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Stroke rehabilitation using noninvasive cortical stimulation: hemispatial neglect Expert Rev. Neurother. 12(8), 983–991 (2012)

Veit Mylius*1,2, Samar S Ayache1,3, Hela G Zouari1,3,4, Mehdi Aoun-Sebaïti5, Wassim H Farhat1,3 and Jean-Pascal Lefaucheur1,3 Université Paris-Est-Créteil, Faculté de Médecine, EA 4391, Créteil, France 2 Department of Neurology, Philipps University Marburg, Baldingerstrasse, Marburg 35033, Germany 3 Assistance Publique – Hôpitaux de Paris, Hôpital Henri Mondor, Service de Physiologie – Explorations Fonctionnelles, Créteil, France 4 CHU Habib Bourguiba, Service d’explorations fonctionnelles, Sfax, Tunisia 5 Assistance Publique – Hôpitaux de Paris, Hôpital Henri Mondor, Service de Neurologie, Créteil, France *Author for correspondence: Tel.: + 49 6421 58 65200 Fax: + 49 6421 58 65208 [email protected] 1

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The rehabilitation of neuropsychological sequels of cerebral stroke such as hemispatial neglect by noninvasive cortical stimulation (NICS) attracts increasing attention from the scientific community. The NICS techniques include primarily repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). They are based on the concept of either reactivating a hypoactive cortical region affected by the stroke (the right hemisphere in case of neglect) or reducing cortical hyperactivity of the corresponding cortical region in the contralateral hemisphere (the left hemisphere). In the studies published to date on the topic of neglect rehabilitation, rTMS was used to inhibit the left parietal cortex and tDCS to either activate the right or inhibit the left parietal cortex. Sham-controlled NICS studies assessed short-term effects, whereas long-term effects were only assessed in noncontrolled rTMS studies. Further controlled studies of large series of patients are necessary to determine the best parameters of stimulation (including the optimal cortical target location) according to each subtype of neglect presentation and to the time course of stroke recovery. To date, even if there are serious therapeutic perspectives based on imaging data and experimental studies, the evidence is not compelling enough to recommend any particular NICS protocol to treat this disabling condition in clinical practice. Keywords: cortical excitability • hemispatial neglect • neuromodulation • stroke • theta burst stimulation • transcranial direct current stimulation • transcranial magnetic stimulation

The development of new treatment strategies of hemispatial neglect is of considerable importance since it is frequently associated with right hemispheric stroke (at least in 20% of all types of stroke and 48% of the right hemispheric strokes) with a negative influence on the rehabilitation of various functions and thereby on the clinical outcome [1]. Current therapeutic strategies comprise mainly visual exploration with visuo spatial training [2] and neck muscle vibration [3]. Some studies showed beneficial effects of optokinetic stimulation, prism adaption as well as of peripheral sensory stimulation [4–6]. Similarly to poststroke motor deficit or aphasia (for review see [7,8]), noninvasive cortical stimulation (NICS) could be used as a therapy also for neglect, either solely or in addition to conventional therapy (for review see [9]). Hemispatial neglect is defined as a failure “to report, respond or orient to novel or meaningful 10.1586/ERN.12.78

stimuli presented to the side opposite a brain lesion” [10]. In general, motor responses and/or perceptual processes (motor or perceptual neglect) associated with lesions located in frontal or temporoparietal networks of the right hemisphere (90 %) are concerned [11]. Neglect can be divided into personal neglect (contralesional body side), peripersonal neglect (near space) or extrapersonal neglect (the space beyond a distance) [12]. In addition, egocentric neglect can be distinguished from allocentric neglect when the neglect refers to objects. Extinction (visual or tactile) is frequently associated with neglect, but represents at least in part a distinct feature with a strong association of visual but not of tactile extinction with neglect [13]. A variety of neuropsychological paper and pencil tests comprising mainly the line bisection, the landmark task, and cancellation tests using various objects or letters (e.g., Bells Tests or letter

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Mylius, Ayache, Zouari, Aoun-Sebaïti, Farhat & Lefaucheur

cancellation task) allows for its assessment [14–16] . The Behavioural Inattention Test, comprising various tests or the computerized assessment with the Test Battery for Attention Performance, represent alternative tools [17,18] . The Ota search task serves to divide egocentric from allocentric neglect [19] , whereas the Lateralized Target and the Lateralized Response Test is one of the tests proposed to distinguish motor from perceptual neglect [20,21] . Hemispatial neglect can be attributed to lesions within broad areas of the right hemisphere depending on assessment time (e.g., basal ganglia and inferior and mesial temporal cortex in acute stroke and orbito–frontal, sensory–motor, inferior and mesial temporal, inferior parietal and occipital cortices in chronic stroke) [13], comprising two functional related networks [22]. Lesions of the right inferior parietal lobe lead to perceptive/visuospatial neglect, the lesion of the right dorsolateral prefrontal cortex is responsible for the exploratory/visuomotor neglect, deep temporal regions account for the allocentric component and subcortical damage leads to an increased severity (presumably associated with a dysexecutive syndrome) [22]. Concerning the course, the impairment of the bilateral frontal or temporoparietal networks is often followed by a lateralized dysfunction of the posterior parietal network leading to the symptoms of left biased neglect [23]. This posterior parietal dysfunction seems crucial to induce neglect symptoms and its restoration during the course correlates with clinical recovery [23]. In fact, the cortical process involved in one hemisphere regarding the attention to the contralateral hemispace is balanced by inhibitory influences from the other hemisphere via interhemispheric connections. A cerebral stroke of one or more cortical areas in the right hemisphere leads to a reduced cortical excitability within the affected zones and thus to a disinhibition of the corresponding cortical areas in the left hemisphere due to a reduced transcallosal inhibition from the right to the left hemisphere [24–26]. Consequently, the increased activity of the left hemisphere shifts the attention to the right hemispace and further reduces the activity of the right hemisphere due to an increased transcallosal inhibition from the left to the right hemisphere. Thus, protocols of NICS in neglect are based on the concept to either increase the excitability of the right hemisphere or to decrease the excitability of the left hemisphere [26,27]. This theoretical approach is based also on the first descriptions of hemispheric rivalry as described by Kinsbourne et al. [28] and was employed for therapeutic studies in the rehabilitation of poststroke motor deficit or aphasia. A recent study has demonstrated that neglect patients had an increased excitability of left parietal regions, compared to non-neglect patients and healthy volunteers [29]. The present review includes the nine studies published to date that report clinical effect of NICS (repetitive transcranial magnetic stimulation [rTMS] or transcranial direct current stimulation [tDCS]) on neglect in stroke patients. Experimental studies explaining the mechanisms involved in such a strategy will be discussed before summarizing the therapeutic approaches. Modulation of parietal cortex activity by NICS in healthy volunteers & stroke patients

The magnetic field of the TMS coil induces an electrical current within the underlying cortical region that can influence neural 984

activities in the stimulated cortical area and the connected brain structures [30] . A transient alteration of the function of the stimulated cortical target (‘virtual lesion’ type of protocol) can be obtained by using various single-pulse TMS (sTMS), paired-pulse TMS (ppTMS) or rTMS paradigms [31] . ppTMS can also be used to assess intracortical excitability, the effects of a conditioning stimulus on the test stimulus depending on the recruitment of various neural circuits at given interstimuli intervals (ISIs) [32] . Finally, rTMS can modulate cortical excitability depending on stimulation frequency, cortical target location, pathophysiological condition and interindividual differences. In a majority of normal subjects, when applied to the primary motor cortex, low-frequency rTMS (LF-rTMS) decreases corticospinal output, whereas highfrequency rTMS increases it [33,34] . The clinical impact of rTMS can occur or last beyond the time of stimulation. The critical stimulus onset asynchrony (SOA) for an interaction of sTMS with visual attention or extinction was found to be 150 ms [35] , whereas SOAs of 40 ms were assessed for sensory extinction as shown in the first study performed on this topic by Oliveri et al. (Table 1) [36] . These intervals were then used in further studies examining sTMS-induced visuospatial interactions. When sTMS is applied over the left or right posterior parietal cortex (PPC; P3 or P4 in the International 10–20 EEG Electrode System) with such a delay before visual stimulation, the detection of contralaterally applied stimuli was impaired whether unilateral or bilateral application [37] . However, bilateral sensory extinction was induced only for right parietal stimulation [36] . A further study revealed that extinction-like behavior can also be obtained when the temporoparietal junction (TPJ) but not the superior temporal gyrus (STG) is targeted [38] . Similarly, rTMS protocols showed that extinction and visuospatial hemineglect can be induced by bihemispheric stimulation of P3 and P4 [27] , whereas only right-sided stimulation induced visuospatial hemineglect in a second study targeting P5 and P6 [39] . In these studies, both stimulation frequency and cortical target location differed (P6/5 vs P4/3), presumably explaining the difference in right-biased effects for the target located more posteriorly. According to anatomical data, it has been proposed that the right inferior PPC and the TPJ have distinct contributions to different aspects of neglect [40] . TMS protocols of ‘virtual lesion’ type over the right hemisphere showed that the PPC could contribute to perceptual visual neglect and easy exploratory search, whereas the STG could be involved in more difficult exploratory search [41] . A subsequent investigation pointed out that the right dorsolateral prefrontal cortex could contribute to motor neglect, whereas PPC could be rather involved in perceptual forms of neglect [21] . The excitability of the parietal cortex can be assessed with ppTMS using similar paradigms as employed for the motor cortex: a conditioning stimulus applied to the right PPC (P4; at infrathreshold intensity) being followed by a test stimulus applied to the motor cortex (at suprathreshold intensity) at different ISIs. When applied 150 ms following a visual stimulation, the perception of left-applied visual stimuli was enhanced at ISI of 3 ms, and suppressed at ISI of 5 ms when presented bilaterally (extinction phenomenon) [42] . One further study showed that ppTMS applied over Expert Rev. Neurother. 12(8), (2012)

Noninvasive cortical stimulation in hemispatial neglect

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Table 1. Experimental transcranial magnetic stimulation studies of hemispatial neglect and extinction in healthy volunteers and stroke patients. Study (year)

Number and type of subjects/patients

Target, coil type

Control Parameters of condition stimulation

Results

Ref.

Experimental studies in healthy volunteers Oliveri et al. (1999)

17 healthy volunteers

4 cm in front and 4 cm behind the hot spot

Control site (O1, O2, FP1 and FP2)

Fierro et al. (2000)


P5/P6, F8

Sham rTMS Ten pulses rTMS at 25 Hz, 400 ms, 115% RMT

Hilgetag et al. (2001)

Seven healthy volunteers P3/P4, F8

Active M1 rTMS 1 Hz, 600 s, 90% Visual extinction induced stimulation RMT contralaterally and visual attention increased ipsilaterally

[27]

Dambeck et al. (2006)

Ten healthy volunteers

P3/P4 or both, F8

Sham TMS sTMS, 60% MSO, 150 and catch or 250 ms following a trials visual detection task

Impairment of contralateral visual stimulus detection for both P3 and P4 stimulation when presented alone or with ipsilateral presentation at an ISI of 150 ms, but not at an ISI of 250 ms or after bilateral TMS

[37]

Meister et al. (2006)


Right TPJ/STG, F8

Sham TMS sTMS, 60% MSO, 150 and catch or 250 ms following a visual detection task trials

Impairment of contralateral visual stimulus detection when presented with ipsilateral presentation and the right TPJ stimulation

[38]

sTMS at 100% RMT with intervals of 20 or 40 ms

Interference with bilateral detection of cutaneous stimuli for right parietal stimulation

[36]

Increased leftwards errors for the right TMS

[39]

Experimental studies in stroke patients Oliveri et al. (1999)

14 left and 14 right cerebral infarction

F3/4, P3/4

Control sTMS at 110% RMT site (FP1/2) with an interval of 40 ms to cutaneous stimulation

Left frontal TMS reduced the rate of contralaterally applied stimulations only in right cerebral infarction

[47]

Oliveri et al. (2000)

Eight right cerebral infarction (30–365 days after stroke)

F3/P3, F8

No

sTMS and ppTMS (ISI 1–10 ms), 70% (CS) –130% (TS) RMT, at different delays to tactile stimulation (10, 20, 30 and 40 ms)

Improvement of tactile extinction by sTMS and ppTMS (ISI 1 ms), but worsening of tactile extinction by ppTMS (ISI 10 ms). Earlier effects for P3 stimulation (after a delay 20–30 ms versus 40 ms for ISI 1 ms)

[26]


F3/4, FP3/4, No 15 left and 15 right cerebral infarction (three P3/4, F8 groups: tactile extinction, neglect and somatosensory deficit)

sTMS, four blocks with 45 stimuli for each target, at 40 ms after electrical stimulation

Left frontal sTMS reduced contralateral extinction in rightsided cerebral infarction but had no effect in left-sided cerebral infarction. Right-sided stimulation had no effect

[25]

CS: Conditioning stimulation; F8: Figure-of-eight coil; ISI: Interstimulus interval; MSO: Maximal stimulator output; ppTMS: Paired-pulse transcranial magnetic stimulation; RMT: Resting motor threshold; rTMS: Repetitive transcranial magnetic stimulation; STG: Superior temporal gyrus; sTMS: Single-pulse transcranial magnetic stimulation; TMS: Transcranial magnetic stimulation; TPJ: Temporoparietal junction; TS: Test stimulation.

the right parietal cortex (P6) at ISI of 5 ms and SOA of 150 ms was able to restore the reduced detection that was observed for sTMS or ppTMS at ISIs of 1–3 ms [43] . The differences between the two studies on the ISIs were presumably due to the fact that both cortical targets (P4 vs P6) and tests performed (extinction vs detection) were different [42,43] . This further suggests that either intracortical inhibitory control or a release of interhemispheric inhibition leads to a shift of attention. Similar patterns of inhibition were also observed for other perceptual modalities (e.g., sensory stimuli) [44] . www.expert-reviews.com

For sensory stimulation applied peripherally, ppTMS of the right parietal sensory cortex produced a decreased detection at ISI of 1 ms and an increased detection at ISI of 5 ms [45] , suggesting that a modality-independent perception process exists in the parietal cortex. Differences in the profile of results for ppTMS paradigms between parietal and motor cortex excitability further underscore the specificity of intracortical parietal patterns. Interestingly, LF-rTMS was found to be able to restore a normal excitability for ppTMS paradigms in the unaffected left hemisphere, which 985

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showed an increased excitability at baseline in neglect patients [29] . According to the concept of interhemispheric rivalry, this result supports the potential therapeutic value of inhibitory rTMS applied to the unaffected hemisphere. In summary, TMS studies performed in healthy volunteers showed that neglect- and extinction-like symptoms could be experimentally produced and that fronto-temporoparietal cortical regions were involved in such symptoms. By contrast, only a few tDCS studies performed in normal subjects relate to this topic. In one sham-controlled study, excitatory tDCS was applied to the right or left PPC with multisensory visual field exploration and showed beneficial effects only for right-sided stimulation on visual scanning in healthy volunteers [46] . The effects on visual exploration found in this study suggest that an increased excitability of the PPC could enhance visuo spatial orienting strategies, opening perspectives for the use of this approach to improve visuospatial neglect in stroke patients [46] . In patients, experimental sTMS and ppTMS paradigms were also applied [25,26,36] . In one study, it was shown that sTMS applied contralaterally to the lesioned hemisphere at a SOA of 40 ms decreased the level of extinction only in right-sided strokes following frontal [47] or frontal and parietal TMS pulses [25] . A further study of the same group showed that sTMS applied over left frontal and parietal areas decreased extinction but that the effects of ppTMS depended on the ISI, with a further improvement at ISI of 1 ms and a return to baseline at ISI of 10 ms [26] . However, these effects were seen at shorter ISIs for parietal targets than for frontal targets, showing a time-dependent processing of visuospatial information in the unaffected hemisphere. NICS studies attempting to reduce hemispatial neglect in stroke patients

To date, nine studies have examined the clinical effects of NICS protocols on patients with hemispatial neglect related to rightsided hemispheric stroke due to ischemia or hemorrhagic infarction (Tables 2 & 3) . NICS was delivered at various times after stroke (from 7 days [24] to 3 years [48]). The parameters of stimulation were also very variable, but in all cases the cortical target was parietal (P3/P4, P5/P6). Some studies were based on a single session [29,48–50] , whereas the others include 10–20 daily rTMS sessions [51–54] . Five rTMS studies assessed the therapeutic effects of LF-rTMS delivered to the left parietal cortex (P3/P5) [29,51–54] . This type of NICS protocol is thought to be inhibitory, as continuous theta burst stimulation (cTBS), high-frequency rTMS (interference protocol) and cathodal tDCS were also applied to P3 [24,48,50] . By contrast, excitatory protocols, such as anodal tDCS, were applied to the right parietal cortex (P4/P6) [49,50] . According to the model of reciprocal interhemispheric inhibition, these strategies aimed at reducing the activity of the disinhibited parietal cortex in the left hemisphere or at reactivating the lesioned parietal cortex in the right hemisphere [28] . All these studies showed a significant positive impact of NICS on hemispatial neglect. However, most of rTMS studies had an open design, without any placebo-controlled condition. The only two rTMS studies that included a control 986

condition (sham stimulation) [24,48] were based on a single session, and therefore were of limited therapeutic value. Similarly, the sham-controlled tDCS studies were based on a single session and only assessed short-term effects [49,50] . Three studies assessed the long-term effects of repeated rTMS sessions for at least 10 days, but did not present a sham-controlled design. They reported beneficial effects in the Line Bisection Test for up to 2 weeks [51,54] and in the Behavioural Inattention Test for up to 6 weeks in a case report of two patients [53] . Interestingly, one of those trials employed a stimulation twice daily for 10 days [54] . Another study with a parallel-group design showed that rTMS coupled with behavioural therapy was superior to behavioural therapy only [52] . However, this study did not evaluate the long-term effects, although ten sessions were performed. The difference in the location of the target of stimulation between these studies merits discussion, since either P3/P4 or P5/P6 scalp site, according to the International 10–20 EEG Electrode System, was chosen. Most imaging studies locate P3/P4 and P5/P6 over the posterior part of the inferior parietal lobe (Brodmann area 7/40) [37,55] . In experimental studies, targeting was rather based on individual anatomy using a neuronavigation system, in order to stimulate the STG or TPJ [38,56] , while the PPC was targeted by using an interference procedure [41] . However, this latter approach cannot be employed in patients. So far, in therapeutic rTMS and cTBS studies, P3 [29,48,54] or P5 [24,51–53] was targeted (including two sham-controlled studies for each target), without any clear difference between these two targets in terms of efficacy. Two studies showed that targeting P5 with an inhibitory rTMS protocol for 10 days resulted in an improvement on various visuospatial tasks, which lasted for 2 and 6 weeks in three and two patients, respectively [51,53] . One study targeting P3 with 20 rTMS sessions (twice daily) also showed some beneficial effects on visuospatial neglect for 2 weeks [54] . Thus, there is no convincing evidence to date to make distinctions between the therapeutic value of these two parietal targets. The inhibition of the contralesional (posterior) parietal cortex appeared to be the best NICS strategy to treat visuospatial neglect, at least using rTMS. However, until now, no therapeutic studies targeted more frontal regions that have yet shown interest in experimental TMS and neuroimaging studies [13,22,23,38,41] . Also, there has been no rTMS studies based on ipsilesional excitatory protocols, whereas excitatory anodal tDCS protocols showed beneficial effects when applied to P4 or P6 scalp site in the affected parietal regions of the right hemisphere [49,50] . Overall, from the reported results to date, it is difficult to know whether it is better to reactivate the lesioned cortex or to inhibit the contralesional cortex for the rehabilitation of visuospatial neglect. One tDCS study compared both approaches in the same patients and concluded that they were equally effective to reduce neglect symptoms [50] . In summary, inhibitory rTMS protocols were applied over the PPC of the nonlesioned hemisphere (P3/P5) with positive shortterm effects in controlled single-session studies, whereas long-term effects were only seen in open-label studies. tDCS studies showed Expert Rev. Neurother. 12(8), (2012)

None

None

P5, F8


P5, F8

P3, F8

P3, F8

P3, F8

P5, F8

Two (180 days after stroke)

12 neglect and eight non-neglect (31–172 days after stroke) and ten healthy controls

11 (12–1080 days after stroke)


Shindo et al. (2006)

Koch et al. (2008)

Nyffeler et al. (2009)

Song et al. (2009)

Lim et al. 14 (9–470 days after (2010) stroke)

0.5 Hz, 90% RMT

Line Bisection Test [16] , Albert Test [62]

Improvement in the Line Bisection Test 1 day following the stimulation (no follow-up)

Improvement of the line bisection and the line cancellation tests for up to 2 weeks

cTBS: Continuous theta burst stimulation; F8: Figure-of-eight coil; ISI: Interstimulus interval; RMT: Resting motor threshold; rTMS: Repetitive transcranial magnetic stimulation; TBS: Theta burst stimulation.

900 pulses, ten sessions

Line Bisection Test [16] , 450 pulses, 20 sessions (2 per day Line Cancellation Test for 10 days)

[52]

[54]

[48]

Improvement for left-sided targets and reaction time in a visuospatial task for 8 h after two TBS trains and for 32 h after four TBS trains (follow-up for 32 h after two TBS trains and for 96 h after four TBS trains)

[53]

[51]

cTBS train (three pulses at 801 pulses (cTBS train Vienna Test System subtask (peripheral of 44 s), two or four 30 Hz, ISI: 100 ms), visual attention during a trains 100% RMT central tracking task)

Improvement of the Behavioral Inattention Test in the two patients for 6 weeks

Improvement in all tests lasting at least 15 days

[29]

Behavioral Inattention Test [17]

Visuospatial task (exactly bisected test, left-elongated, right-elongated tasks), Line Bisection Test [12] , clock drawing

[24]

Ref.

Improvement from 65 to 80% for the left-sided objects (no follow-up)

600 pulses, one session



Improvement by active rTMS compared to sham rTMS and baseline (no follow-up)

Results

Visual Chimeric Test [61]

1 Hz, 90% RMT

0.9 Hz, 95% RMT

1 Hz, 90% RMT

Behavioural 1Hz, 90% RMT rTMS before behavioural therapy therapy (30 min) only

None

Sham coil

None

Bisected lines length judgment

Three (90–150 days after stroke)

300 pulses, one session

Brighina et al. (2003)

25 Hz, 115% RMT

P5/P6, F8

Seven (7–336 days after stroke)


Sham coil

Target, coil Control Stimulation frequency Number of pulses Tests type condition and intensity per session and number of sessions

Number and type of patients

Study (year)

Table 2. Therapeutic studies using repetitive transcranial magnetic stimulation and continuous theta burst stimulation in stroke patients with hemispatial neglect.


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Table 3. Therapeutic studies using transcranial direct current stimulation in stroke patients with hemispatial neglect. Study (year)

Number and type of patients

Target Control Stimulation Duration Tests condition polarity and and number intensity of sessions

Results

Ko et al. (2008)


P4

Figure cancellation (shape unstructured and letter structured), Line Bisection Test [12]

Improvement of the percent deviation score of the Line Bisection Test and of the omissions for the shape unstructured cancellation test following anodal tDCS (no follow-up)

[49]

Sparing et al. (2009)

10 (15–372 days P3/P4 after stroke), 20 healthy controls

TAP Test Battery subtest ‘neglect’ [18] , Line Bisection Test [12]

Improvement of reaction time in the neglect test (TAP) following right anodal tDCS. Improvement of the Line Bisection Test following right anodal and left cathodal tDCS (no follow-up)

[50]

Sham tDCS

Anodal, 2 mA

20 min, 1 session

Sham tDCS

Anodal (P4) or 10 min, cathodal (P3), 1 session 1 mA

Ref.

TAP: Test Battery for Attention Performance; tDCS: Transcranial direct current stimulation.

no significant differences between the beneficial effects of excitatory stimulation of the lesioned cortex and inhibitory stimulation of the nonlesioned cortex. However, we must be cautious in recommending excitatory protocols applied to lesioned cortical areas because of the risk of inducing seizures in stroke patients, particularly in the acute/postacute phase. In epileptic patients, a meta-analysis showed that the overall risk of inducing seizures was 1.4%, whatever the type of rTMS protocol and patient [57] . In fact, stroke cannot be an absolute contraindication for excitatory NICS protocols, but the risk–benefit ratio of such protocols must be thoroughly evaluated in stroke patients. For the use of a classical tDCS technique, the stimulated cortical areas are larger than with rTMS, reducing the need for precise targeting. However, the precise definition of the cortical target is a challenge before considering most clinical applications of NICS to treat neglect in the future. In this regard, various recent technical developments, such as image-guided navigated rTMS [38,58] or high-definition tDCS (HD-tDCS) [59], should be taken into account. For example, the cortical NICS target could be defined according to the structures of which lesion would be involved in the clinical symptoms to adequately modulate cortical excitability for each individual. According to recent imaging studies, it seems conceivable to promote stroke recovery by modulating neural excitability of selected networks only [22,23]. Also, the temporospatial relationship between the time course of the recovery process and the interaction between the frontal and parietal networks should be taken into consideration [23]. Another important consideration is the duration of the effects after the application of a NICS protocol. In most studies, NICS effects were assessed immediately after stimulation and, therefore, no conclusions can be drawn about long-term effects. To repeat daily NICS sessions for several days or weeks is thought to enhance and prolong the effects of a single session [60] . However, it is currently not clear whether NICS could be a suitable therapeutic 988

tool in the clinical management of poststroke neglect, even in an add-on design, combined with other therapeutic approaches. Furthermore, the best time of its use with respect to stroke onset and assumed additive effects with conventional or currently developed therapies enhancing right hemisphere activities shall be determined. Expert commentary

As for other poststroke symptoms, NICS techniques, including rTMS and tDCS, appear to be a promising tool for the treatment of patients suffering from hemispatial neglect. However, there is still a lack of convincing studies to date, especially regarding the long-term effects, before considering this approach in clinical application. Short-term improvement has been reported in stroke patients with hemispatial neglect following LF-rTMS or brief cTBS trains applied to the parietal cortex of the unaffected left hemisphere or anodal tDCS applied to the lesioned parietal cortex of the right hemisphere. Open, non-sham-controlled rTMS studies showed a clinical effect of NICS on neglect up to 2 weeks after a series of ten daily sessions of cortical stimulation. Five-year view

According to the rules of evidence-based medicine, double-blind placebo-controlled multicenter trials are essential to determine the therapeutic value of NICS in the long term in patients with visuospatial neglect. Inhibitory protocols delivered to the contralesional cortex should be compared to excitatory protocols delivered to the lesioned cortex in terms of efficacy and risk, especially of inducing seizures. Different cortical targets remain to be investigated for their interest to influence the various clinical aspects of the right-hemisphere syndrome, including motor and perceptual neglect, but also anosognosia or other attention disorders. Image-guided navigated rTMS or HD-tDCS should be useful for this purpose. The place of NICS as an add-on Expert Rev. Neurother. 12(8), (2012)


therapy combined with other therapeutic strategies of neglect should be assessed, especially in their ability to promote longterm synaptic plasticity. Finally, based on recent neuroimaging studies, the time-depending interactions of different cortical networks and their relationship with the clinical symptoms should be taken into account in the design of future trials. One last remark concerns the use of sham stimulation as control condition. Such stimulation is perhaps not ideal for controlling nonspecific effects related to attention/arousal processes and it may be useful to compare the effects of ‘real’ stimulations of

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different targets, relevant or not relevant in this given, disabling clinical problem. ‍Financial & competing interests disclosure

This review was supported by a research grant from the Prof. Schmidtmann Foundation in Marburg, Germany. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.

Key issues • Paired-pulse transcranial magnetic stimulation or repetitive transcranial magnetic stimulation (rTMS) delivered to the right parietal cortex is able to induce a pseudo-neglect phenomenon in healthy volunteers. • The stimulation of different parietal regions can modulate different aspects of neglect in healthy volunteers. • rTMS studies reported to date mainly employed inhibitory paradigms (low-frequency rTMS) applied to the contralesional parietal cortex in the left hemisphere. • Clinical effects of left-sided low-frequency rTMS coupled with behaviour therapy are superior to behavioural therapy only. • Transcranial direct current stimulation studies were based on excitatory paradigms (anodal stimulation) applied to the lesioned parietal cortex as well as on inhibitory paradigms (cathodal stimulation) applied to the contralesional parietal cortex. • The parietal cortex was mainly targeted on P3/P4 or P5/P6 scalp sites, according to the International 10–20 EEG Electrode System. • There is a lack of sham-controlled studies to determine the long-term therapeutic effects of noninvasive cortical stimulation on neglect. • Future trials should consider the correlation between the location of the cortical lesion and the resulting clinical symptoms, as shown by recent neuroimaging studies. • Future trials should consider the time-dependent functional relationship between various neural networks in both hemispheres and the development and recovery of hemispatial neglect, as also disclosed by recent neuroimaging studies.

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