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Modulation of brain plasticity in stroke: A novel model for neurorehabilitation

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 REVIEWS
Modulation of brain plasticity in stroke:
a novel model for neurorehabilitation
Giovanni Di Pino, Giovanni Pellegrino, Giovanni Assenza, Fioravante Capone, Florinda Ferreri,
Domenico Formica, Federico Ranieri, Mario Tombini, Ulf Ziemann, John C. Rothwell and
Vincenzo Di Lazzaro
Abstract | Noninvasive brain stimulation (NIBS) techniques can be used to monitor and modulate the
excitability of intracortical neuronal circuits. Long periods of cortical stimulation can produce lasting effects
on brain function, paving the way for therapeutic applications of NIBS in chronic neurological disease. The
potential of NIBS in stroke rehabilitation has been of particular interest, because stroke is the main cause
of permanent disability in industrial nations, and treatment outcomes often fail to meet the expectations of
patients. Despite promising reports from many clinical trials on NIBS for stroke recovery, the number of studies
reporting a null effect remains a concern. One possible explanation is that the interhemispheric competition
model—which posits that suppressing the excitability of the hemisphere not affected by stroke will enhance
recovery by reducing interhemispheric inhibition of the stroke hemisphere, and forms the rationale for
many studies—is oversimplified or even incorrect. Here, we critically review the proposed mechanisms of
synaptic and functional reorganization after stroke, and suggest a bimodal balance–recovery model that
links interhemispheric balancing and functional recovery to the structural reserve spared by the lesion. The
proposed model could enable NIBS to be tailored to the needs of individual patients.
Di Pino, G. et al. Nat. Rev. Neurol. advance online publication 9 September 2014; doi:10.1038/nrneurol.2014.162

Introduction
Stroke is among the principal causes of death worldwide, The lack of effective neurorepair after stroke and the
and although most stroke survivors achieve at least some limitations of functional recovery attained by physio­
spontaneous recovery after the ictus, it remains the main therapy have led researchers to consider alternative
Institute of Neurology, cause of permanent disability in Europe and the USA.1–3 approaches that improve the scope for recovery by
Campus Bio-Medico The only existing treatment for stroke is tissue plasmino­ enhancing the natural plasticity of the sensorimotor
University, Via Álvaro
del Portillo 200,
gen activator, which can salvage tissue at risk in the system. If recovery depends on ‘relearning’ new patterns
00128 Rome, Italy penumbra of a brain infarct and reduce future disability of activity to maximize the use of remaining u ­ ndamaged
(G.D.P., G.P., G.A., F.C., if administered within a few hours after stroke onset.4 brain, interventions that increase plasticity, and thereby
F.F., F.R., M.T., V.D.L.).
Laboratory of No treatments specifically designed to restore function the ability to learn, should improve recovery. Two
Biomedical Robotics through repair of damaged tissue have been developed approaches are of great current interest: pharmaco­logical
and Biomicrosystem,
Center for Integrated to date. Current best practice in stroke management is to interventions and noninvasive brain stimulation (NIBS).
Research, Campus Bio- reduce initial impact, take precautions to avoid the further In this Review, we focus on NIBS. Although NIBS has
Medico University, Via
Álvaro del Portillo 28,
burden of complications, and maximize f­unctional ability been used to improve gait, neglect symptoms and lan­
00128 Rome, Italy through extensive physiotherapy. guage after stroke, we will concentrate here on its appli­
(D.F.). Department of Although early rehabilitative interventions can improve cation to recovery of arm and hand function, because
Neurology & Stroke,
and Hertie Institute for arm function above what would be achieved by natural most studies have assessed the efficacy of NIBS on upper
Clinical Brain Research, recovery alone,5 the majority of patients are still unable limb function.
Eberhard Karls-
University Tübingen,
to use the affected hand and/or arm for simple activities More than 350 articles have been published on trans­
Hoppe-Seyler-Strasse 3, of daily living 6 months after the stroke.6 Robot-assisted cranial stimulation in stroke since 2012. These include
D‑72076 Tübingen, therapy has been proposed as an excellent low-cost way to more than 50 small clinical trials that evaluated the
Germany (U.Z.). Sobell
Department of Motor increase the amount of therapy that an individual patient potential for NIBS to enhance recovery of hand and arm
Neuroscience and receives, because a robot can deliver a higher amount function. Recent meta-analyses disagree on the effective­
Movement Disorders,
UCL Institute of
of exercise in the same time than can a human physio­ ness of these techniques: two Cochrane reviews do not
Neurology, Queen therapist,7 but in controlled trials robot-assisted therapy support the use of repetitive transcranial magnetic stimu­
Square, London has shown disappointingly little additional benefit over lation (rTMS)10 or transcranial direct current stimu­lation
WC1N 3BG, UK (J.C.R.).
­conventional regimes of intensive physiotherapy.8,9 (tDCS)11 in stroke rehabilitation, whereas two other sys­
Correspondence to: tematic reviews conclude that NIBS can have a moder­
V.D.L.
V.DiLazzaro@ Competing interests ate benefit in terms of stroke recovery, with few major
unicampus.it The authors declare no competing interests. adverse effects.12,13 Here, we discuss the factors that have

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© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Key points
■■ Noninvasive brain stimulation (NIBS) is a promising approach to enhance
recovery after stroke, but its beneficial effect is limited and the technique is
not yet ready for broad clinical use
■■ We suggest that the disappointments in NIBS trials are related to over-reliance
on the interhemispheric competition and vicariation models of recovery, which
are oversimplified and do not apply to all patients with stroke
■■ The concept of ’structural reserve’ integrates the effects that interhemispheric
inhibition and vicariation exert on the unlesioned residual network
■■ We propose a unified ‘bimodal balance–recovery model’ that takes into account
this individual residual network
■■ The model could be used to tailor treatment for individual patients and increase
the efficacy of NIBS in stroke rehabilitation
Box 1 | TMS protocols for assessment of brain excitability and connectivity
TMS has been widely used to investigate excitability and connectivity in M1 after
stroke. Single-pulse, paired-pulse and repetitive TMS protocols probe different
aspects of excitatory and inhibitory function (Figure 1).
A single pulse of TMS applied over M1 can produce a peripheral muscular
response, or MEP. TMS that triggers MEPs is called suprathreshold TMS, whereas
TMS that is not of sufficient intensity to trigger MEPs is called subthreshold TMS.
The threshold and recruitment of MEPs at different intensities of stimulation
provide information about the level of corticospinal excitability.
The effect of GABA receptor type A‑modulated inhibitory circuits on corticospinal
neurons can be probed by short-interval intracortical inhibition paradigm
(Figure 1a).146,147 The role of GABA receptor type B‑expressing interneurons can be
probed by the controlateral cortical silent period protocol, in which a single TMS
pulse is delivered during tonic contralateral hand/arm contraction,148 or by the
long-interval intracortical inhibition protocol.149 Other inhibitory mechanisms can
be evaluated with short-latency afferent inhibition, which depends on GABAergic
and cholinergic circuits.150 Studies using these protocols have elucidated the
involvement of GABAergic circuits in intracortical inhibition,148,151,152 whereas
the origin and nature of the increased excitability of the intracortical facilitation
(Figure 1b) is still poorly defined.
TMS can also be paired with neuroimaging or electrophysiological techniques.153,154
TMS–EEG could aid probing of the functional impact of a stroke lesion on the
connectivity of the whole brain, even when the lesion is not located at the site of
stimulation.155 In TMS–EEG, a TMS pulse evokes an initial activation of the target
area, followed by later effects that are attributable to activity triggered by axonally
and synaptically propagated signals.145
Abbreviations: GABA, γ-aminobutyric acid; M1, primary motor cortext; MEP, motor evoked
potential; TMS, transcranial magnetic stimulation.
contributed to the slow progress of accepting NIBS as
a part of routine clinical practice, and suggest ways to
develop the use of NIBS in stroke rehabilitation.
Synaptic dysfunction in stroke
Noninvasive neuromodulatory strategies are thought to
alter synaptic efficacy in glutamatergic and γ-aminobutyric
acid-mediated (GABAergic) circuits,14 which are essen­
tial for motor learning. Knowing how stroke alters these
circuits, and determining the time course over which the
stroke-related changes occur, might aid the development
of more-effective n ­ euromodulatory strategies.
Brain infarcts lead to an imbalance in energy demand
and blood supply. The majority of energy consumed
by the brain is devoted to synaptic transmission and
the postsynaptic effects of glutamate,15 and interrup­
tion of synaptic transmission accounts for the electrical
silence in the penumbra after stroke.16,17 At the level of
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the gluta­matergic synapse, hypoxic failure leads to focal
post­synap­tic hyperpolarization18,19 followed by a massive
hypoxic depolarization of the postsynaptic terminal.20
Even though inhibitory synapses are more resistant to
hypoxia than are excitatory synapses,21 synaptic disinhib­
ition fails before synaptic excitation because of reduced
excitatory input to inhibitory interneurons,22 poten­
tially c­ ontributing to excitotoxicity that causes delayed
cell death.
During days and weeks following stroke, slower syn­
aptic changes can emerge. A critical period of approxi­
mately 90 days of increased synaptic plasticity is thought
to parallel the initial period of rapid behavioural recov­
ery.5,23 Two factors exert opposing effects during this
period. First, in mouse models of stroke, a sustained
increase in tonic GABAergic signalling—lasting over
a month—can reduce plasticity; during this period
behavioural recovery can be enhanced by blocking
extrasynaptic GABA receptors.24 Simultaneously, a sus­
tained increase in glutamatergic excitability mediated by
AMPA receptors promotes plasticity and the release of
­brain-derived neurotropic factor.25
Data from rodent studies have shown that stroke-
related changes can also involve brain regions in the
hemisphere unaffected by stroke. These changes
include bihemispheric reductions in phasic (synaptic)
GABAergic inhibition,26 in parallel with downregula­
tion of GABAA receptor binding and GABAA receptor
subunit expression.27 Changes in calcium currents have
also been demonstrated in the noninfarcted tissue of the
unaffected hemisphere.28
Excitability and connectivity in stroke
Several methods and protocols are available for assess­
ing the altered excitability and connectivity after stroke,
both in acute and chronic phases. (Box 1, Figure 1). In
this article, we have adopted the following classification
of the phases of stroke: hyperacute: the first 6 h post-
ictus; acute: 6–24 h post-ictus; subacute: 24 h to 6 weeks
­post-ictus; chronic: greater than 6 weeks post-ictus.12,29
During the acute phase after stroke, TMS of the
affected hemisphere is often unable to elicit motor
evoked potentials (MEPs), even at maximum deliverable
stimulation intensity. In patients with preserved MEPs,
the motor thresholds are generally higher and MEPs are
smaller compared with those recorded from the unaffec­
ted hemisphere or from healthy individuals. Within the
first few months, MEPs may reappear and gradually
increase in amplitude,30–33 while the motor threshold
tends to decrease.34–38 Many authors have reported that
TMS measures of corticospinal tract integrity evaluated
early after stroke,35,39–41 and the improvement of TMS
measures of corticospinal integrity during the first few
months33,39 of recovery, both correlate with the long-
term functional outcome. Absence of MEPs in the first
few hours or days following stroke is associated with
poor clinical recovery,42 although exceptions have been
reported.36,44–46 Presence or absence of MEPs in arm
muscles within the first week after stroke is an impor­
tant component of the ‘PREP algorithm’ proposed by
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a Subthreshold TMS TMS ◀ Figure 1 | TMS paired-pulse protocols. The approach is also
outlined in Box 1. a | TMS paired-pulse protocols for testing
– intracortical inhibitory circuitry. In SICI, a subthreshold TMS
1–5 ms
SICI ISI stimulus is followed by a subthreshold TMS pulse after a
Conditioning stimulus Test stimulus 1–5 ms delay. In LICI, a suprathreshold conditioning
TMS Suprathreshold TMS stimulus precedes the test stimulus by 50–200 ms. In cSP,
a TMS pulse is delivered during tonic contralateral hand/
– arm contraction. b | Intracortical facilitation is measured by
50–200 ms
LICI ISI ICF, in which a subthreshold conditioning pulse is followed
by a TMS pulse after a 8–30 ms delay. c | Protocols for
20% max Contralateral M1 TMS testing afferent inhibition. In SAI and LAI, a peripheral
contraction suprathreshold
stimulation stimulus is paired with a TMS pulse on M1. In SAI, ISI is
Silent period – shorter (N20lat + 2–5 ms) than in LAI (N20lat + 100–300 ms)
EMGA
cSP ISI d | iSP and IHI protocols evaluate transcallosal inhibitory
drive. Abbreviations: cSP, contralateral cortical silent period;
EMGA, electromyographic activity; ICF, intracortical
facilitation; IHI, interhemispheric inhibition; ISI, interstimulus
b Subthreshold TMS TMS interval; iSP, ipsilateral cortical silent period; LAI, long-
latency afferent inhibition; LICI, long-interval intracortical
+
8–30 ms inhibition; M1, primary motor cortex; MNS, median nerve
ICF ISI stimulation; N20lat, latency of the N20 component of
somatosensory evoked potentials; SAI, short-latency
afferent inhibition; SICI, short-interval intracortical inhibition;
TMS, transcranial magnetic stimulation.
c Suprathreshold MNS TMS

–
N20lat + 2–5 ms Short-interval intracortical inhibition (SICI)36,48–50 and
SAI ISI
long-interval intracortical inhibition (LICI)50—­indicators
MNS Suprathreshold TMS of GABAA and GABAB receptor-mediated inhib­ition
(Figure 1a)—are suppressed, whereas intracortical
–
N20lat + 100–300 ms facilitation (ICF; Figure 1b) remains normal.48,50,51 In a
LAI ISI recent study from our group, short-latency afferent inhib­
ition (SAI; Figure 1c)—a marker of central cholinergic
activity—­was suppressed in the acute phase of stroke,
Max Ipsilateral M1 with increased suppression of SAI correlating with better
d suprathreshold TMS
contraction
stimulation motor function recovery at 6 months.52 Although motor
EMGA Silent period – threshold and MEP amplitude in the unaffected hemi­
iSP ISI sphere are generally within normal limits,32,36,43,45,46,51,53–55
there are some reports of a reduction of SICI.36,51,54,56
TMS can be used to investigate interhemispheric con­
Ipsilateral M1 TMS TMS Contralateral M1
subthreshold stimulation nectivity between the two motor cortices, using a paired-
stimulation coil method to test interhemispheric inhib­ition (IHI;
–
10–40 ms
IHI ISI
Figure 1d). In stroke survivors, IHI from the unaffected
hemisphere to the affected hemisphere abnormally per­
sists at the onset of attempted contraction of the paretic
limb,31,57 and could potentially interfere with initiation
of movement.
Longitudinal studies describing detailed neurophysio­
logical and clinical data over the first few months after
stroke are scarce, but in one small study, neurophysio­
logical measures of corticospinal integrity—such as MEP
TMS MNS EMGA and motor threshold—in the affected hemisphere were
found to correlate with motor function in the acute and
– Protocol to measure inhibition + Protocol to measure facilitation subacute phase, whereas at >3 months, motor function
correlated better with measures of intracortical excit­
ability (SICI, LICI and ICF) than with measures of corti­
Stinear et al.,47 in which recovery prospects of individual cospinal integrity.50 Although this study comprised only
patients can be forecast through a combination of clinical 10 patients, the data are consistent with the hypothesis
upper limb strength measures, TMS response, and MRI that intracortical and corticospinal excitability probe
­measures of corticospinal tract asymmetry. different aspects of the recovery process. In the acute
After stroke, the balance between inhibition and excita­ period, motor performance relies on remaining cor­
tion in the affected hemisphere shifts towards excitation, ticospinal connections of the affected hemisphere,
while activity in the local inhibitory circuits is reduced. while sub­s equent recovery may depend more on the

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Acute stroke
aH uH
SICI Normal MEP
LICI Normal MTs
Normal ICF SICI
IHI aH uH IHI uH aH
∆power
Bad prognosis Good prognosis
aH uH aH
No MEP MEP LTP-like LTD-like
MTs MTs SAI
∆power MEP present
Figure 2 | Neurophysiological parameters in acute stroke predict prognosis.
Schematic illustration of the typical changes in neurophysiological parameters that
characterize the acute phase in stroke, and predictors of bad and good recovery.
Abbreviations: aH, affected hemisphere; ICF, intracortical facilitation; IHI,
interhemispheric inhibition; LICI, long-interval intracortical inhibition; LTD, long-term
depression; LTP, long-term potentiation; MEP, motor-evoked potential; MT, motor
threshold; SAI, short-latency afferent inhibition; SICI, short-interval intracortical
inhibition; uH, unaffected hemisphere; Δpower, power spectral density in the delta
band (<4 Hz) EEG.
recruitment of alternative cortical networks in both
hemispheres.50 According to this view, intracortical dis­
inhibition of the affected hemisphere (as indicated by
reduced SICI, LICI and SAI) might facilitate remain­
ing motor output in the acute stage, and subsequently
facilitate synaptic plasti­city to promote r­eorganization
of cortical networks in the subacute phase.58
Taken together, the results from the studies reviewed
above suggest that reduced corticospinal excitability in
the affected hemisphere increases intracortical excitabil­
ity in both hemispheres and changes the balance of inter­
hemispheric interactions (Figure 2). However, despite the
large number of investigations performed so far, different
groups have reported highly variable and even opposite
results, leading to some uncertainty about the clinical
significance of these findings.
Plasticity changes during recovery
Neuronal reorganization and plasticity that follow stroke
begin in the very early stages, continue for several weeks,
and involve brain regions distant to the affected site.
Imaging studies (PET, EEG and functional MRI) have
revealed widespread changes in patterns of brain acti­
vation during simple movements of the affected hand
after stroke; these alterations evolve over a timescale
that is consistent with a gradual reorganization of the
sensori­motor system. Activation in the primary motor
cortex (M1) of the affected hemisphere is reduced,
and—­depending on the size and location of the ischae­
mic lesion—the activity can be relocated to more-­
posterior 59–61 or more-anterior regions,46 particularly
towards the premotor cortex and supplementary motor
area (SMA), which are often spared by a typical middle
cerebral artery occlusion.62–65
The unaffected hemisphere can also show widespread
activation accompanying movements of the paretic hand
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that exceeds the activation seen in healthy individuals
performing movements of the same difficulty.36,49,54,56
The extent of this activity seems to depend on the degree
of functional impairment, being greatest in patients with
the greatest impairment.
Is increased activation of the premotor cortex, SMA
and unaffected hemisphere an epiphenomenon, or does
activity in those areas compensate for the lost motor func­
tion and, if so, through what mechanisms? Attempts to
address these questions have used TMS to disrupt activ­
ity in selected cortical areas to see if there is any impact
uH on movement of the paretic arm. In patients with sub­
cortical stroke, disruptive TMS impairs simple reaction
time of the paretic hand when applied over the dorsal
premotor cortex (PMd) of both the unaffec­ted66 and the
affected hemisphere.55 In well-recovered patients with
chronic stroke, complex finger movements were also dis­
rupted by TMS to M1 and the superior parietal lobe of
the unaffected hemisphere.67 The conclusion is that activ­
ity in these areas can be compensatory and contribute
to recovery of movement. No similar evidence exists for
involvement of other brain areas, particularly in less well-
recovered patients; however, several clinical case reports
indicate that new infarcts affecting the previously unaffec­
ted hemisphere worsen the primary hemiparesis.68–71
Similar data have been reported in animals. For example,
application of lidocaine to the unaffected hemisphere
of rats 3–4 weeks after occlusion of the middle cerebral
artery on the contralateral side reduced performance of
the paretic forelimb.72 Interestingly, the effect was most
dramatic in animals with large lesions and was much less
noticeable in animals with small lesions.
Direct projections from the PMd to the lower motor
neurons are scarce,73,74 making it unclear how increased
activity in the PMd can be transformed into functional
benefit. One possible mechanism is involvement of pro­
jections from the PMd to reticulospinal motor pathways
in the brainstem, some of which innervate distal arm and
hand muscles.75 Increased activity in the PMd might also
simply increase the drive to any remaining corticospinal
projections from the affected hemisphere, thereby boost­
ing the output projecting to the hand. Increased activity
in M1 of the unaffected hemisphere might contribute to
recovery via the small percentage of uncrossed cortico­
spinal fibres that can innervate paretic muscles on the
ipsilateral side. Finally, if the SMA contributes to recov­
ery of motor function, its extensive input directly to the
corticospinal tract could enable this region to provide
important input to spinal motor neurons. In line with this
hypothesis, findings from squirrel monkeys indicate that
3 months after stroke, expansion of the distal representa­
tion of the paretic forelimb into the SMA of the affected
hemisphere is proportional to the size of M1 lesion.76 Of
note, in rats, recovery from a unilateral cerebral lesion
can be accompanied by sprouting of corticospinal fibres
from the intact hemisphere at the level of the spinal cord:
the fibres branch and re-cross the spinal cord to inner­
vate neurons on the paretic side.77 However, no evidence
for spinal cord level reinnervation from the contralateral
affected hemisphere exists in human patients.
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Max
High
probability
Recovery
1 interhemispheric competition model—suggests exactly
3 the opposite. This model assumes the presence of a
Min
Low
2 probability
Max
Str
uc
tur ncing
al ala
res ic b
er v pher
e mis
rhe
Inte
Max Min
Figure 3 | The bimodal balance–recovery model. Structural reserve is the quantity
of strategic neural pathways and relays that are spared by the lesion and can
reallocate previous or outsource new functions. Patients with high structural reserve
often achieve better functional recovery. In such cases, the balance of activity
between the two hemispheres tends toward the previous equilibrium (1), whereas
persistence of interhemispheric imbalance is a predictor of worse outcome (2).
When structural reserve is low—such as in a subclass of patients with more-severe
impairment—and the sensorimotor network is far from reaching a physiological
restitutio ad integrum, persistence of interhemispheric imbalance promotes vicarious
activity of the unaffected hemisphere (3), allowing compensatory plasticity. Colour
code indicates frequency distribution of an event in a population of stroke patients,
which is equivalent to the probability that a given individual is represented by that
point of the surface. ‘Hot’ colours indicate higher probability than ‘cold’ colours. The
probability distribution presented here follows a bimodal statistical distribution,
which arises from the superimposed distributions of two populations: patients with
high reserve and high balancing versus patients with low reserve and low balancing.
Although the factors that determine the reorganiza­
tion of activity after stroke remain unknown, bilateral
activity accompanies certain unilateral movements even
in healthy individuals. Simple movements, for example,
moving the wrist or one finger, involve unilateral activity
in the contralateral primary sensorimotor and premotor
cortex, whereas more-complex or sequential movements
can involve the same areas bilaterally, together with
the SMA and possibly other areas. The complexity of the
task correlates with the amount of involvement of non-
primary and ipsilateral areas of cortex.78,79 It seems pos­
sible that attempted movements of a paretic limb could
be processed in the brain in the same way as complex
movements of the limb in healthy individuals, thereby
recruiting similar areas to produce movement.
Reorganization of activity can also have maladaptive
effects. Stroke often hampers bimanual performance,80,81
an impairment that has recently been linked with
reduced task-related facilitatory activity from SMA onto
M1 in the affected hemisphere and disrupted control of
inhibitory connections between the M1 regions of the
two hemispheres. Thus, impaired bimanual perfor­
mance could be explained by abnormal interhemispheric
­interaction of primary and supplementary motor areas.82
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Current models of functional recovery
The studies described above that used TMS to disrupt
the function of motor areas suggest that activity in the
unaffec­ted hemisphere is likely to contribute to func­
tional recovery after stroke; this pattern of reorganization
is referred to as the vicariation model, in which activity
in residual networks substitutes for those functions lost
by damaged areas. In practice, this presumably occurs
via the intact, unaffected hemisphere.83 However, an
influential model of hemispheric interactions—the
mutual, balanced inhibition between the hemispheres
in the healthy brain. Damage to one hemisphere in
stroke disrupts this balance, with reduced inhibition of
the unaffec­ted hemisphere by the affected hemisphere,
resulting in increased inhibition of the affected hemi­
sphere by the unaffected hemisphere. The affected
­h emisphere is thus thought to be ‘double-­d isabled’,
because ipsilateral damage is coupled with excess
­inhibition from the o­ pposite hemisphere.
In healthy individuals, IHI decreases and reverses to
facilitation shortly before the onset of unilateral index
finger movements. In relatively well-recovered stroke
patients who are able to make index finger movements
with the affected hand, this mechanism fails because the
inhibition–facilitation reversal is lacking, potentially
interfering with movement of the paretic side.57,84 These
data are in line with the interhemispheric competition
model; however, the results suggest abnormal control of
interhemispheric interaction during task performance
only. It is important to note that resting levels of IHI are
generally reported to be within the normal range after
stroke, whereas the interhemispheric competition model
would predict IHI from the affected to the unaffected
hemisphere to be reduced, and IHI from the unaffected
to the affected hemisphere to be increased.
Other data support the interhemispheric competition
model. In healthy volunteers, reducing somatosensory
input from one hand by cutaneous anaesthesia improves
performance in the unanesthetized hand.85 Similarly, in
patients with chronic stroke, cutaneous anaesthesia of
the intact hand results in behavioural gains in the paretic
hand that briefly outlast the duration of the anaesthesia.86
The two models of reorganization—vicariation and
interhemispheric competition—lead to opposite predic­
tions about whether the optimal neuromodulatory treat­
ments for an individual patient would be inhibitory or
excitatory. Interhemispheric competition predicts that
disruption of activity in the unaffected hemisphere would
be beneficial for stroke recovery by releasing the affected
hemisphere from abnormal inhib­ition by the unaffec­
ted hemisphere. Conversely, the vicariation model pre­
dicts that such a strategy would be counter­productive,
because it would interfere with c­ ompensatory activity in
the ­unaffected hemisphere.
The bimodal balance–recovery model
We suggest that neither the interhemispheric competi­
tion model nor the vicariation model is sufficient on its
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Box 2 | Strategies for neuromodulation in humans
Noninvasive neuromodulatory techniques are divided into inhibitory and excitatory
protocols on the basis of their effects on the amplitudes of motor evoked potentials
(MEPs; Figure 4).156 The most extensively used protocols in humans include
repetitive transcranial magnetic stimulation (rTMS; Figure 4a), paired associative
stimulation (PAS; Figure 4b) and transcranial direct current stimulation (tDCS;
Figure 4c).
rTMS can increase excitability of corticospinal neurons directly (suprathreshold
>5 Hz rTMS) or decrease excitability through cortical interneurons projecting
to corticospinal cells (suprathreshold low-frequency rTMS).14,120 Intermittent
and continuous theta-burst stimulation (iTBS and cTBS) are subthreshold rTMS
paradigms (that is, the stimulator delivers an intensity below the one needed to
evoke the MEP); iTBS increases and cTBS decreases corticospinal excitability.158 The
balance of long-term potentiation (LTP)-like plasticity in the affected hemisphere and
the long-term depression (LTD)-like plasticity in the unaffected hemisphere evoked by
TBS predicts motor recovery at 6 months after stroke.159
PAS induces LTP/LTD-like changes by pairing an electrical stimulus to a peripheral
nerve with a time-locked TMS pulse to the contralateral primary motor cortex
(M1).160 Both intracortical and thalamocortical inhibitory and excitatory networks
are thought to be involved in the alterations of synaptic strength.105,161–164 The
interstimulus interval (ISI) determines whether the modulation is excitatory
or inhibitory.
tDCS delivers a low-intensity constant current through the scalp to the brain,
and often exerts polarity-specific modulation of corticospinal excitability.165
tDCS can activate LTP-like and LTD-like processes166 and many neurotransmitter
systems.167,168 Unlike TMS, tDCS does not trigger action potentials; instead, it is
thought to cause a small change (in the order of 1 mV) in the membrane potential
of cortical neurons.169
Repetitive electrical stimulation (rES) of peripheral nerves or muscles could
increase the efficacy of rehabilitation after stroke; it is portable and does not
require the patient’s active participation,170–175 and has been demonstrated to
improve the motor performance of the paretic limb.176
own to explain recovery in all patients, owing to vari­
ability in time elapsed from the stroke event, residual
functions, and lesion size and location.
Our proposal is to combine these models into a
new model—the bimodal balance–recovery model
(Figure 3)—by introducing a new parameter, structural
reserve, which describes the extent to which neural path­
ways and relays spared by the lesion contribute to recov­
ery in an individual patient. The amount of structural
reserve determines whether interhemispheric imbalance
dominates over vicariation: if the structural reserve is
high, the interhemispheric competition model can
predict recovery better than vicariation model, which is
more useful in predicting recovery in patients with little
structural reserve.
Integrity of brain regions in both hemispheres is
likely to influence structural reserve, but undoubtedly
the most important contributory factor is the remaining
function of the motor areas and corticospinal tract in
the affected hemisphere. Preservation of these structures
in the affected hemisphere correlates with functional
recovery and involvement of the stroke hemisphere in
movement control.87,88 Greater damage produces worse
deficits, and is accompanied by increased levels of activ­
ity in the unaffec­ted hemisphere, which in most cases
will represent vicariation of function. Hence, the level of
lateralization of neural activity alone is not always able
to predict the response to rehabilitation.88
6 | ADVANCE ONLINE PUBLICATION
© 2014 Macmillan Publishers Limited. All rights reserved
Some evidence supporting the bimodal balance–­
recovery model has come from studies assessing the
efficacy of different neuromodulatory techniques in
promoting recovery of motor function after stroke.
Fractional anisotropy of the internal capsule, a micro­
structural marker of damage to descending motor path­
ways,89 has been demonstrated to differentiate patients
who respond better to an inhibitory cathodal tDCS
stimulation protocol applied to the unaffected hemi­
sphere from patients who benefit more from excitatory
stimulation of the affected hemisphere.90 Patients with
extensive damage to the corticospinal tract of the affected
hemisphere responded poorly to inhibitory (cathodal)
stimulation of the unaffected hemisphere, whereas
patients with smaller lesions responded well.
These findings are in line with previous publications
suggesting that interhemispheric competition would
dominate in patients with more-limited damage in the
affected hemisphere, but would be less relevant in patients
with more-severe damage to the affected hemisphere.91–94
Similarly, TMS–fMRI studies of functional connectivity
between the motor areas of the two hemispheres have
shown that in severely affected patients, the influence
of the PMd of the unaffected hemisphere on M1 of the
affected hemisphere is facilitatory, whereas it is inhibitory
in patients with minimal impairment 95 and in healthy
individuals.96,97 Finally, an fMRI study has demonstrated
that inhibition from the unaffected to the affected hemi­
sphere is greater during paretic hand movements in
relatively well-recovered patients than in patients who
show poorer recovery, consistent with the notion that the
interhemispheric competition model predicts recovery in
patients with high functional reserve.98
Towards more-successful clinical trials
Repetitive activation of synapses results in strengthen­
ing (long-term potentiation; LTP) or weakening (long-
term depression; LTD) of synaptic connections and
efficacy.99–101 Although LTP and LTD have been mostly
studied in vitro, synaptic connections in the human brain
can be activated with noninvasive brain s­ timulation
(Box 2, Figure 4).102–105
Several recent studies have addressed the topic of
neuromodulation and stroke recovery, but the evi­
dence supporting the use of NIBS in stroke rehabilita­
tion remains inconsistent. In 2012, two meta-analyses
of clinical trials concluded that both rTMS and tDCS
can enhance motor recovery after stroke; the effect
sizes were substantial (0.4–0.6) and no major adverse
effects were observed.12,13 In contrast with those promis­
ing results, however, two systematic Cochrane reviews
published in 2013 concluded that good-quality evidence
for the efficacy of rTMS10 and tDCS11 to improve motor
function of patients with stroke is lacking. Below, we
discuss the factors that are likely to contribute to the
inconsistent findings.
The need for patient stratification
In the NIBS trials conducted to date, similar neuro­
modulation was often delivered regardless of lesion site
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 REVIEWS

a rTMS over the M1 of the affected hemisphere in patients

–
1–4 Hz Total time 20 min
with subcortical but not cortical stroke lesions.114 The
rTMS 1s 1s 1s
5–20 Hz Total time 6 min extent of the damage is also highly important. To the
+
best of our knowledge, apart from a single case,115 the lit­
erature is devoid of positive responses to NIBS in stroke
TMS Suprathreshold
patients with severe impairments. Finally, it should be
Subthreshold noted that the stroke phase (acute, subacute or chronic)
TMS can determine the brain state and the plastic changes that
5 Hz are ongoing or already achieved. Nevertheless, similar
–
cTBS Total time 40 s protocols, for instance, continuous theta burst stimula­
TBS 2s 8s
tion, have been used in the ­subacute113,116 and chronic107
iTBS Total time 190 s
160
ms
+ stages after stroke.
5 Hz 20 20
ms ms
50 ms Refining stimulation techniques and protocols
In most trials, the NIBS technique used is chosen on
b
the basis of ease of use, patient comfort, availability of the
TMS + MNS n=1 n=2 n=3 n = 90
stimulation equipment, and effects on cortico­spinal
ISI = 10 ms
Total time 45 min
– excitability, irrespective of the underlying mechanism
PAS of action. We argue, however, that the choice of NIBS
Total time 67.5 min + should depend on the predicted mechanism of recov­
TMS + MNS
ery in each individual patient. The ideal NIBS protocol
ISI = 25 ms ISI 20 s depends on the patient’s functional reserve (which deter­
mines whether or not the model of interhemispheric
rivalry is applicable), type of stroke (subcortical versus
c – – – – – – – – – – – – – cortical; or ischaemic versus haemorrhagic), and stroke
c-tDCS Total time 15–60 min stage (acute, subacute or chronic).
tDCS
a-tDCS Total time 15–60 min +
NIBS techniques also have high interindividual vari­
+ + + + + + + + + + + +
ability: in many cases, stimulation parameters chosen to
tDCS increase corticospinal excitability can have a inhibitory
effect,117–120 possibly because of the variable effects of the
protocol on the mixed populations of cortical neurons,120
which might depend on genetic factors.121 As discussed
above, stroke may increase the variation in response
to NIBS, particularly if additional pharmacological
­treatment has been introduced.122
Heterogeneity of the stimulation protocols, with
TMS tDCS MNS respect to the number of sessions delivered107,113,116 and
the timing of the concomitant physical therapy,109,110
– Protocol to measure inhibition + Protocol to measure facilitation
adds to the confusing complexity. Trials of tDCS in
stroke are hampered by these issues and show high inter­
Figure 4 | Noninvasive neuromodulatory techniques. a | Depending on the study variability regarding electrode placing, intensity
stimulation frequency, suprathreshold rTMS can increase (>5 Hz rTMS) or decrease
of the delivered current, session schedule, and type of
(suprathreshold <5 Hz rTMS) the excitability of corticospinal neurons (Box 2). TBS
protocols are subthreshold rTMS paradigms that, depending on the pattern stroke.110,123 Only a few investigations have linked stimu­
(intermittent versus continuous) of the stimulation, can either increase (iTBS) or lation parameters to a neurophysiological evaluation
decrease (cTBS) corticospinal excitability. b | In the PAS protocol, median nerve of the motor system and have addressed the effects of
stimulation is combined with TMS to the contralateral M1. c | tDCS can exert the intervention on both excitability–connectivity and
polarity-specific modulation of corticospinal excitability; in the M1, a‑tDCS increases ­clinical outcome.109,116
corticospinal excitability, whereas c‑tDCS decreases it. Abbreviations: a‑tDCS,
anodal tDCS; cTBS, continuous theta burst stimulation; c‑tDCS, cathodal tDCS;
Heterogeneity in outcome measures
ISI, interstimulus intervals; iTBS, intermittent theta burst stimulation; M1, primary
Outcome measures vary widely between studies, ranging
motor cortex; PAS, paired associative stimulation; rTMS, repetitive TMS; TBS, theta
burst stimulation; tDCS, transcranial direct current stimulation; TMS, transcranial from measures of dexterity (Jebsen–Taylor Test,109 Action
magnetic stimulation. Research Arm Test,90,114 Purdue Pegboard Test,124 Box
and Block Test 125) to measures of strength (handgrip,126
pinchforce106), reaction time,127 and disability or stroke
or stroke aetiology. Unfortunately, this drawback has not severity (Barthel ,128 Fugl–Meyer,129 National Institutes of
been overcome by the most recent trials. Patients with Health Stroke Scale125) Meta-analyses equate the hetero­
cortical and subcortical stroke,106–111 or ischaemic and geneity of the outcome measures in different trials and
haemorrhagic stroke,109–111 are often merged into the same express the effects of the interventions as z‑scores, but
group, even though such factors can influence recovery: the different outcome measures make comparison of the
one study has described a positive response to facilitatory outcomes between studies very challenging.

NATURE REVIEWS | NEUROLOGY ADVANCE ONLINE PUBLICATION | 7

© 2014 Macmillan Publishers Limited. All rights reserved
REVIEWS
Our conclusion is that noninvasive neuromodulation
is not yet ready to be implemented in stroke rehabilita­
tion in the current clinical practice, for several reasons.
First, the concept of interhemispheric imbalance, which
has been employed as the rationale in most of the studies,
is likely to be too simplistic to be successfully applied
in each individual patient. Second, very few trials have
used exactly the same protocols, meaning that estimat­
ing the real effectiveness and reproducibility is often
impossible. Third, the use of different outcome measures
means that studies are not readily comparable. Last, the
number of negative ­standardized clinical trials cannot
be overlooked.90,125,130
Individual multimodal diagnostic approach
The bimodal balance–recovery model proposed in
this Review (Figure 3) implies that we cannot hope to
improve the function of the affected hand in patients
with stroke through a one-size-fits-all-strategy,90 and
that multiple factors, such as the severity of clinical
impairment, determine the strategies and success of
­neuromodulatory treatment.131
The idea of a patient-tailored approach is not new: a
similar idea has been proposed by Pascual-Leone and
colleagues132,133 and Byblow and Stinear.47 An individu­
alized, multimodal pre-therapy diagnosis is envisaged,
involving the clinical history of the patient, time elapsed
after the stroke, topography of the lesion, and type and
severity of functional impairment. Stinear and Byblow
proposed a simple diagnostic algorithm to predict func­
tional recovery at 6 months on the basis of measures
collected during the first 7–10 days after stroke.88 We
propose that a similar algorithm should be developed to
facilitate an individualized approach to NIBS.
The algorithm of Stinear and Byblow incorporates
clinical strength measures, response to TMS, and frac­
tional anisotropy measures on MRI. The proposed NIBS
algorithm could rely on similar measures. However,
given that functional brain connectivity might also
be relevant, other methods could prove valuable. For
example, EEG could provide a useful and cheap func­
tional way to measure the state of remaining brain areas
and aid the selection of the NIBS protocol. EEG can be
used to explore resting-­state activity and connectivity
of the brain and to provide immediate information on
the functional integrity of cortical tissue. Delta waves
increase bilaterally in acute stroke, but are raised particu­
larly over the affected hemisphere, where they are related
to the acute clinical impairment.134 Symmetry of spec­
tral power between the two hemispheres is associated
with mild neurological deficits,135 and a sudden emer­
gence of delta waves in the unaffected hemisphere136–138
or of an asymmetry across the hemispheres139 can reveal
acute worsening with a poor prognosis. In the chronic
phase, the reduction of the beta band (12.5–30.0 Hz)
oscillatory activity in the motor cortex correlates with
motor impairment.140
Further information on connectivity might be
obtained with TMS–EEG co-recording, which offers
the possibility for noninvasive probing of the brain’s
8 | ADVANCE ONLINE PUBLICATION
© 2014 Macmillan Publishers Limited. All rights reserved
cortical excitability and time-resolved effective con­
nectivity.141–143 TMS–EEG could, therefore, provide new
insights into the interaction between brain areas during
motor function, 142,144,145 and elucidate how the areas
involved in motor control react to acute damage, such
as stroke.
Conclusions
The interhemispheric competition and vicariation
models of motor recovery after stroke lead to oppos­
ing conclusions about the best NIBS interventions. We
suggest introduction of a weighting term, ‘structural
reserve’, which describes the remaining functional
motor output, and propose a unifying bimodal balance–­
recovery model, which determines the amount of recov­
ery limited by interhemispheric competition and the
recovery supported by vicariation. This threshold varies
from patient to patient and enables us to determine how
best to apply NIBS interventions on an individual basis.
For such patient-tailored treatment, development of
standardized methods of meas­uring structural reserve,
such as clinical, anatomical and functional measures
of motor connectivity, is important. Future studies will
refine the bimodal balance–recovery model and test
whether the efficacy of individualized NIBS therapy is
superior to the current methods.
Our analysis has a number of unavoidable limita­
tions. Besides the factors included in our model, several
additional factors will contribute to the efficacy of
NIBS, including the timeliness of the intervention, age,
sex, comorbidities, concurrent pharmacological treat­
ments, the ischaemic versus haemorrhagic nature of the
lesion, and whether the stroke affects the dominant or
the nondominant hemisphere. However, we believe that
in the future, these factors can be successfully integrated
into the proposed bimodal balance–recovery model
and the ­a ssociated concept of individually tailored
NIBS treatment.
Finally, there is no comprehensive agreement on the
optimal combination of NIBS parameters, the duration
of the NIBS treatment, and clinical outcome measures
(force versus dexterity; time of follow-up) in evaluating
the efficacy of the therapy. We envision that progress
in the near future will provide in-depth knowledge of
stroke rehab­i litation, and that individualized neuro­
modulation will result in notable enhancements in
rehabilitation success.
Review criteria
We searched the literature for recent trials and meta-
analyses assessing the efficacy of noninvasive brain
stimulation. Rather than adding to the growing body of
existing systemic reviews of clinical trials, our intention
is to introduce a scientific rationale for improving the
outcome of those trials. We do not claim to have read all
relevant literature; however, we have tried to incorporate
the whole range of present viewpoints into a coherent
and logical structure. Thus, our scope was extremely
broad and relied extensively on the long experience of
the authors in this field.
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Author contributions
G.D.P. developed the model and wrote the article.
G.P. searched the literature and wrote the section
on the stimulation protocols and clinical trials. G.A.
searched the literature and wrote the section on EEG
and repetitive electric stimulation. F.C. searched the
literature and participated in writing the section on
predictors of recovery. F.F. searched the literature
and wrote the section on TMS–EEG in the multimodal
diagnostic approach. D.F. was involved in the
computational development of the model. M.T.
searched the literature and wrote the section on
synaptic dysfunctions following stroke. F.R. provided
substantial contributions to discussion of the
content. U.Z., J.C.R. and V.D.L. guided the
manuscript development and revised the manuscript.
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