the DYT1 gene 137. Angelica MD, Fong Y. Anticholinergic drugs rescue synaptic
mutation. Brain 2003;126(9):2074e80. http://dx.doi.org/ plasticity in DYT1 dystonia: role of M1 muscarinic receptors.
10.1093/brain/awg209. October 2008;141(4):520e9. http://dx.doi.org/10.1016/
122. Edwards MJ, Huang YZ, Mir P, Rothwell JC, Bhatia KP. j.surg.2006.10.010.Use.
Abnormalities in motor cortical plasticity differentiate 138. Ben-Ari Y. Basic developmental rules and their implications
manisfesting and nonmanifesting DYT1 carriers. Mov Disord for epilepsy in the immature brain. Epileptic Disord
2006;21(12):2181e6. http://dx.doi.org/10.1002/mds.21160. 2006;8(2):91e102.
123. Quartarone A, Bagnato S, Rizzo V, Siebner HR, Dattola V, 139. Benke TA, Brooks-Kayal AR. Section B epileptogenesis, genetics,
Scalfari A, et al. Abnormal associative plasticity of the human and epilepsy substrates chapter 3 experimental models of seizures
motor cortex in writer's cramp. Brain 2003;126(12):2586e96. and mechanisms of epileptogenesis animal models of seizures and
http://dx.doi.org/10.1093/brain/awg273. Epilepsy: what is the. 2006. p. 20e33.
124. Tisch S, Rothwell JC, Bhatia KP, Quinn N, Zrinzo L, 140. Pitkanen A, Engel J. Past and present definitions of
Jahanshahi M, et al. Pallidal stimulation modifies after- epileptogenesis and its biomarkers. Neurotherapeutics
effects of paired associative stimulation on motor cortex 2014;11(2):231e41. http://dx.doi.org/10.1007/s13311-014-
excitability in primary generalised dystonia. Exp Neurol 0257-2.
2007;206(1):80e5. http://dx.doi.org/10.1016/ 141. Lukasiuk K, Pitka € nen A. Encyclopedia of basic epilepsy research.
j.expneurol.2007.03.027. Elsevier; 2009.
125. Maltese M, Martella G, Madeo G, Fagiolo I, Tassone A, 142. Pitka€ nen AST. Is epilepsy a progressive disease? Prospects
Ponterio G, et al. Anticholinergic drugs rescue synaptic for new therapeutic approaches in temporal lobe epilepsy.
plasticity in DYT1 dystonia: role of M1 muscarinic receptors. Lancet Neurol 2002;1(1):73e81.
Mov Disord 2014;29(13):1655e65. http://dx.doi.org/10.1002/ 143. Khalilov I, Holmes GL, Ben-Ari Y. In vitro formation of a
mds.26009. secondary epileptogenic mirror focus by interhippocampal
126. Lumsden DE, Kaminska M, Tomlin S, Lin J-P. Medication use propagation of seizures. Nat Neurosci 2003;6(10):1079e85.
in childhood dystonia. Eur J Paediatr Neurol 2016;20(4):625e9. 144. Doucet GE, Sharan A, Pustina D, Skidmore C, Sperling MR,
http://dx.doi.org/10.1016/j.ejpn.2016.02.003. Tracy JI. Early and late age of seizure onset have a
differential impact on brain resting-state organization in 162. Khalilov I, Le Van Quyen M, Gozlan H, Ben-Ari Y.
temporal lobe epilepsy. Brain Topogr 2014:113e26. http:// Epileptogenic actions of GABA and fast oscillations in the
dx.doi.org/10.1007/s10548-014-0366-6. developing hippocampus. Neuron 2005;48(5):787e96. http://
145. Pitka€ nen A, Lukasiuk K. Mechanisms of epileptogenesis and dx.doi.org/10.1016/j.neuron.2005.09.026.
potential treatment targets. Lancet Neurol 2011:173e86. 163. Nardou R, Ferrari DC, Ben-Ari Y. Mechanisms and effects of
http://dx.doi.org/10.1016/S1474-4422(10)70310-0. seizures in the immature brain. Semin Fetal Neonatal Med
146. Johnston MV, Nakajima W, Hagberg H. Mechanisms of 2016;18(4):175e84. http://dx.doi.org/10.1016/
hypoxic neurodegeneration in the developing brain. j.siny.2013.02.003.
Neuroscientist 2002;8(3):212e20. http://dx.doi.org/10.1177/ 164. Kang SK, Markowitz GJ, Kim ST, Johnston MV, Kadam SD.
10758402008003007. Age- and sex-dependent susceptibility to phenobarbital-
147. Douglas-Escobar M, Weiss MD. Hypoxic-ischemic resistant neonatal seizures: role of chloride co-transporters.
encephalopathy. JAMA Pediatr 2015;169(4):397e403. http:// Front Cell Neurosci 2015;9:1e16. http://dx.doi.org/10.3389/
dx.doi.org/10.1001/jamapediatrics.2014.3269. fncel.2015.00173. May.
148. Johnston MV, Fatemi A, Wilson MA, Northington F. 165. Gursoy S, Ercal D. Diagnostic approach to genetic causes of
Treatment advances in neonatal neuroprotection and early-onset epileptic encephalopathy. J Child Neurol
neurointensive care. Lancet Neurol 2011;10(4):372e82. http:// 2015;1606. http://dx.doi.org/10.1177/0883073815599262.
dx.doi.org/10.1016/S1474-4422(11)70016-3. 0883073815599262.
149. Blanco M, Lizasoain I, Sobrino T, Vivancos J, Castillo J. 166. Casanova EL, Sharp JL, Chakraborty H, Sumi NS,
Ischemic preconditioning: a novel target for neuroprotective Casanova MF. Genes with high penetrance for syndromic and
therapy. Cerebrovasc Dis 2006;21(Suppl. 2):38e47. http:// non-syndromic autism typically function within the nucleus
dx.doi.org/10.1159/000091702. and regulate gene expression. Mol Autism 2016;7(18):1e17.
150. Kostandy BB. The role of glutamate in neuronal ischemic http://dx.doi.org/10.1186/s13229-016-0082-z.
injury: the role of spark in fire. Neurol Sci 2012;33(2):223e37. 167. Ebrahimi-Fakhari D, Sahin M. Autism and the synapse:
http://dx.doi.org/10.1007/s10072-011-0828-5. emerging mechanisms and mechanism-based therapies.
151. Johnston MV. Excitotoxicity in neonatal hypoxia. Ment Retard Curr Opin Neurol 2015;1(617):1e12. http://dx.doi.org/10.1097/
Dev Disabil 2001;7:229e34. WCO.0000000000000186.
152. Ma Q, Zhang L. Epigenetic programming of hypoxic- 168. Auvin S, Roberta M, Vezzani A. Current understanding and
ischemic encephalopathy in response to fetal hypoxia. Prog neurobiology of epileptic encephalopathies. Neurobiol Dis
Neurobiol 2015;124:28e48. http://dx.doi.org/10.1016/ 2016. http://dx.doi.org/10.1016/j.nbd.2016.03.007.
j.pneurobio.2014.11.001. 169. Kabova R, Liptakova S, lamberova R, Pometlova M, Velisek L.
153. Johnston MV. Neurotransmitters and vulnerability of the Age-specific N-methyl-D-aspartate-induced seizures:
developing brain. Brain Dev 1995;17(5):301e6. http:// perspectives for the west syndrome model. Epilepsia
dx.doi.org/10.1016/0387-7604(95)00079-Q. 1999;40(10):1357e69. http://dx.doi.org/10.1111/j.1528-
154. Johnston MV, Hoon AH. Possible mechanisms in infants for 1157.1999.tb02006.x.
selective basal ganglia damage from asphyxia, kernicterus, 170. Stafstrom CE, Sasaki-Adams DM. NMDA-induced seizures in
or mitochondrial encephalopathies. J Child Neurol developing rats cause long-term learning impairment and
2000;15(9):588e91. http://dx.doi.org/10.1177/ increased seizure susceptibility. Epilepsy Res
088307380001500904. 2003;53(1e2):129e37. http://dx.doi.org/10.1016/S0920-
155. Rocha-Ferreira E, Hristova M. Plasticity in the neonatal brain 1211(02)00258-9.
following hypoxic-ischaemic injury. 2016. p. 2016. http:// 171. Galanopoulou AS, Moshe SL. Pathogenesis and new
dx.doi.org/10.1029/2005JE002426. candidate treatments for infantile spasms and early life
156. Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, Van epileptic encephalopathies: a view from preclinical studies.
Emde Boas W, et al. Revised terminology and concepts for Neurobiol Dis 2015;79:135e49. http://dx.doi.org/10.1016/
organization of seizures and epilepsies: Report of the ILAE j.nbd.2015.04.015.
Commission on Classification and Terminology, 2005-2009. 172. Fosi T, Chu C, Chong WK, Clark C, Scott RC, Boyd S, et al.
Epilepsia 2010;51(4):676e85. http://dx.doi.org/10.1111/j.1528- Quantitative magnetic resonance imaging evidence for
1167.2010.02522.x. altered structural remodeling of the temporal lobe in West
157. Lujan R, Shigemoto R, Lopez-Bendito G. Glutamate and syndrome. Epilepsia 2015;56(4):608e16. http://dx.doi.org/
GABA receptor signalling in the developing brain. 10.1111/epi.12907.
Neuroscience 2005;130(3):567e80. http://dx.doi.org/10.1016/ 173. Widjaja E, Go C, McCoy B, Snead OC. Neurodevelopmental
j.neuroscience.2004.09.042. outcome of infantile spasms: a systematic review and meta-
158. Herlenius E, Lagercrantz H. Development of neurotransmitter analysis. Epilepsy Res 2015;109(1):155e62.
systems during critical periods. Exp Neurol 2004;190(Suppl. 174. Wiesel TN, Hubel DH. Responses in striate deprived of vision
1):8e21. http://dx.doi.org/10.1016/j.expneurol.2004.03.027. cortex of one Eye1. J Neurophysiol 1963;26:1003e17.
159. Dzhala VI, Talos DM, Sdrulla DA, Brumback AC, 175. Wiesel TN. Medical School, Boston, Massachusetts 02115, U.S.A.
Mathews GC, Benke TA, et al. NKCC1 transporter facilitates 1970. p. 419e36.
seizures in the developing brain. Nat Med 176. Knudsen EI. Sensitive periods in the development of the
2005;11(11):1205e13. brain and behavior. J Cogn Neurosci 2004;16(8):1412e25.
160. Sipila ST. Depolarizing GABA Acts on intrinsically bursting http://dx.doi.org/10.1162/0898929042304796.
pyramidal neurons to drive giant depolarizing potentials 177. Barth AL. Differential plasticity in neocortical networks.
in the immature Hippocampus. J Neurosci Physiol Behav 2002;77(4e5):545e50. http://dx.doi.org/10.1016/
2005;25(22):5280e9. http://dx.doi.org/10.1523/ S0031-9384(02)00932-0.
JNEUROSCI.0378-05.2005. 178. Hensch TK. Critical period regulation. Annu Rev Neurosci
161. Khalilov I, Minlebaev M, Mukhtarov M, Khazipov R. Dynamic 2004;27(1):549e79. http://dx.doi.org/10.1146/
changes from depolarizing to hyperpolarizing GABAergic annurev.neuro.27.070203.144327.
actions during giant depolarizing potentials in the neonatal 179. Hensch TK, Bilimoria PM. Re-opening windows:
rat hippocampus. J Neurosci 2015;35(37):12635e42. http:// manipulating critical periods for brain development.
dx.doi.org/10.1523/JNEUROSCI.1922-15.2015. Cerebrum 2012;2012(August):11.
180. Levelt CN, Hubener M, Hübener M. Critical-period plasticity 196. Krishnan K, Wang B-S, Lu J, Wang L, Maffei A, Cang J, et al.
in the visual cortex. Annu Rev Neurosci 2012;35(May):309e30. MeCP2 regulates the timing of critical period plasticity that
http://dx.doi.org/10.1146/annurev-neuro-061010-113813. shapes functional connectivity in primary visual cortex. Proc
181. Chugani HT, Kumar A, Muzik O. GABAA receptor imaging Natl Acad Sci U. S. A 2015;112(34):E4782e91. http://dx.doi.org/
with positron emission tomography in the human newborn: 10.1073/pnas.1506499112.
a unique binding pattern. Pediatr Neurol 2013;48(6):459e62. 197. Mcintyre S, Badawi N, Goldsmith S, Hines M, Karlsson P,
http://dx.doi.org/10.1016/j.pediatrneurol.2013.04.008. Novak I, et al. Australian cerebral palsy registre report 2013. 2013.
182. Chugani DC, Muzik O, Juhasz C, Janisse JJ, Ager J, 198. Reid LB, Rose SE, Boyd RN. Rehabilitation and neuroplasticity
Chugani HT. Postnatal maturation of human GAB(A) in children with unilateral cerebral palsy. Nat Rev Neurol
receptors measured with positron emission tomography. 2015;11(7):390e400. http://dx.doi.org/10.1038/
Ann Neurol 2001;49(5):618e26. nrneurol.2015.97.
183. Kujala J, Jung J, Bouvard S, Lecaignard F, Lothe A, Bouet R, et al.
Gamma oscillations in V1 are correlated with GABAA receptor
density: a multi-modal MEG and Flumazenil-PET study. Sci Glossary
Rep 2015;5:16347. http://dx.doi.org/10.1038/srep16347.
184. Harrison RV, Gordon KA, Mount RJ. Is there a critical period [Cl-]: Chloride concentration
for cochlear implantation in congenitally deaf children? AED: antiepileptic medications
Analyses of hearing and speech perception performance AMPA: a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
after implantation. Dev Psychobiol 2005;46(3):252e61. http:// receptor
dx.doi.org/10.1002/dev.20052. Arc: activity-regulated cytoskeleton-associated protein
185. Holmes JF, Dagi LR, Donahue SP, Ph D, Marcela G, Hertle RW, ARX: Aristaless-related homeobox gene
et al. NIH Public Access129; 2012. p. 1451e7. http://dx.doi.org/ AS: Angelman syndrome
10.1001/archophthalmol.2011.179.Effect. 11. ASD: Autism spectrum disorders
186. Baroncelli L, Scali M, Sansevero G, Olimpico F, Manno I, BDNF: Brain-derived neurotrophic factor
Costa M, et al. Experience affects critical period plasticity in CDKL5: Cyclin dependent kinase like 5
the visual cortex through an epigenetic regulation of histone CMCT: Central motor conduction time.
post-translational modifications. J Neurosci CNS: central nervous system
2016;36(12):3430e40. http://dx.doi.org/10.1523/ CP: Cerebral palsy
JNEUROSCI.1787-15.2016. CST: Corticospinal tract
187. Vetencourt JFM, Tiraboschi E, Spolidoro M, Castrn E, cTBS: continuous theta burst stimulation
Maffei L. Serotonin triggers a transient epigenetic DBS: Deep brain stimulation
mechanism that reinstates adult visual cortex plasticity in DTI: Diffusion tensor imaging
rats. Eur J Neurosci 2011;33(1):49e57. http://dx.doi.org/ DYT1: primary monogenetic dystonia
10.1111/j.1460-9568.2010.07488.x. EEG: electroencephalogram
188. Hensch TK. Critical period plasticity in local cortical circuits. EES: Epileptic Encephalopathy syndromes
Nat Rev Neurosci 2005;6(11):877e88. http://dx.doi.org/10.1038/ EphA4/EphrinB3: axon guidance molecules
nrn1787. Ephexin-5: protein that negatively regulates excitatory synapse
189. Davis MF., Figueroa DX., Carathedathu MC., Gandhi SP., FMRP: Fragile X mental retardation Protein
Velez DXF., Guevarra RP., et al. Inhibitory neuron FXS: Fragile X syndrome
transplantation into adult visual cortex creates a new GABA-A: Gamma-Aminobutyric acid A receptor
critical period that rescues article inhibitory neuron GABA: Gamma-Aminobutyric acid
transplantation into adult visual cortex creates a new GAD67: glutamic acid decarboxylase enzyme
critical period that rescues impaired vision. Neuron; GDP: giant depolarizing potentials
86(4):1055e1066. Doi: 10.1016/j.neuron.2015.03.062. GluN2A: Glutamate [NMDA] receptor subunit epsilon-1
190. Pernet V, Schwab ME. The role of Nogo-A in axonal GluN2B: Glutamate [NMDA] receptor subunit epsilon-2
plasticity, regrowth and repair. Cell Tissue Res HCN1: hyperpolarization-activated cyclic nucleotide-gated
2012;349(1):97e104. http://dx.doi.org/10.1007/s00441-012- channel 1
1432-6. HIE: hypoxic ischemic encephalopathy
191. Thompson B, Mansouri B, Koski L, Hess RF. From motor HMG-Co A reductase: 3-hydroxy-3-methyl-glutaryl-coenzyme A
cortex to visual cortex: the application of noninvasive brain reductase enzyme
stimulation to amblyopia. Dev Psychobiol 2012;54(3):263e73. ICI: Intracortical inhibition
http://dx.doi.org/10.1002/dev.20509. ID: Intellectual disability
192. Robinson K. Implications of developmental plasticity for the IGF-1: Insulin-like growth factor-1
language acquisition of deaf children with cochlear iPSC: induced pluripotent stem cells
implants. Int J Pediatr Otorhinolaryngol 1998;46(1e2):71e80. IS: Infantile spasms
193. Niechwiej-Szewdo E, Chin J, Wolfe PJ, Popovich C, KCC2: Chloride exporter
Staines WR. Abnormal visual experience during KCNQ2: Voltage-gated potassium channel (KV7.2)
development alters the early stages of visual-tactile L-Dopa: L-3,4-dihydroxyphenylalanine
integration. Sci Rep 2016;304:111e9. http://dx.doi.org/ LTD: Long term depression
10.1016/j.bbr.2016.02.018. LTP: Long term potentiation
194. Kral A. Neuroscience forefront review auditory critical MeCP2: Methyl-CpG-binding protein 2
periods: a review from system's perspective. Neuroscience MEG: Magnetoencephalography
2013;247:117e33. http://dx.doi.org/10.1016/ Mg: Magnesium
j.neuroscience.2013.05.021. MRI: Magnetic Resonance Imaging
195. Friedmann N, Rusou D. Critical period for first language: the MRS: Magnetic Resonance spectroscopy
crucial role of language input during the first year of life. mTOR: mammalian Target Of Rapamycin
Curr Opin Neurobiol 2015;35:27e34. http://dx.doi.org/10.1016/ NF-1: Neurofibromatosis type 1
j.conb.2015.06.003. NKCC1: Chloride importer
NMDA: N-methyl-D-aspartate receptor SICI: Short intracortical inhibition

OTX2: Orthodenticle Homeobox 2 SLC25A22: Solute Carrier Family 25 (Mitochondrial Carrier:
P13K-mTOR: phosphoinositide 3-kinase-mammalian target of Glutamate)
Rapamycin SP: Silent period
PCDH19: Protocadherin 19 SSRI: Selective serotonin reuptake inhibitor
PD: Parkinson's disease STXBP1: Syntaxin Binding Protein 1
PET: Positron emission tomography TBI: Traumatic brain injury
PMS: Phelan-McDermid syndrome tDCS: transcranial direct current stimulation
RI: Reciprocal inhibition TMS: Transcranial magnetic stimulation
rsfMRI: resting state functional MRI TOR1A: Gene encoding for torsin A protein
rTMS: repetitive TMS TrkB1: Tropomyosin receptor kinase B signaling pathway
SCN1A: Sodium channel, voltage-gated, type I, alpha subunit TSC: Tuberous sclerosis complex
SHANK 3: SH3 and multiple ankyrin repeat domains 3 UBE3A gene: ubiquitin protein ligase E3A gene

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e u r o p e a n j o u r n a l o f p a e d i a t r i c n e u r o l o g y 2 1 ( 2 0 1 7 ) 2 3 e4 8

Official Journal of the European Paediatric Neurology Society

Cerebral plasticity: Windows of opportunity in the

Fatima Yousif Ismail a,b,*, Ali Fatemi c, Michael V. Johnston c

1. Introduction achieved by modulating subsets of genetic, molecular and

Normal Impaired Experience- Post sensory Dystonia HIE

Synaptogenesis Synapse Signaling

Prerequisites Open CriƟcal and SensiƟve Periods Prerequisites Closed

GeneƟc Molding and EpigeneƟc ModulaƟon

GeneƟc EpilepƟc Syndromes

Latent Period IIP IIP IIP Refractory Epilepsy

SensiƟve or criƟcal period(s) for progressive epileptogenesis? Too late to intervene?

GeneƟc Molding and EpigeneƟc ModulaƟon

Behavioral Pharmacological Electrical Cell-based

• Training-based • CNS acƟve • DBS • rTMS • Stem cell

in our understanding of young brain plasticity. We strongly

NMDA: N-methyl-D-aspartate receptor SICI: Short intracortical inhibition

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