Clinical Neurophysiology of Stroke: EEG, Excitability, Rehabilitation

Handbook of Clinical Neurology, Vol. 161 (3rd series)
Clinical Neurophysiology: Diseases and Disorders
K.H. Levin and P. Chauvel, Editors
https://doi.org/10.1016/B978-0-444-64142-7.00044-8
Copyright © 2019 Elsevier B.V. All rights reserved
Chapter 7
Clinical neurophysiology of stroke
MARTINE GAVARET1,2*, ANGELA MARCHI2, AND JEAN-PASCAL LEFAUCHEUR3,4
1
INSERM UMR894, Paris Descartes University, Paris, France
2
Service de Neurophysiologie Clinique, Centre Hospitalier Sainte Anne, Paris, France
Service de Physiologie—Explorations Fonctionnelles, H^opital Henri Mondor, Assistance Publique—H^
opitaux de Paris, Creteil,
France
3
4
EA 4391, Universite Paris Est Creteil, Creteil, France
Abstract
Stroke constitutes the third most common cause of death and the leading cause of acquired neurologic
handicap. During ischemic stroke, very early after the onset of the focal perfusion deficit, excitotoxicity
triggers a number of events that can further contribute to tissue death. Such events include peri-infarct
depolarizations and spreading depolarizations (SDs) within the ischemic penumbra. SDs spread slowly
through continuous gray matter at a typical velocity of 2–5 mm/min. SDs exacerbate neuronal injury
through prolonged ionic breakdown and SD-related hypoperfusion (spreading ischemia). Scalp EEG alone
is not yet sufficient to reliably diagnose SDs. Hyperexcitability occurs in parallel, both in the acute and
chronic phases of stroke. Stroke is a common cause of new-onset epileptic seizures after middle age
and is the leading cause of symptomatic epilepsy in adults. The last part of this chapter is dedicated to
noninvasive neurophysiologic techniques that can be used to promote stroke rehabilitation. These techniques mainly include repetitive transcranial magnetic stimulation and tDCS. These approaches are based
on the concept of interhemispheric rivalry and aim at modulating the imbalance of cortical activities
between both hemispheres resulting from stroke.
Stroke is the third most common cause of death and the
leading cause of acquired neurologic handicap. Treatment
of this disabling and very heterogeneous disease has
benefited from major therapeutic improvements over the
past 25 years, both in terms of preventive strategies and
acute care. The first part of this chapter, which is dedicated
to the clinical neurophysiology of stroke, focuses on slow
EEG potentials recorded in stroke. EEG is very sensitive to
changes in neuronal function resulting from ischemia (van
Putten and Hofmeijer, 2016). In the second part of the
chapter, hyperexcitability, occurring both in the acute
and chronic phases of stroke, is discussed. Stroke is a common cause of new-onset seizures after middle age and is
the leading cause of symptomatic epilepsy in adults. The
third part of the chapter is dedicated to noninvasive neurophysiologic techniques useful in stroke rehabilitation.
SLOW POTENTIALS
Brain injury following transient or permanent focal cerebral ischemia develops from a complex series of pathophysiologic events that evolve in time and space (Dirnagl
et al., 1999). In conditions of mild to moderate ischemia,
EEG shows changes in rhythmic activities. A decrease in
alpha and beta activities is followed by an increase in the
delta band, depending on the severity and duration of
ischemia (Finnigan et al., 2004). Not all synapses or neurons are equally sensitive to ischemic incidents, with
inhibitory neurons being more likely to be affected. This
may explain the increased synchronization during hypoxic damage with generalized periodic discharges (van
Putten and Hofmeijer, 2015; van Putten and Hofmeijer,
2016). Using continuous EEG (cEEG) in the acute phase
*Correspondence to: Prof. Martine Gavaret, MD, PhD, Service de Neurophysiologie Clinique, Centre Hospitalier Sainte Anne, 1 rue
Cabanis, 75014 Paris, France. Tel: +33-1-45-65-81-89, Fax: +33-1-45-65-74-21, E-mail: [email protected]
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of stroke, a measure of symmetry, the brain symmetry
index, has been proposed. This measure is defined as
the mean of the absolute value of the difference in mean
hemispheric power in the frequency range from 1 to
25 Hz (van Putten and Tavy, 2004). The lower bound
for the brain symmetry index is 0 (perfect symmetry for
all channels) and the upper bound is 1 (maximal asymmetry). The brain symmetry index values were correlated
with the patient clinical condition using the National
Institute of Health Stroke Scale (NIHSS) (van Putten and
Tavy, 2004). Evoked potentials, motor evoked potentials,
and somatosensory evoked potentials can also provide a
real-time assessment of somatomotor functions during
recanalyzing therapies. It has been demonstrated that,
during mechanical endovascular therapy, motor evoked
potentials and median nerve somatosensory evoked potentials allow real-time monitoring of reperfusion success
with respect to functional outcome (Shiban et al., 2016).
During ischemic stroke, excitotoxicity triggers a number of events that can further contribute to tissue death.
Such events include peri-infarct depolarizations and
spreading depolarization (SD) within the ischemic penumbra. The sequence of pathophysiologic events following ischemia has been well characterized. With energy
depletion, the cell homeostasis cannot be maintained.
Extracellular potassium increases and diffuses in the
extracellular space. The increase in extracellular potassium concentration contributes to cell depolarization
and notably opens voltage-gated calcium channels,
which causes calcium to enter neurons and astrocytes.
The excess of calcium propagates across astrocytes
through gap junctions. The rise in intracellular calcium
concentration contributes to opening calcium-dependent
potassium channels, which causes more potassium to go
out of the cells. The abrupt extracellular concentration
changes of potassium, glutamate, cellular swelling, and
dendritic beading are SD correlates (Dreier et al.,
2017). When the various ionic concentrations are disturbed, the ionic pumps try to increase their activity to
bring the system back to its resting state. Large amounts
of energy are required to reestablish ionic gradients after
SD. Effective vascular supply is therefore required
following SD (Chapuisat et al., 2008).
SD was first observed by Leão (1947). SDs are waves
of abrupt, near-complete breakdown of neuronal transmembrane ion gradients (Dreier et al., 2017). Recorded
slow negative direct current–EEG (DC-EEG) shifts are
thought to reflect tonic depolarization of the apical
dendrites of cortical pyramidal neurons. However, the
negative ultraslow DC potential is possibly of glial and
neuronal origin. Recent studies on neuron–glia interactions have indeed indicated that the glial syncytium may
contribute to slow and infraslow field patterns (Buzsáki
et al., 2012). Ischemia causes SDs within minutes. SDs
represent a crucial mechanism of lesion development.
Within minutes of acute severe ischemia, the onset of
persistent depolarization triggers the breakdown of ion
homeostasis and development of cytotoxic edema. Further
SDs arise over hours to days due to energy supply–demand
mismatch in viable tissue. SDs exacerbate neuronal injury
through prolonged ionic breakdown and SD-related
hypoperfusion. Indeed, while SDs in uninjured cortex
evoke a spreading hyperemia, in the penumbra they elicit
an inverse hemodynamic response, known as spreading
ischemia (Dreier et al., 2017).
SDs occur in human ischemic stroke with high
incidence (Dohmen et al., 2008). They spread slowly
through continuous gray matter at a typical velocity of
2–5 mm/min and are locally sustained for at least 15 s.
It has been observed that SDs cannot propagate in the
white matter, although the extracellular potassium can
diffuse in it (Chapuisat et al., 2008). In cortices, the geometry of the circumvolutions has a crucial influence on SD
propagation. Using simultaneous magnetoencephalography and electrocorticography (EcoG) in a gyrencephalic
species (swine), it has been demonstrated that SD propagation velocity is not uniform. SD velocity decreases in
sulci (2 mm/min). SD then continues to propagate across
the next gyrus at a slower rate (Bowyer et al., 1999). The
highly folded nature of the cortex has a strong impact on
SD propagation characteristics.
The number of SDs has a clear influence on the size of
the final infarcted area (Chapuisat et al., 2008). SDs cycle
around and enlarge focal ischemic brain lesions
(Nakamura et al., 2010). In delayed lesion growth, SDs
arise spontaneously in the ischemic penumbra, progressively expanding the ischemic core (Fabricius et al.,
2006; Hartings et al., 2017).
In neurocritical care, long-term monitoring of SDs can
be achieved with direct current electrocorticography (DCECoG) using a linear subdural platinum electrode strip.
SDs in human ECoG are characterized by an abrupt, negative DC shift with sequential onset in adjacent electrodes.
Assessment of the raw DC shift can only be achieved if the
amplifier is DC-coupled, that is, has no lower frequency
limit. With an AC-coupled amplifier with a lower frequency limit of 0.01 or 0.02 Hz, the cortical DC shift of
SD is distorted by the filtering but is still recorded as a slow
potential change. These DC-ECoG recordings provide a
diagnostic summary measure of metabolic failure and
excitotoxic injury (Dreier et al., 2017) in which characteristic patterns, including temporal clusters of SDs,
can be recognized and quantified. These methods offer
distinct advantages over other neuromonitoring modalities
and allow for future refinement through less invasive
approaches (Dreier et al., 2017).
Although correlates of SDs were clearly identified
in continuous scalp EEG recordings performed
CLINICAL NEUROPHYSIOLOGY OF STROKE
simultaneously with ECoG (Drenckhahn et al., 2012),
scalp EEG alone is not yet sufficient to reliably diagnose SDs. It has been demonstrated that sintered Ag
AgCl electrodes and a Cl containing gel are prerequisite in order to perform DC-stable scalp-EEG recording
(Tallgren et al., 2005). Further studies of the combined
technologies, ECoG and scalp-EEG, are strongly
recommended (Dreier et al., 2017).
Whether SDs have a role in epileptogenesis is not yet
clear, but seizures may occur in association with SDs in
the injured human brain (Fabricius et al., 2008).
HYPEREXCITABILITY
Stroke is a common epileptogenic cause of new-onset
seizures after middle age. Moreover, stroke is the leading
cause of symptomatic epilepsy in adults, accounting for
up to one-third of newly diagnosed seizures among the
elderly (Ryvlin, 2006; Tanaka et al., 2015). Acute stroke
causes 22%–30% of adult status epilepticus cases
(Trinka et al., 2012).
In children with perinatal ischemic stroke, estimates
of poststroke epilepsy vary widely (Golomb et al.,
2007a). Perinatal ischemic stroke represents the second
leading cause of neonatal seizures (Suppiej et al.,
2016). Long-term cumulative risk of poststroke epilepsy
varies from 3% to 30% (Pitkanen et al., 2016) and the risk
of developing epilepsy remains high up to 10 years after
stroke (Hauser, 2013).
Poststroke seizures or epilepsy share common features with posttraumatic and postinfectious epilepsy
(Menon and Shorvon, 2009). Seizures can be the presenting symptom as well as the result of stroke. Seizures can
lead to additional injury and worsen prognosis (Claassen
et al., 2014). The International League Against Epilepsy
differentiates between early (within 7 days poststroke)
and late seizures (Beghi et al., 2010); cEEG monitoring
studies show that most early seizures occurred within the
first 24 h (Claassen et al., 2004).
Pathophysiology and prognosis are different for early
and late seizures. Animal models of poststroke epilepsy
demonstrate three stages: original brain insult, latent
period, and recurring seizures. Potential mechanisms
implicated in the development of poststroke epilepsy
are loss of neurovascular unit integrity, hypoxia and
metabolic dysfunction, blood–brain barrier dysfunction,
and glutamate excitotoxicity (Reddy et al., 2017). Early
seizures are the consequence of acute biochemical disturbances provoked by ischemia, such as increased intracellular concentration of calcium and sodium, responsible
for neuronal membrane depolarization; increased concentration of extracellular glutamate; changes in ionic
channel properties; and functional impairment of
GABAergic interneurons (Sun et al., 2002; Karhunen
111
et al., 2005). These changes cause the ischemic penumbra to be predisposed to develop seizure activity. Late
seizures are symptomatic of profound neuroanatomic
changes, such as neuronal cell death, apoptosis, deafferentation, and collateral sprouting (Kelly, 2002).
A hyperexcitability of the injured cortex, followed by
plastic rearrangements in a wider cortical network, have
been proposed as mechanisms for poststroke epilepsy
(Villani et al., 2003).
Risk factors of seizures and poststroke epilepsy have
been studied in several publications. Early age at first
stroke in adulthood, hemorrhagic stroke, cardioembolic
stroke, total anterior circulation infarction, and cortical
and subcortical involvement are some known risk factors
associated with a higher incidence of seizures and poststroke epilepsy (Graham et al., 2013). Leukoaraiosis has
been particularly correlated with temporal lobe epilepsy
(Pitkanen et al., 2016). Stroke severity, in terms of
functional outcome and size of stroke, predicts the likelihood of developing poststroke seizures. The role of
acute seizures in developing poststroke epilepsy remains
ambiguous (Lamy et al., 2003).
Some studies have attempted to delineate interictal
EEG findings able to predict a major risk of developing
seizures or epilepsy. Patients with seizures showed EEG
abnormalities: diffuse or focal slowing, sharp waves,
focal spikes, spike-and-wave, or periodic lateralized
epileptic discharges (PLEDs). PLEDs are significantly
more frequent in patients with early-onset seizures
(De Reuck et al., 2006). Frontal intermittent rhythmic
delta activity (FIRDA) is defined as moderate to highvoltage monorhythmic and sinusoidal 1- to 3-Hz activity
seen bilaterally, maximal in anterior leads. FIRDA and
diffuse slowing are observed in both early and late seizure groups. Conversely, in the case of normal EEG,
late-onset seizures are observed in less than 1%
(Holmes, 1980; Gupta et al., 1988; De Reuck et al.,
2006; Mecarelli et al., 2011). In a focal ischemic rat
model, PLEDs appear over the penumbra and FIRDA
in the contralateral hemisphere (Hartings et al., 2003).
Additionally, PLEDs seem to be a marker of worsened
prognosis. PLEDs are associated with higher mortality
within the first week poststroke. Moreover, PLEDs are
associated with a higher occurrence of early-onset seizures and status epilepticus (Giroud et al., 1994;
Claassen et al., 2007; Fig. 7.1). Two types of PLEDs have
been described, proper and plus. PLEDs-plus are characterized by a rhythmic rapid discharge over the periodic
complex and have been correlated with forthcoming seizures (Reiher et al., 1991; Garcia-Morales et al., 2002).
Development of late seizures has been correlated with
a higher number of spreading depressions recorded using
EcoG (Dreier et al., 2012). In animal models, Leão in
1944 noted that, after repetitive SD, it was possible to
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Fig. 7.1. A 76-year-old right-handed man was referred to the stroke department for left hemiparesis. (A) Diffusion-weighted imaging (DWI) showed a hyperintense lesion in the right middle cerebral artery territory. On day-2, neurologic deterioration occurred.
EEG demonstrated PLEDs over right suprasylvian leads. (B) Continuous-EEG demonstrated that these PLEDs were associated
with several pauci-symptomatic seizures (C).
observe ample repetitive runs of spikes, which he named
spreading convulsion. Spreading convulsion is defined
as SD with ictal epileptic field potentials riding on the
final shoulder of the slow potential change. Relationships between SD and spreading convulsion are complex. They are induced by common pathways in
experimental epilepsy. A reduction of inhibitory GABA
tone increases susceptibility to SD and spreading convulsion. Recent evidence has showed that glial function
impairment can elicit both. During recovery from SD,
neurons are likely to be synchronized. The propagation
of SD is indeed accompanied by a glutamate and lactate
increase, as demonstrated by recent microdialysis studies
(Pinczolits et al., 2017; Rogers et al., 2017), the transient
increase in lactate possibly reflecting anaerobic glycolytic metabolism of glucose (Rogers et al., 2017). However, SD susceptibility is increased in acute epilepsy
models but seems to be strongly decreased in tissue of
patients with chronic epilepsy, suggesting the development of protective mechanisms (Fabricius et al., 2008;
Dreier et al., 2012; Winkler et al., 2012).
Poststroke epileptogenicity also depends on the
affected cortical area. The involvement of the parietotemporal junction, supramarginal gyrus, and superior
temporal gyrus enhances the risk of developing epilepsy
(Heuts-van Raak et al., 1996). Around 25% of patients
with poststroke epilepsy become drug resistant. Few
studies are dedicated to this subject in the literature. Most
of them concern childhood populations in the context of
perinatal stroke. Two main localizations of the epileptogenic zone have been described in these patients, motor
and posterior cortex, with a frequent bilateral involvement. Ulegyria due to perinatal stroke is considered to
be a frequent cause of posterior cortex epilepsy. Other
surgical series report especially a middle cerebral artery
occlusion as stroke localization (Kuchukhidze et al.,
CLINICAL NEUROPHYSIOLOGY OF STROKE
2008; Usui et al., 2008; Schilling et al., 2013). These
patients often need presurgical invasive investigations
using intracranial recordings. During presurgical assessment, interictal and ictal high-resolution EEG allow a
better understanding of ictal and interictal relationships
(Fig. 7.2). In those patients with drug-resistant poststroke
epilepsy,
intracranial
EEG
demonstrates
an
epileptogenic zone often organized remotely from the
lesion (Carreno et al., 2002; Ghatan et al., 2014).
Regarding seizure semiology, simple partial seizures
are the most reported with a difference between earlyonset and late seizures. Early seizures are more frequently
partial seizures. Late seizures are more frequently generalized or secondarily generalized (Gupta et al., 1988;
Bladin et al., 2000; De Reuck et al., 2006). In drugresistant poststroke epilepsies, motor system seizures
and occipital seizures are more frequent.
Cerebrovascular disease accounts for 25% of status
epilepticus, being associated with higher morbidity and
mortality (Trinka et al., 2012). Status epilepticus occurs
more frequently within the first 7 days poststroke
(De Reuck and Van Maele, 2009). More than half of these
113
are nonconvulsive status epilepticus (Afsar et al., 2003).
Nonconvulsive status epilepticus is often underestimated. In stroke patients with unexplained alteration of
consciousness, cEEG may allow a diagnosis of nonconvulsive seizures. Nonconvulsive seizures and status
epilepticus occur in a higher percentage of hemorrhagic
strokes than ischemic strokes (Claassen et al., 2007).
Finally, poststroke seizures may exacerbate secondary injury by enhancing the mismatch between energy
supply and demand, worsening functional outcome
(Lamy et al., 2003). In a population with nontraumatic
intracerebral hemorrhage, hematoma growth was associated with electrographic seizures detected using cEEG
(Claassen et al., 2007). Furthermore, poststroke seizures
and poststroke epilepsy are independent predictors of
vascular cognitive impairment (Golomb et al., 2007b;
Pendlebury and Rothwell, 2009).
In conclusion, PLEDs have to be considered an EEG
signature of an unstable neurobiologic condition that
creates an ictal–interictal continuum and can lead to
seizures (De Reuck et al., 2006). In stroke patients, cEEG
is indicated in the case of unexplained alteration of
Fig. 7.2. Presurgical assessment using interictal and ictal high-resolution EEG. This patient was characterized by drug-resistant
epilepsy symptomatic of a left middle cerebral artery stroke. (A) Interictal spikes were recorded with high-resolution EEG, 64 electrodes (Gavaret et al., 2004). (B) Selection of time window analysis. (C) Interictal source localization using MUSIC algorithm
(Mosher et al., 1992). (D) Seizure recorded with high-resolution EEG. Several ictal spikes preceded a tonic discharge.
(E) Selection of time window analysis. (F) Ictal source localization using MUSIC algorithm. The maximal source probability
was slightly more medial for the ictal spike than for interictal spikes.
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consciousness and should be performed in the case of
PLEDs. It appears to have maximal yield for capturing
potentially epileptogenic abnormalities within the first
48 h of recording, and cEEG is essential for the detection
of seizures with subtle or no clinical manifestations. In
patients with intracerebral hemorrhage, ictal discharges
are recorded using cEEG in 30% of them, half of these
ictal discharges being purely electroencephalographic.
Ictal discharges are important to detect, as seizures
may indeed lead to increased blood flow, elevated blood
pressure, and blood–brain barrier disruption that could
cause additional hemorrhage (Claassen et al., 2007).
POSTSTROKE NEUROMODULATION
A large amount of data supports the value of noninvasive brain stimulation techniques to promote stroke rehabilitation in clinical practice (Grefkes and Fink, 2016;
Smith and Stinear, 2016). These techniques mainly
include repetitive transcranial magnetic stimulation
(rTMS) and transcranial direct current stimulation
(tDCS). The level of evidence for clinical efficacy is
B or C (probable or possible efficacy) for rTMS
(Lefaucheur et al., 2014) and remains lower for tDCS
(Lefaucheur et al., 2017), for which there is only 10 years
of clinical application (Lefaucheur, 2016).
Any rTMS or tDCS approach is based on the concept
of interhemispheric rivalry and aims at modulating
the imbalance of cortical activities between both
hemispheres resulting from stroke. In the brain region
affected by stroke, neuronal activity rapidly decreases
and this is followed by an increased activity in the homologous region of the contralesional hemisphere due to
diminished ipsilesional-to-contralesional interhemispheric inhibition (Grefkes and Ward, 2014). In turn, this
contralesional increase in neuronal activity reinforces
ipsilesional inhibition via transcallosal pathways. Contralesional activity returns close to normal values when
motor function improves but remains elevated when significant clinical impairment persists. All these poststroke
changes in cortical excitability can be objectified by
single- and paired-pulse paradigms of transcranial
magnetic stimulation (TMS) (Traversa et al., 1998;
Murase et al., 2004; Lefaucheur, 2006).
Any technique able to reduce excitability of the unaffected hemisphere or to increase excitability of the
affected hemisphere could be relevant for poststroke
rehabilitation. For example, the stroke-lesioned brain
region can be reactivated directly by an “excitatory” stimulation applied to it or indirectly by an “inhibitory” stimulation applied to the disinhibited homologous region of
the contralesional hemisphere. Regarding noninvasive
brain stimulation techniques, the main protocols thought
to increase excitability are high-frequency (HF) rTMS
and anodal tDCS, whereas low-frequency (LF) rTMS
and cathodal tDCS are thought to decrease cortical excitability (Fig. 7.3).
In normal subjects, HF rTMS (repeated short trains
with inner frequency of 5 Hz or more) increases cortical
excitability beyond the time of stimulation (PascualLeone et al., 1994), whereas LF rTMS (long tonic train
at 1 Hz or less) leads to a long-lasting decrease in cortical
excitability (Chen et al., 1997). These changes were
thought to correspond to long-term synaptic potentiation
and depression processes, respectively. Mansur et al.
(2005) first showed that to inhibit the unaffected primary
Fig. 7.3. Model of interhemispheric rivalry on which noninvasive brain stimulation (NBS) protocols are based to promote poststroke recovery. IHI, transcallosal interhemispheric inhibition; LF/HF-rTMS, low-frequency/high-frequency repetitive transcranial magnetic stimulation; tDCS, transcranial direct current stimulation.
CLINICAL NEUROPHYSIOLOGY OF STROKE
motor cortex (M1) by LF rTMS within the first year after
stroke led to substantial gain of motor function for the
affected hand in hemiparetic patients (Mansur et al.,
2005). Takeuchi et al. (2005) confirmed that motor
performance could improve after a single LF rTMS session applied over the unaffected M1 of hemiparetic
patients (Takeuchi et al., 2005). Moreover, this latter
study showed that functional improvement correlated
with a reduced interhemispheric inhibition from the
unaffected to the affected hemisphere.
However, a single rTMS session only provides shortlasting effects. Both magnitude and duration of rTMS
effects show increase with the repetition of the sessions.
In this regard, Fregni et al. (2006) first reported that a
significant improvement in motor performance could last
for at least 2 weeks beyond the time of a 5-day protocol of
contralesional M1 LF rTMS in chronic hemiplegics
(Fregni et al., 2006). Moreover, motor improvement
correlated with increased corticospinal excitability in
the affected hemisphere. Since then, several controlled
studies have confirmed the value of this approach not
only in the chronic, but also in the acute or postacute,
phase of stroke. It is important to underline that the
potential therapeutic value of rTMS appears to depend
on the time between stroke onset and treatment application. The highest level of evidence for contralesional M1
LF rTMS efficacy was reached in the chronic phase of
poststroke recovery (Lefaucheur et al., 2014).
Fewer studies were based on HF rTMS delivered to
ipsilesional M1. In the acute or postacute poststroke
stage, beneficial results were reported (Khedr et al.,
2005; Khedr et al., 2009; Chang et al., 2010; Khedr
et al., 2010; Chang et al., 2012). Ipsilesional HF rTMS
could be as efficacious as contralesional LF rTMS in a
more chronic stage (Emara et al., 2009, 2010).
Conversely, one study showed that contralesional LF
rTMS was able to produce a greater improvement in
motor function than ipsilesional HF rTMS (Khedr
et al., 2009). Therefore, the question of whether contralesional LF rTMS, ipsilesional HF rTMS, or both should be
preferentially used still requires further investigation,
especially regarding the real therapeutic impact of rTMS
therapy in the long term.
In addition to classical protocols of LF/HF rTMS,
other TMS methods have been proposed to enhance
motor stroke recovery, i.e., theta-burst stimulation
(TBS) and interventional paired associative stimulation
(IPAS). Motor performance in stroke patients was shown
to improve following a single session of continuous TBS
aimed at decreasing contralesional M1 excitability
(Meehan et al., 2011) or intermittent TBS trains aimed
at increasing ipsilesional M1 excitability (Ackerley
et al., 2010; Hsu et al., 2013). It is difficult to draw
115
any conclusion from these results, since one study based
on repeated daily sessions remained negative for both
approaches (Talelli et al., 2012). However, some promising results were reported by using a combination of TBS
and more classical rTMS protocol to promote motor
recovery according to poststroke interhemispheric metaplasticity (Sung et al., 2013; Wang et al., 2014). Regarding IPAS, it consists of pairing electrical stimuli
delivered to a peripheral nerve and cortical TMS pulses
to generate long-term potentiation (LTP) like effects
within M1 (Stefan et al., 2000). One study reported beneficial IPAS effects on stroke recovery (Uy and Ridding,
2003). In this study, electrical stimulation of the common
peroneal nerve at the leg was associated with single-pulse
TMS of lower limb M1 over 4 weeks in nine chronic
hemiplegics. Improvement was observed on several
objective and subjective measurements. Therefore
inducing cortical plasticity and LTP-like effects would
be feasible, even a long time after stroke occurred.
Regarding tDCS, it consists of delivering lowintensity direct currents on the scalp that cross the skull
to induce sustained changes in neural cell membrane
potential and cortical excitability (Nitsche and Paulus,
2000). Cathodal tDCS leads to brain hyperpolarization
(inhibition) and therefore should be applied to the unaffected motor cortex, whereas anodal tDCS results in
brain depolarization (excitation) and should be applied
to the lesioned hemisphere. In clinical practice, the
potential advantage of tDCS, as compared to rTMS, is
that tDCS can be employed as a low-expense, batterydriven, portable system.
Two large randomized controlled tDCS trials did not
report beneficial effects of tDCS on poststroke motor
recovery, presumably because of the inclusion of patients
with severe cortical stroke in one study (Hesse et al.,
2007) and the application of tDCS in the immediate acute
phase (2 days after stroke) in the second study (Rossi
et al., 2013). Other controlled tDCS studies reported
either positive or negative results, along with a great heterogeneity in the methods of performing and assessing
tDCS. For example, in chronic stroke patients, anodal
tDCS of ipsilesional motor cortex was shown to improve
quality of life but not motor performance in one study
(Viana et al., 2014) and to improve some motor tests
but not all in another study (Allman et al., 2016). One
meta-analysis showed small to moderate effect sizes
for the improvement of upper limb function following
anodal tDCS of ipsilesional M1 in chronic stroke patients
(Butler et al., 2013). Another meta-analysis showed
moderately beneficial effect of tDCS on daily living
activities but no evidence for motor function improvement (Elsner et al., 2016). A third meta-analysis showed
moderate long-term effects on motor learning after anodal
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tDCS of ipsilesional M1, cathodal tDCS of contralesional
M1, or even bihemispheric stimulation of M1 in the postacute or chronic stage of poststroke recovery (Kang et al.,
2016). Indeed, one promising approach is to perform
bihemispheric stimulation, with the cathode over the
contralesional M1 region and the anode over the lesioned
M1 (Lindenberg et al., 2010). However, the level of evidence remains insufficient to make any recommendation
regarding the application of any tDCS protocol to promote
poststroke recovery in clinical practice to date.
The size and site of the lesion could also influence the
potential therapeutic efficacy and underlying mechanisms of action of cortical stimulation in poststroke rehabilitation. For example, several studies suggest that the
beneficial effect of rTMS is more marked in subcortical
rather than cortical stroke (Ameli et al., 2009; Emara
et al., 2009). In fact, rTMS can enhance stroke recovery
by acting directly on the underlying cortical region or
through its connections with other structures, via either
ipsilateral or transcallosal pathways. When motor structures are rather preserved in the affected hemisphere,
inhibition of contralesional homologous motor cortex
can positively impact on stroke recovery. This strategy
may be less relevant when neuronal destruction is more
extensive in the stroke region (Bradnam et al., 2012).
A bimodal balance-recovery model, correlating the
extent of stroke, interhemispheric connections, and the
potential for functional recovery, was proposed to set
up cortical stimulation protocols on a more personalized
approach (Di Pino et al., 2014).
Another unresolved question is to what extent noninvasive cortical stimulation techniques could be synergistic with other nonpharmacologic therapies, such as
virtual reality training, occupational therapy, physical
therapy, motor training, robot-assisted training, or
constraint-induced movement therapy (Avenanti et al.,
2012; Conforto et al., 2012; Viana et al., 2014; Picelli
et al., 2015; Rocha et al., 2016). A combination of
several rehabilitation techniques could bring the effect
of noninvasive brain stimulation to a more clinically
meaningful level.
Beyond increasing motor performance of the affected
limbs, noninvasive brain stimulation could also be
valuable to promote recovery from poststroke swallowing dysfunction, spasticity, aphasia, or hemispatial
neglect (Lefaucheur et al., 2014, 2017). In all these
domains, the main questions that should be addressed
in future large controlled studies are: how to stimulate
(regarding side, site, and parameters of stimulation)
and when to stimulate (at what delay after stroke
onset), according to the degree of clinical impairment, the location and extent of stroke lesion, and
the combination with concomitant neurorehabilitation
programs.
ABBREVIATIONS
cEEG, continuous EEG; DC, direct current; ECoG,
electrocorticography; FIRDA, frontal intermittent rhythmic delta activity; IHI, transcallosal inter-hemispheric
inhibition; IPAS, interventional paired associative stimulation; LF/HF-rTMS, low-frequency/high-frequency
repetitive transcranial magnetic stimulation; LTP, longterm potentiation; M1, primary motor cortex; NBS,
non-invasive brain stimulation; PID, peri-infarct depolarizations; PLEDs, periodic lateralized epileptic discharges; SD, spreading depolarization; TBS, theta
burst stimulation; tDCS, transcranial direct current
stimulation.
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