1846

CLINICAL IMPLICATIONS OF BASIC RESEARCH

Neuroplasticity: An Appreciation From Synapse to System

Bernadette T. Gillick, PhD, MS, PT, Lance Zirpel, PhD
ABSTRACT. Gillick BT, Zirpel L. Neuroplasticity: an
appreciation from synapse to system. Arch Phys Med Re-
habil 2012;93:1846-55.
Objective: To integrate our functional knowledge in neurore-
habilitation with a greater understanding of commonly held
theories and current research in neuroplasticity.
Design: Literature review.
Setting: Not applicable.
Participants: Animal and human research.
Interventions: Interventions specific to application in hu-
mans: constraint-induced movement therapy, transcranial mag-
netic stimulation, and transcranial direct current stimulation.
Main Outcome Measures: Cortical excitability, blood oxygen
level– dependent signal, and functional outcomes.
Results: There is increasing evidence elucidating the cellular
and molecular mechanisms of plasticity of the nervous system
including growth, modification, degradation, and even death of
neurons. Some of these mechanisms directly correlate with ther-
apy-induced behavioral changes, and all provide an understanding
of the response of the nervous system to altered inputs. The
understanding of neural correlates of behavior can then form the
foundation for more productive, comprehensive interventions.
Conclusions: The focus of recent research surrounds transla-
tional projects aimed at enhancing clinical outcomes. Knowl-
edge of mechanisms underlying this adaptability is the foun-
dation for our treatments, diagnoses, and prognoses. The
increasing understanding of the mechanisms underlying neu-
roplasticity can guide, direct, and focus the practice of current
and future therapies to greater efficacy and better functional
outcomes in clinical rehabilitation.
Key Words: Gamma-aminobutyric acid; Magnetic reso-
nance imaging; Motor cortex; N-methylaspartate; Receptors,
glutamate; Rehabilitation; Transcranial magnetic stimulation;
Transcription, genetic.
© 2012 by the American Congress of Rehabilitation
Medicine
coined “synapses.”1-3 In 1949, a Canadian psychologist, Don-
ald Hebb, postulated that if the activity between the presynaptic
terminal of one neuron and the postsynaptic terminal of another
was coordinated, their connection strengthens. Hebb’s postu-
late states that neurons that fire together, wire together.4 The
relation is one of synaptic strength, efficiency, and improved
functional performance in the location of the brain in which
such change is induced by the concomitant activity.
BACKGROUND PHYSIOLOGY
Neurotransmitters
Two major brain neurotransmitters are glutamate and ␥-ami-
nobutyric acid (GABA).5 Glutamate is excitatory with specific
receptors dictating the effect on the postsynaptic neuron. Glu-
tamate can produce excitatory (depolarizing) responses (excit-
atory postsynaptic potentials [EPSPs]) in the postsynaptic neu-
ron. These responses can change the concentration of key
messenger ions, such as calcium (Ca2⫹), and hence influence
virtually every aspect of cell function, including gene transcrip-
tion and survival.
GABA serves as the brain’s major inhibitory neurotransmit-
ter, producing inhibitory postsynaptic potentials (IPSPs)
through specific receptors on postsynaptic neurons. The action
of GABA on the postsynaptic receptors can cause ions, such as
chloride (Cl⫺), to flow across the postsynaptic membrane,
producing a hyperpolarization of the cell. Therefore, the cell
membrane potential moves away from the threshold cell mem-
brane potential that would initiate an action potential, thus
“inhibiting” the postsynaptic cell. EPSPs increase and IPSPs
decrease the probability of an action potential’s occurring in
the postsynaptic neuron.
List of Abbreviations
AMPA ␣-amino-3-hydroxyl-5-methyl-4-isoxazole
propionate

A T THE TURN OF THE 20th century, a Spanish histolo-

gist, Santiago Ramón y Cajal, expanded our understanding
of the central nervous system. His work revealed (1) the
BDNF
CaMK
CIMT
brain-derived neurotrophic factor
calcium/calmodulin-dependent kinase
constraint-induced movement therapy
existence of an axonal growth cone and dendritic spines; and CREB cyclic adenosine monophosphate response
(2) that neurons are each distinctly separate, communicating element-binding protein
via what Charles Sherrington, a British physiologist, earlier EPSP excitatory postsynaptic potential
fMRI functional magnetic resonance imaging
GABA ␥-aminobutyric acid
HABIT hand-arm intensive bimanual therapy
From the Department of Physical Medicine and Rehabilitation, Program in Physical IHI interhemispheric inhibition
Therapy, University of Minnesota Medical School, Minneapolis, MN (Gillick); and IPSP inhibitory postsynaptic potential
the Graduate Nurse Anesthesia Program, Schools of Graduate and Professional
LTD long-term depression
Programs, Saint Mary’s University of Minnesota, Minneapolis, MN (Zirpel).
Supported in part by a Promotion of Doctoral Studies II Scholarship from the LTP long-term potentiation
Foundation for Physical Therapy. MEP motor-evoked potential
No commercial party having a direct financial interest in the results of the research NGF nerve growth factor
supporting this article has or will confer a benefit on the authors or on any organi-
NMDA N-methyl-D-aspartate
zation with which the authors are associated.
Reprint requests to Bernadette T. Gillick, PhD, MS, PT, 420 Delaware St SE-MMC PMF pulsed magnetic field
388, Minneapolis, MN 55455, e-mail: gillick@umn.edu. rTMS repetitive transcranial magnetic stimulation
In-press corrected proof published online on Jun 26, 2012, at www.archives-pmr.org. tDCS transcranial direct current stimulation
0003-9993/12/9310-00093$36.00/0 TMS transcranial magnetic stimulation
http://dx.doi.org/10.1016/j.apmr.2012.04.026

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 NEUROPLASTICITY: SYNAPSE TO SYSTEM, Gillick
A human subjects study by Butefisch et al6 used drugs that
modify receptor function typically involved in neuroplasticity.
The action at a specific receptor can be either enhanced or
thwarted by pharmacologic intervention. Lorazepam enhances
the function of GABA receptors. Such enhancement of GABA-
mediated inhibition blocks increases in synaptic strength and
the potential for plasticity through increased neuronal activity.
In contrast, dextromethorphan blocks N-methyl-D-aspartate
(NMDA) receptors, a specific subtype of glutamate receptor.
NMDA receptors contribute to an increase in synaptic strength
by affecting ion flow and further receptor construction and
function in a cell.6 Performance in a thumb movement task was
analyzed through responses to transcranial magnetic stimula-
tion (TMS) and resultant motor-evoked potentials (MEPs). By
administering lorazepam (enhancing inhibition) and dextro-
methorphan (blocking excitation), the induction of neuroplastic
change, as well as the resulting improvement in the motor task
performance, was thwarted, thus highlighting the critical role
of these neurotransmitters and their receptors in the adaptabil-
ity—plasticity— of the human brain. Therefore, by manipulat-
ing the cell pharmacologically, the mechanisms underlying
plasticity can be revealed.
Receptors and Ions
Central nervous system long-term potentiation (LTP) and
long-term depression (LTD) are terms used to describe modi-
fications of synaptic efficacy. In the early 1970s, researchers
performed electrophysiologic studies of the rodent hippocam-
pus, a brain region implicated in learning and memory.7 Spe-
cific frequencies of stimulation of the axons in 1 area of the
hippocampus, the CA3 pyramidal neurons, resulted in a
long-lasting increase in EPSP amplitude in postsynaptic
neurons located in the CA1 hippocampal area. With high-
frequency stimulation, there was a long-lasting change in the
postsynaptic neuronal response to a subsequent stimulus
identical to a stimulus applied before the high-frequency
stimuli. How do such changes occur? Two types of gluta-
mate receptors, ␣-amino-3-hydroxyl-5-methyl-4-isoxazole
propionate (AMPA) and NMDA, underlie the mechanism.
In figure 1A, the postsynaptic AMPA receptor binds gluta-
mate released from the presynaptic neuron after the arrival of
an action potential in the synaptic terminal. Influx of sodium
ions (Na⫹) resulting in depolarization of the postsynaptic cell
occurs. AMPA receptor action does not depend on the state of
depolarization of the postsynaptic cell. The NMDA receptor
has a magnesium ion (Mg2⫹) blocking the receptor channel,
but when the postsynaptic cell is depolarized, the Mg2⫹ is
expelled, allowing influx of Ca2⫹ on concomitant glutamate
binding. Calcium has important second messenger capabilities
and is highly regulated in the extracellular and intracellular
fluids.8
Simultaneous activation of NMDA receptors and postsynap-
tic cell depolarization (mediated in the hippocampus by gluta-
mate activation of AMPA receptors) leads to an enhanced
response to a subsequent stimulus.9
Ca2⫹ influx can activate protein kinases— enzymes that fa-
cilitate a modulatory addition of a phosphate group to certain
proteins (fig 1B). Calcium/calmodulin-dependent kinase (CaMK)
can modulate numerous activities of the neuron that ultimately
lead to the transcription, translation, and insertion of new AMPA
receptors. Thus, the new AMPA receptors can increase synap-
tic strength after increased activity.10 Considered a long-term
mechanism, cyclic adenosine monophosphate response ele-
ment-binding protein (CREB) is a transcription factor activated
by Ca2⫹-dependent enzymes, including a particular isoform of
CaMK. Activated CREB mediates gene transcription, the for-
1847
mation of new proteins, changes in the connectivity between
neurons, and ultimately, synaptic plasticity.11 Protein synthesis
is a key contributor to regeneration of cellular structures. As an
important feature of neuroplasticity, the dendritic spines of
neurons, where most glutamatergic synapses are located, may
increase in number, length, and size, creating an environment
for improved synaptic communication and activation of the
neuron. New dendritic spines reveal new synapses, with in-
creased ability to encode new information.12
Plasticity does not always result in synthesis of new proteins.
In contrast to our discussion of LTP, it has been found that if
a neuron receives low-frequency stimulation, a low-amplitude
increase in calcium causes activation of phosphatases that
affect the activity of various proteins and enzymes by removing
the modulatory phosphate group previously attached by kinases
(fig 1C). These effects cause a cascade of events that can
culminate with internalization (removal from the membrane) of
AMPA receptors that can actually decrease, or cause long-term
depression of, synaptic strength.13 Depression is the opposite
effect of potentiation in that a test stimulus given after the
low-frequency stimulation is smaller in amplitude than the
same stimulus given before the low-frequency pulse. This
process of LTD therefore contributes to a reduction in the
efficacy of synaptic transmission (notably different than the
inhibition described for GABA).
The receptors, ions, and influences they produce create the
basis for long-term changes in neuronal communication. LTP
and LTD reveal modifications to synaptic efficacy manifested
by changes in functional protein expression. The transcription
of glutamate receptor genes, as evidenced by the appearance
of AMPA receptors in LTP, may also be involved.14 In a
study by Shi et al,14 high-frequency stimulation of cultured
hippocampal neurons resulted in an increase of AMPA
receptors in dendritic spines, suggesting contribution to
“activity-dependent plasticity.”
Magnetic Influence on Cell Development
Investigation of the application of magnetic force influenc-
ing the brain and neuronal process regeneration has also been
performed using in vitro cell cultures.15-18 Kim et al18 were
able, using nerve growth factor (NGF), to stimulate the growth
of neurites, which are projections from developing cell bodies
that become axons or dendrites. Under constant magnetic force,
the neurites were influenced in direction of growth, although no
differences were found compared with controls in the quantity
of neurofilament (an indicator of process growth) or changes in
synaptic formation.
Macias et al15 found that pulsed magnetic stimulation influ-
enced and directed axonal growth. Cultured mammalian cells
displayed increased neurite growth in the presence of both
NGF and a pulsed magnetic field (PMF). The use of NGF alone
enhanced neurite growth, yet PMF created “polarized” out-
growth, suggesting influence of directionality. PMF also influ-
enced neurite outgrowth length.
In vitro neurons have also been stimulated using magnetic
fields.17 With the use of rat hippocampal cells, it was found that
cells that were excitable had a threshold of action potential
firing at least 2 times lower than control neurons. Although one
must use caution directly correlating culture environments with
studies of the functioning human brain, information regarding
potential growth vehicles, influence of direction, and numbers
of potential cells that can be stimulated allow us further insight
into the plastic capabilities of the nervous system.
Arch Phys Med Rehabil Vol 93, October 2012
1848 NEUROPLASTICITY: SYNAPSE TO SYSTEM, Gillick

A. SYNAPSE ON DENDRITIC SPINE

Synapse

Glutamatergic Synapse

Glutamate

PRE-SYNAPTIC TERMINAL

AMPA Receptor NMDA Receptor

POST-SYNAPTIC MEMBRANE

Na+ Mg 2+
Ca2+
(EJECTED)
Glu
Glu
Depolarization + Glutamate

+
Na Intracellular Depolarization Ca 2+ Entry

B. LTP C. LTD
High Frequency Activity Low Frequency Activity
Postsynaptic Membrane Postsynaptic Membrane
Ca 2+ Mg 2+
Ca 2+ Mg 2+
AMPA AMPA
Glu Glu
NMDA NMDA

Activation [ ] Activation
[ ]
Synthesis and of Kinases
Internalization of Phosphatases
insertion of new
AMPA Receptors of AMPA Receptors

AMPA NMDA AMPA NMDA

Additional AMPA Receptors increase Fewer AMPA Receptors decrease

synaptic strength and responsiveness synaptic strength and responsiveness to
to glutamate glutamate

Fig 1. Mechanisms of synaptic change between 2 neurons. Abbreviations: Ca2ⴙ, calcium ion; Glu, glutamate; Mg2ⴙ, magnesium ion; Naⴙ,
sodium ion.

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 NEUROPLASTICITY: SYNAPSE TO SYSTEM, Gillick
ASSESSMENT OF NEUROPLASTICITY
Techniques derived from bench science influence rehabili-
tation and are the basis for current translational clinical science
in neuroplasticity. We are cautioned, however, to recognize
that neural plasticity is defined by the observation of change in
neuronal structure or function, not the observation of change in
behavior. We can extrapolate from animal studies and apply
similar principles to the sensory and motor cortex of humans,
and begin to sort out the underpinnings related to neuroplas-
ticity resulting in improved function in rehabilitation.19
Neuronal Electrical Activity
Extracellular recording measures the electrical activity of the
neurons using a nearby microelectrode. Single-unit extracellu-
lar recording and intracellular microelectrodes allow for the
monitoring and measuring of the electrical activity of a single
neuron. A neuron’s receptive field, or the region defined by the
electrical response to a stimulus, allows exploration of both the
sensory and motor systems.20
A series of works by and about Hubel and Wiesel21-27
opened the topic of neuroplasticity and continues to influence
research. Using single-cell recordings from cat visual cortex,
these scientists explored the environmental influence on visual-
response properties of the central nervous system. This work
addressed at-birth capabilities of the visual system and central
visual components to adapt to changes in the activity impinging
on them—the plasticity of the visual system. Monocular visual
deprivation, achieved by suturing the eyelid closed, was per-
formed in young kittens just before the normal period of eye
opening. The sutured eye was opened at 3 months of age, and
the retinal axons and target thalamic nucleus, the lateral genic-
ulate nucleus, were analyzed using single-neuron or single-cell
recordings. The lateral geniculate nucleus neurons had some
similar characteristics to those of adult cats without a period of
visual deprivation (normal controls). However, when corre-
sponding thalamic layers of the visually deprived kittens were
analyzed, few single-cell responses could be evoked. Histolog-
ically, distinct cell shrinkage from that particular visual layer
was observed. By studying adult cats that had experienced
monocular deprivation during this same period as kittens, input
to the visual cortex was found to come primarily from the eye
that remained open.28 However, if adult cats had been monoc-
ularly deprived only during their adult life, the input to the
visual cortex was not altered, showing normal binocular re-
sponses. This critical period, when the visual cortex required
afferent visual input to develop normal connection patterns,
proved crucial for normal visual function of those cortical
neurons. These studies demonstrated robust developing brain
plasticity with persistent effects into adulthood, yet the same
adult brain plasticity was not evident.
Studies in adult primates have shown evidence for plasticity.
With the use of intracortical microstimulation in the motor
cortex, maps of the distal forelimb representation from the
primary motor area in brains of adult squirrel monkeys were
obtained before and after task-specific training of a forelimb
motor task.29,30 As the task became more specific to finger
extension and flexion, so did the mapped cortical representa-
tion. Accordingly, the relative mapped area representing not
the fingers but the wrist decreased. After an increasingly
smaller food-pellet removal task, wherein the digital use was
manipulated and isolated, the area of digital representation
increased. After training on a specific forelimb supination/
pronation task, the area in the cortex representing the forearm
expanded. This strengthened neuronal cell assembly could pro-
vide a stronger drive to the neighboring neurons and result in
1849
synchronous firing and an increased representational area in the
cortex. This study demonstrates the potential for change in the
mature brain during the acquisition of a novel task.
In a similar study31 focusing on the somatosensory cortex,
changes in brain representation of the hand were explored
using a grid of electrodes. In this study, adult monkeys re-
sponded to a stimulus over the course of 4 to 6 weeks by
pressing a bar that crossed digits 2 through 4. In this manner,
the digits were not acting independently but as a whole. In
untrained monkeys, each digit had its own representation. In
trained monkeys, cortical mapping revealed multidigit recep-
tive fields that may have unmasked a function not previously
used. Through the ability of science to measure in vivo re-
sponse to stimulation, the revised cortical maps after alteration
in activity allow exploration of that change.
Functional Magnetic Resonance Imaging
Functional magnetic resonance imaging (fMRI) is a nonin-
vasive method of measuring the brain’s blood oxygen level–
dependent response to changes in cortical activity and oxygen
demand.32 Hemodynamic changes in fMRI responses have
shown simultaneous intracortical recordings of neural signals
representing intracortical processing of a region.33,34 Most typ-
ically, a subject performs a cognitive, sensory, or motor task
while in the scanner, and the fMRI images are collected and
compared, giving an indication of changes in neuronal activity.
fMRI can be used to examine brain activity concurrent with
changes in behavioral activity. In a study involving a form of
behavioral intervention, constraint-induced movement therapy
(CIMT), and a 2-week home-based therapy program in people
with stroke, Johansen-Berg et al35 found that improvements in
hand function correlated significantly with increases in fMRI
activity in the premotor cortex and somatosensory cortex con-
tralateral to the affected hand. A pediatric study by Sutcliffe et
al36 found clinical improvements in scores on the Pediatric
Motor Activity Log as well as evidence of cortical reorgani-
zation by fMRI and magnetoencephalography.37 Resting state
fMRI allows analysis of the brain and connectivity between
neural networks at a state of relative rest. Synchronized
changes in the blood oxygen level– dependent signal are as-
sumed to be an indication of the functional connectivity be-
tween brain areas, and distortion of the cortical interhemi-
spheric function of the brain can therefore be identified.38
Transcranial Magnetic Stimulation
In 1985, Barker et al39,40 discovered a noninvasive, painless
technique of using a changing magnetic field to induce small
intracranial electrical current in the membrane of the neural
tissue of the brain. TMS began as a test for excitability of the
brain. The brain’s ability to respond to TMS through the
corticospinal tract can be measured using MEPs with surface
electromyogram electrodes positioned over specific target mus-
cles (fig 2). The amplitude of the response and the threshold
that is required to elicit that response can be assessed for
change.
TMS has now been used experimentally in exploring neu-
roplasticity through brain reorganization after performance of
specific tasks or after injury or insult.41,42 A study by Wheaton
et al43 investigated the effects of treadmill walking on the
quadriceps and corticospinal activation in adults with hemipa-
resis resulting from stroke by using TMS. The quadriceps
muscle of the paretic limb revealed decreased MEP amplitudes
and increased thresholds at baseline. The treadmill-trained pa-
tients showed increases in paretic-side MEP amplitudes. TMS
was therefore used as a testing mechanism to explore the
Arch Phys Med Rehabil Vol 93, October 2012
1850 NEUROPLASTICITY: SYNAPSE TO SYSTEM, Gillick

Fig 2. TMS. (A) Individual receiving TMS testing. (B) Motor-evoked response as indicated by electromyogram.

integrity of the central motor pathways. A study by Eyre et al44 assessment scores. This study suggests that perhaps not only
investigated development of the corticospinal tract in both training the affected extremity leads to improvement, but in-
normal and neurologically impaired subjects. Healthy subjects corporating the unaffected upper extremity adds to recovery of
showed larger-amplitude contralateral MEPs than ipsilateral
MEPs. This allowed exploration of central changes or plasticity
that occurs during typical development. In subjects with uni-
lateral lesions, the presence of an initial MEP was subsequently
lost in 50% of the children studied, and thresholds were sig-
nificantly greater than those in control subjects. TMS allows a
manner of investigating this change and contributing to our
understanding of the brain’s ability to reorganize.
THERAPEUTIC INTERVENTIONS

Constraint-Induced Movement Therapy

Within the last 2 decades, hemiparesis has been treated using
CIMT with an emphasis on training of the affected limb cou-
pled with constraint of the unaffected limb (fig 3).45 In a
multicenter adult clinical trial, Wolf et al46 reported significant
gains from CIMT. Liepert et al47 documented therapy-associ-
ated changes of motor cortex excitability primarily in the
ipsilesional hemisphere of adult stroke patients. More recently,
a systematic review48 of 13 randomized clinical trials with 278
total patients summarizes the study authors’ findings in support
of CIMT as contributing to improved function of the paretic
upper extremity. Recent pediatric CIMT intervention has also
shown improved functional outcomes.49
Optimal CIMT dosaging has yet to be defined. A random-
ized multisite clinical trial50 explored outcomes in 18 children
with hemiparesis, aged 3 to 6 years, by varying the duration of
the treatment. All children received 21 days of CIMT yet were
randomly assigned to 1 of 2 groups: 3 or 6 total hours of CIMT
per day. Although all improved, no significant differences in
upper extremity function were found between the 2 groups.
Another form of upper extremity intervention called “hand-arm
intensive bimanual therapy” (HABIT), adopts the comparative
practice rigor of CIMT in bimanual training tasks, without
constraint. Comparing CIMT and HABIT, Gordon et al51
found similar improvement in children with hemiparesis in Fig 3. Child in CIMT. Note active use of the child’s right, affected
each group. However, the HABIT group revealed greater im- upper extremity while the left, unaffected upper extremity is con-
provement using the Goal Attainment Scale and caregiver strained by the cast.

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 NEUROPLASTICITY: SYNAPSE TO SYSTEM, Gillick
function. Furthermore, improvements in gross motor function
and gait have been seen after CIMT.52,53
Repetitive TMS
TMS used repeatedly in succession is called repetitive TMS
(rTMS). rTMS can be either excitatory or inhibitory, depending
on the parameters of the stimulation. High-frequency rTMS,
defined as a stimulation rate ⬎1Hz, produces an excitatory
after-effect. Conversely, low-frequency rTMS, defined as a
stimulation rate ⬍1Hz, can create a transient period of depres-
sion of cortical activity.54 The advantages of the use of 1
frequency rate may be beneficial to the lesioned hemisphere or
to the nonlesioned hemisphere, depending on the interplay
between the 2 hemispheres.
As a component of reorganization, a brain lesion may
disrupt the crossed corticospinal tract from the lesioned
cortical hemisphere to the contralateral, affected hand.
Therefore, the contralesional, ipsilateral hemisphere then
contributes to movement in a manner it might not have
previously or typically44,55,56 (fig 4). This type of reorgani-
zation may contribute to improvements in function of the limb
yet may also mask the potential capabilities of the ipsilesional
hemisphere. In a study by Kuhnke et al,56 TMS was used to test
corticospinal tract reorganization in congenital hemiparesis.
TMS allowed exploration of the ipsilesional or contralesional
hemispheric contributions to movement through assessment of
the presence (or absence) of an MEP through primary motor
cortex stimulation. The patients with hemiparesis involved in
the study then were classified as either ipsilaterally reorganized
or preserved crossed-corticospinal tracts. Subjects participated
in a CIMT, and although significant improvements in motor
function were observed in patients with both types of organi-
zation, the patients with more predominant ipsilateral, contra-
lesional projections through the use of TMS testing also
showed a reduction in the performance speed of the test task
(eg, more efficient digital activation).
Interhemispheric inhibition (IHI) is the typical inhibitory
interaction between the motor cortices of the right and left
hemispheres that occurs concomitant with corticospinal activa-
tion, allowing isolated movement. For example, as a person
activates the left motor cortex to move the right hand through
corticospinal pathways, interhemispheric pathways traversing
the corpus callosum are also activated and exert an inhibitory
effect on motor neurons in the right hemisphere (left hand).57
Heinen et al58,59 supported the presence of IHI in the age range
of 10 to 15 years in typically developing children, yet found
that it was not yet present in healthy preschool children with a
mean age of 4.6 years. In a study60 of healthy children aged 8
to 16 years, a significant decline in motor threshold and an
increase in intracortical or interhemispheric inhibition were
seen with increasing age.
The brain shows a remarkable ability to reorganize, espe-
cially after a neural insult or interruption resulting from a
reduction in GABA inhibition processes.61 Widespread inhib-
itory decreases in motor, sensory, and visual cortices have been
found in rat studies.61,62 Unfortunately, some reorganization
can be maladaptive and leave additional loss of function be-
yond that caused directly by stroke or neurologic insult.63 In
hemiplegia,64,65 motor neurons in the ipsilesional (stroke)
hemisphere that have survived the stroke can undergo a loss of
excitability because of exaggerated IHI imposed on them from
neurons in the contralesional (nonstroke) hemisphere66 (fig 5).
One explanation suggests an overuse of the nonparetic hand as
a compensatory reaction for the paretic hand.39 Another inter-
pretation suggests that instead of assuming that such increased
activation in the ipsilateral corticospinal projections is repara-
1851
tive, projections are “competitively displacing” surviving pro-
jections from the contralateral, infarcted cortex.44
Given the imbalance of IHI in both adult64 and pediatric65
hemiplegia with abnormally inhibited motor cortex in the ip-
silesional hemisphere and abnormally disinhibited motor cor-
tex in the contralesional hemisphere, different parameters of
rTMS can be applied to influence the imbalance. High-fre-
quency excitatory rTMS could be applied to the suppressed
ipsilesional hemisphere. Alternatively, low-frequency inhibi-
tory rTMS could be applied to the contralesional hemisphere.
The effectiveness of low-frequency rTMS to the contralesional
hemisphere has been studied in adult hemiplegia and shows
effectiveness in promoting motor recovery coupled with brain
reorganization.66,67
Transcranial Direct Current Stimulation
Transcranial direct current stimulation (tDCS) is another
type of noninvasive brain stimulation used as a neuromodula-
tory intervention. tDCS has shown beneficial behavioral ef-
fects68 and is more cost-effective and portable than rTMS.
tDCS acts by changing the spontaneous neuronal firing rate,
and therefore resting membrane threshold, influencing polar-
ization.69 One use of tDCS involves downregulating or inhib-
iting the excitability of the motor cortex in the contralesional
hemisphere and the influence it has on the ipsilesional hemi-
sphere, in an effort to upregulate excitability or disinhibit the
ipsilesional hemisphere. As is currently revealed using tDCS in
adults with stroke, applying cathodal tDCS to the contra-
lesional hemisphere can provide this inhibitory component,
leading to improved motor function.70
Antidepressants and Stimulants
Antidepressants and stimulants are frequently used in neu-
rorehabilitation. The pharmacologic effects of these medica-
tions on neuroplasticity should be considered. For example,
review articles have shown that antidepressants have been
found to promote neurogenesis, increase motor recovery of
function, and increase levels of brain-derived neurotrophic
factor (BDNF).71 BDNF is a protein secreted in the body that
acts to preserve nerve function and support nerve growth. The
effectiveness of stimulants such as dexamphetamine in con-
junction with physical therapy revealed significant improve-
ments in function after stroke in adults.72 Selective serotonin
reuptake inhibitors have also been shown to significantly in-
fluence motor function after stroke, perhaps through potentia-
tion of synaptic signaling and/or anatomic changes in neuronal
connectivity.73 Linking these pharmacologic agents experi-
mentally with improvements in neurorecovery shows the po-
tential for neuroplastic change induced by pharmacologic ma-
nipulation of neural activity and connectivity.
IMPLICATIONS
LTP is induced through the use of high-frequency stimula-
tion and results in long-lasting increases in EPSP amplitude.
Low-frequency stimulation produces LTD with the concomi-
tant decrease in excitability. Translating this knowledge, the
use of high-frequency or fast-pulse rTMS creates a state of
increased excitability in the brain that parallels high-frequency
stimulus induction of LTP on the cellular level, whereas low-
frequency or low-pulse rTMS acts in an inhibitory manner,
paralleling the low-frequency stimulus parameters that induce
LTD. This example of the application of a technique applied on
a cellular level in vitro and now applied on a systems level in
humans exemplifies incorporation of translational neuroscience
and neuroplasticity.
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1852 NEUROPLASTICITY: SYNAPSE TO SYSTEM, Gillick

Fig 4. Conceptual representation of MEPs and corticospinal tract integrity in 2 subjects. (A) Subject with porencephalic cyst. With the use
of TMS, no noted contralateral resting or active hand MEP was elicited in the ipsilesional hemisphere. MEP was elicited bilaterally by
contralesional hemisphere. Contralateral control to both upper extremities is represented by nonlesioned hemisphere (red line). (B) Subject
with birth-related middle cerebral artery ischemic infarct. Contralateral hand resting MEP was elicited in each hemisphere. Intact crossed
corticospinal tract integrity is represented by yellow and red lines, respectively.

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Fig 5. Exaggerated IHI and intervention. (A) Conventional transverse depiction of normal brain with right hemisphere on left. Right and left
primary motor areas (M1) are in gray. Arrows reflect balanced IHI. (B) Infarct (white square) in right M1 surrounded by peri-infarct zone (red
border), which is dysfunctional but can become functional if disinhibited. Compensatory behaviors with the nonparetic (right) hand directed
by contralesional (left) M1 result in overactivity of a portion of left M1 (dark gray circle), which increases the IHI from the left to the right (thick
arrow) and decreases excitability in some surviving neurons of ipsilesional (right) M1 (whitish gray ⴝ diaschisis). (C) Intervention includes
rTMS (energy bolt) to left M1 to disrupt excitability there combined with forced use of paretic hand and nonuse of nonparetic hand. (D)
Idealized outcome of disinhibited right M1 and associated rebalancing of IHI allowing function to return to peri-infarct zone (white square)
and adjacent gray matter but not to infarct itself.

A transient depression of activity on the undamaged hemi-
sphere may provide the opportunity for a damaged hemisphere
to increase neuronal activity and enhance recovery. CIMT may
inhibit overuse of the contralesional hemisphere, entreating the
ipsilesional hemisphere to become more actively involved in
use of the affected limb. The effect produced by rTMS or
CIMT may be the result of a decreased influence of GABA-
mediated inhibition from the nonlesioned hemisphere and an
overall reduction of exaggerated IHI.74 Emergent activity in the
affected limb may contribute to increased synaptic efficacy75
and synaptogenesis.76 Understanding neuroplasticity and
studying the potential benefit of interventions that may influ-
ence neuroplasticity can strengthen our appreciation of the
ability of the nervous system to change and our practice in
rehabilitation.
Acknowledgments: We thank Debbie Kartin, PT, PhD, for her
review of this manuscript, and Katie Tobin, BA, for her design work.
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