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: martine.gavaret@parisdescartes.fr 110 M. GAVARET ET AL. 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 112 M. GAVARET ET AL. 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. 114 M. GAVARET ET AL. 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 116 M. GAVARET ET AL. 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. REFERENCES Ackerley SJ, Stinear CM, Barber PA et al. (2010). Combining theta burst stimulation with training after subcortical stroke. Stroke 41 (7): 1568–1572. Afsar N, Kaya D, Aktan S et al. (2003). Stroke and status epilepticus: stroke type, type of status epilepticus, and prognosis. Seizure 12 (1): 23–27. Allman C, Amadi U, Winkler AM et al. (2016). 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