Enhancing treatment effects by combining continuous theta burststimulation with smooth pursuit training

Simone Hopfner a, Dario Cazzoli a,b,e, René M. Müri a,c,d, Tobias Nef d,e, Urs P. Mosimann d,e,g,Stephan Bohlhalter a,f, Tim Vanbellingen a,f, Thomas Nyffeler a,d,f,n

a Perception and Eye Movement Laboratory, Departments of Neurology and Clinical Research, Inselspital, Bern University Hospital and University of Bern,Switzerlandb Nuffield Department of Clinical Neurosciences, University of Oxford, United Kingdomc Division of Cognitive and Restorative Neurology, Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Switzerlandd Gerontechnology & Rehabilitation Group, University of Bern, Switzerlande ARTORG Center for Biomedical Engineering Research, University of Bern, Switzerlandf Neurology and Neurorehabilitation Center, Luzerner Kantonsspital, Luzern, Switzerlandg University Hospital of Old Age Psychiatry, University of Bern, Switzerland

a r t i c l e i n f o

Keywords:Spatial neglectPursuit trainingContinuous theta burst simulationCancellation task

a b s t r a c t

Continuous theta burst stimulation (cTBS) represents a promising approach in the treatment of neglectsyndrome. However, it is not known whether cTBS in conjunction with another technique may enhancethe therapeutic effects. In the present sham-controlled study, we aimed to combine cTBS with smoothpursuit training (SPT), another method known to effectively improve neglect symptoms, and to evaluatewhether this combination would result in a stronger effect than SPT alone. Eighteen patients with leftspatial neglect after right-hemispheric stroke were included in the study and performed a cancellationtask on a large 54.6″ touchscreen monitor. A sequential application of cTBS and SPT induced asignificantly greater improvement of neglect than SPT alone. After the combined application of thesetwo methods, patients detected significantly more targets and their cancellation behaviour presented asignificantly greater shift towards the contralesional hemispace. We suggest that a combined, sequentialapplication of cTBS and SPT is a promising new approach to treat neglect.

& 2014 Elsevier Ltd. All rights reserved.

1. Introduction

Spatial neglect is defined as a deficit in detecting, responding, ororienting towards the stimuli presented on the contralateral side of abrain lesion (Heilman et al., 2003). Up to 43% of patients with a right-hemispheric stroke show neglect symptoms in the acute phase(Ringman et al., 2004), and it is estimated that 3–5 million newcases of neglect occur worldwide per year (Appelros et al., 2003;Corbetta et al., 2005; Pedersen et al., 1997). Neglect patients have areduced ability to cope with the activities of daily living and generallystay longer in hospital (Buxbaum et al., 2004; Cherney et al., 2001; DiMonaco et al., 2011; Gillen et al., 2005; Katz et al., 1999; Stone et al.,1992), which results in high costs for the health care system (Paolucci

et al., 2001; Wee and Hopman, 2008). Thus, the development ofeffective treatment to improve neglect is of crucial importance.

Continuous theta burst stimulation (cTBS) (Nyffeler et al., 2006)represents a promising transcranial magnetic stimulation protocol(TMS) to treat neglect. The rationale underlying the use of cTBS inneglect is based on the interhemispheric rivalry model by Kinsbourne(1987, 1993). According to this model, a lesion to the attentionalnetwork of one hemisphere leads to a deficient transcallosal inhibitionon the contralateral, intact homologue. This results in a pathologicalhyperexcitability of the undamaged, contralesional hemisphere, bias-ing visuospatial attention towards the ipsilesional side of space andthus resulting in neglect. Several studies have recently corroboratedsome central aspects of this model. For instance, a dysbalance ofinterhemispheric inhibition and a pathologic hyperexcitability of theundamaged PPC have been indeed observed in neglect patients (Kochet al., 2011, 2012). Furthermore, several studies reliably showed that areduction of this hyperexcitability leads to a correction of interhemi-spheric inhibition and to an amelioration of neglect symptoms. Sincean improvement of neglect was not only observed in neuropsycholo-gical tests (Koch et al., 2012; Nyffeler et al., 2009), but also in the

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Neuropsychologia

http://dx.doi.org/10.1016/j.neuropsychologia.2014.10.0180028-3932/& 2014 Elsevier Ltd. All rights reserved.

n Corresponding author at: Perception and Eye Movement Laboratory, Depart-ment of Neurology, Department of Clinical Research, Inselspital, Bern UniversityHospital and University of Bern, Freiburgstrasse 10, 3010 Bern, Switzerland.Tel.: þ41 41 205 56 86; fax: þ41 41 205 24 41.

E-mail address: thomas.nyffeler@luks.ch (T. Nyffeler).

Please cite this article as: Hopfner, S., et al., Enhancing treatment effects by combining continuous theta burst stimulation with smoothpursuit training. Neuropsychologia (2014), http://dx.doi.org/10.1016/j.neuropsychologia.2014.10.018i

Neuropsychologia ∎ (∎∎∎∎) ∎∎∎–∎∎∎

activities of daily living (Cazzoli et al., 2012), cTBS is thus seen as aninfluential, new therapeutic approach of neglect (Müri et al., 2013).

An important challenge for the future is, however, to find suitablecombinations of different therapeutic approaches, with the aim ofenhancing the strength and the duration of their effects. For instance,the combined application of visual exploration training and transcu-taneous electrical nerve stimulation led to a larger improvement ofneglect than visual exploration training alone (Schröder et al., 2008).Furthermore, neck muscle vibration in conjunction with visualexploration training induced superior effects than visual explorationtraining alone (Schindler et al., 2002).

Up to now, no study has examined whether TMS can potentiatethe effect of other methods in neglect treatment. In the presentstudy, we thus aimed to combine cTBS with smooth pursuit eyemovement training (SPT), and to evaluate whether this combinationwould result in a stronger effect than SPT alone. SPT is anotherimportant therapeutic approach of neglect, where patients areasked to pursuit with their eyes an array of stimuli moving fromthe ipsilesional to the contralesional hemispace (see for a reviewKerkhoff and Schenk, 2012). From previous research, it is knownthat SPT positively influences several aspects of the neglect syn-drome. For instance, leftward SPT transiently reduced the rightwardbisection error in a line bisection task (Mattingley et al., 1994), aswell as the ipsilesional deviation of the subjective visual straightahead (Karnath, 1996). Leftward SPT also temporarily improved sizeand space judgments (Kerkhoff et al., 1999; Kerkhoff, 2000), andtactile extinction (Nico, 1999). Recently, it has also been shown thatthe effects of SPT generalize across different tasks administered inthe visual domain (Kerkhoff et al., 2006). Furthermore, the applica-tion of a single SPT session induced not only positive effects onvisual neglect, but also had crossmodal effects, inducing rapid (buttransient) recovery from auditory neglect (Kerkhoff et al., 2012).Concerning the duration of the effects triggered by SPT, several

studies showed that repeated sessions of SPT yield enduring andlong-lasting recovery from neglect symptoms (Kerkhoff et al., 2006,2012, 2014; Schröder et al., 2008).

In the motor domain, Avenanti et al. (2012) recently investi-gated whether rTMS can enhance the effects of physical therapyon motor recovery after stroke. Their findings indicate that whenrTMS was applied immediately before physical therapy, treatmenteffects were enhanced and long-lasting, but not when rTMS wasapplied after physical therapy. Based on these findings, in the mainexperiment our patients received stimulation first (cTBS or sham),then followed by SPT. Furthermore, a control experiment withonly cTBS was performed.

2. Material and methods

2.1. Subjects

A total of 18 patients with left-sided neglect after subacute, right-hemisphericstroke were included in the study. Twelve patients (aged between 45 and 83 years,mean¼62.0, SD¼10.6, 7 women, interval between stroke onset and testing of 18 and63 days, mean¼32.42, SD¼11.95) participated in the main experiment. Additionally,six patients (aged between 41 and 84 years, mean¼65.4, SD¼15.2, 2 women, intervalbetween stroke onset and testing between 11 and 56 days, mean¼31, SD¼16.5)participated in a control experiment. The reasonwhy different patients participated inthe main and in the control experiment was that the hospitalization time was not longenough for patients to participate in both experiments. However, between the twoexperimental groups (main versus control experiment), no significant differences werefound with respect to the mean interval between stroke onset and testing (t(16)¼ .196,p¼ .847), age (t(16)¼� .224, p¼ .825), or gender (χ2(1)¼1, p¼ .620). All patients wererecruited from the Neurology and Neurorehabilitation Center, Luzerner Kantonsspital,Switzerland. Neglect diagnosis was based on clinical judgement and neuropsycholo-gical testing at admission. Two classes of neuropsychological tests for spatial neglectwere administered: a cancellation task [Bells test (Gauthier et al., 1989)] and a linebisection task [Line Bisection test (Wilson et al., 1987)]. For the cancellation task, thecut-off was set at 15% of omitted targets on the left side (Ferber and Karnath, 2001).Accordingly, 3 left-sided omissions in the Bells test are clinically relevant. For the linebisection task, the mean cut-off deviation was set at 11% to the right from the actualmidline (Schenkenberg et al., 1980). A mean deviation of 4 .73 cm to the right is thusclinically relevant. All subjects had normal or corrected-to-normal visual acuity andthe central 301 of their visual field were intact. Demographic data and performance ofthe patients in different clinical tests are shown in Table 1.

Ethical approval to conduct this study was provided by the Ethical Committeeof the State of Lucerne. The present study was carried out in accordance with theprinciples of the latest version of the Declaration of Helsinki.

2.2. Behavioural testing: the Bird Cancellation Task

In the Bird Cancellation Task, patients were requested to cancel target birds(seagulls), embedded among distractor birds (birds of six other species). The taskcomprised 64 targets and 96 distractors (16 of each different species). An exampleof the task array is given in Fig. 1.

Targets and distractors were assigned to 32 subdivisions of the screen, resultingfrom a 4 (vertical)�8 (horizontal) grid. Two targets and three distractors wereallocated to each subdivision, resulting in an even distribution over the screen. Eachtarget and distractor subtended a visual angle of 2�2.51. Stimuli were presented onthe background of a well-balanced clouded sky.

The task was presented on a 54.6″ touchscreen monitor (Elo TouchscreenSystems, Model ET5500L), with a resolution of 1920�1080 pixel, an active screensize of 121�68 cm2, 24 bit colour-depth, and a refresh rate of 60 Hz, connected to alaptop (Asus Zenbook UX31A). The software used to implement the Bird CancellationTask was developed in cooperation with the Institute for ICT-Based Management,Division of Computer Science, Bern University of Applied Sciences, Biel, Switzerland.The software ensures that the exact location of each target cancellation is registeredand stored.

A Pearson's correlation between the Center of Cancellation [CoC; (Binder et al.,1992; Rorden and Karnath, 2010)] scores of the Bells test [(Gauthier et al., 1989);collected during the neuropsychological examination)] and the Bird CancellationTask was calculated. The CoC scores of the two tasks were highly and significantlycorrelated (r(17)¼ .845, po .001). Thus, the Bird Cancellation Task seems to be avaluable method to measure the severity of neglect.

Patients were placed in front of the monitor with their sagittal body-midlinealigned to the midline of the touchscreen. The viewing distance was set at 60 cm,resulting in a visual angle of 901�601. Patients were instructed to touch all targetsthat they could perceive. Since a large-sized touchscreen was used, patientsperformed target cancellation by means of a stick held with their right hand,

Table 1Demographic and clinical data of patients.

Pat.no.

Age/Sex

Etiology Lesionlocation

Timesincelesion(days)

Cancellationtest (Bells)

Linebisection

No. of leftomissions(max. 15)a

MeandeviationL/R (cm)b

1 66/m Ischaemia f,t,p 63 2 þ1.332 67/f Ischaemia f,t,p 36 9 þ5.543 47/f Ischaemia f,t,p 43 15 þ6.44 45/f Ischaemia p,o 28 14 þ5.155 67/m Ischaemia f,t,p 36 15 þ5.776 83/f Ischaemia f 34 10 þ2.127 63/f Haemorrhage f 24 15 þ6.108 69/m Ischaemia f 19 15 þ2.559 61/f Haemorrhage f 35 15 þ6.04

10 71/m Ischaemia f,t,p 33 15 þ5.911 70/m Haemorrhage t,p 20 15 þ5.2312 59/f Ischaemia f,t 18 12 þ4.6513 58/m Ischaemia f,t,p 41 15 þ1.5314 59/f Ischaemia f,t 42 12 þ4.6515 80/m Ischaemia f,t,p 23 15 þ7.0416 71/m Haemorrhage p 11 15 þ .8817 84/f Ischaemia f,t 13 15 þ6.0818 41/m Haemorrhage f,t,p 56 4 þ .85

Note: f¼ frontal; t¼temporal; p¼parietal; o¼occipital.a Number of omitted targets on the left side/total number of targets on the left

side. Cut-off set at 15% of omitted left-sided targets(according to Ferber andKarnath, 2001). Clinically relevant: 3 left-sided omissions.

b Mean deviation to right (R, þ) or left (L, �) from the actual midline incentimeters (cm) in the line bisection test. Cut-off deviation set at 11% (accordingto Schenkenberg et al., 1980). Clinically relevant: mean deviation of 4 .73 cm tothe right.

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allowing them to reach every position on the screen. In order to provide the patientswith a visual feedback, targets were marked by a red cross once touched. No timeconstraint was imposed, and patients were instructed to verbally indicate when theyconsidered to have completed the task.

2.3. Interventions

2.3.1. Smooth pursuit eye movement training (SPT)For the SPT, a computer-generated random display containing the images of 80

birds (similar amongst them, but different from the ones used in the BirdCancellation Task) was used. Each bird had a size of 2�2 cm2, resulting in a visualangle of 1.91�1.91. The visual stimuli were presented on the background of a well-balanced clouded sky, all moving coherently and continuously from the right to theleft side of the screen at a constant speed of 71/s (as described in Kerkhoff et al.,2006). For the presentation of the visual stimuli, the same setup was used aspreviously described for the Bird Cancellation Task.

Patients were placed in front of the monitor, with their sagittal body-midlinealigned to the midline of the screen. The viewing distance and the visual anglewere the same as in the Bird Cancellation Task. Patients were instructed to fixatethe birds and to follow them during their leftward motion, i.e., to make smoothpursuit eye movements towards the left. Patients were instructed to return withtheir gaze to the right side of the array as soon as they reached the left edge of thescreen, and to restart the same procedure. The pursuit training lasted 10 min. Theexperimenter monitored the eyes of the patients during the whole training,checking for continuous smooth pursuit movements.

2.3.2. Continuous theta burst stimulation and sham protocolA MagPro X100 stimulator (Medtronic Functional Diagnostics, Farum, Den-

mark), connected either to a round coil (Magnetic Coil Transducer MC-125) or to aplacebo coil (Magnetic Coil Transducer MC-P-B70), was used to deliver biphasic,repetitive magnetic pulses.

The continuous theta burst stimulation (cTBS) protocol used in this study wasthe same as previously described (Cazzoli et al., 2009a, 2009b, 2012; Nyffeler et al.,2008, 2009). In brief, cTBS comprised 801 pulses, delivered in a continuous train of267 bursts. Each burst included 3 pulses at 30 Hz, repeated at 6 Hz. The totalduration of a single cTBS train was 44 s. Overall, two cTBS trains were applied, withan inter-train interval of 15 min. For stimulation localization, the international 10–20 EEG system was used. cTBS was applied over P3 (Cazzoli et al., 2012; Nyffeleret al., 2009), which overlies the left posterior parietal cortex in proximity of theintraparietal sulcus (Hilgetag et al., 2001). During stimulation, the coil was heldtangentially to the scalp, with the handle pointing posteriorly, the current flowingclockwise as viewed from above. Subjects were asked to keep their eyes closedduring stimulation. Stimulation intensity was set at 100% of subjects' individual restmotor threshold.

2.4. Experimental procedures

Twelve patients were assigned to the main experiment. After a baselineassessment with the Bird Cancellation Task, patients performed a first run of SPTduring 10 min. To evaluate the effect of SPT, the patients were again assessed withthe Bird Cancellation Task. The patients then underwent either cTBS or sham, andperformed a second run of SPT during 10 min. To evaluate the effects of SPT inconjunction with brain stimulation (cTBS or sham), patients were assessed a thirdand last time with the Bird Cancellation Task. The experiment was conducted on

two distinct occasions, once with cTBS and once with sham, separated by one week.The order of the two stimulation conditions (cTBS or sham) was randomly assigned.

In the control experiment, we evaluated the effect of cTBS alone. Six patientsperformed the experiment on two distinct occasions, separated by one week. Theorder of the two stimulation conditions (cTBS or sham) was randomly assigned.Each session started with a baseline assessment with the Bird Cancellation Task,followed by brain stimulation (cTBS or sham), and a second assessment with thesame task to evaluate the effects of the intervention.

2.5. Data analysis

In the two experiments (i.e., main and control experiment), the cancellationbehaviour of the patients in the Bird Cancellation Task was analysed with respect todifferent parameters. First, the Center of Cancellation (CoC; Binder et al., 1992;Rorden and Karnath, 2010) was computed. The CoC takes into account both thenumber of cancelled targets and their spatial distribution, providing an unbiasedmeasure of the homogeneity of cancellation performance across space (Rorden andKarnath, 2010). The CoC score can range between �1 and 1. A homogeneous, well-balanced cancellation performance across the left and the right space would resultin a score close to zero. Conversely, a score approaching �1 or 1 would indicate asevere right- or left-sided neglect syndrome, respectively. Second, in order toevaluate the spatial extension of the cancellation behaviour towards the left, theposition on the x-axis (in pixel) of the leftmost cancelled target was computed.Third, the number of cancelled targets across the screenwas computed. In the mainexperiment, all three parameters underwent separate, repeated-measures ANOVAswith the within factors ‘brain stimulation’ (levels: cTBS, sham) and ‘time point’(levels: baseline, SPT alone, SPT plus brain stimulation). In the control experiment,the three parameters underwent a repeated-measures ANOVA with the withinfactors ‘brain stimulation’ (levels: cTBS, sham) and ‘time point’ (levels: baseline,brain stimulation).

Since different patients participated in two experiments, a direct comparisonbetween the cTBS effect in the main and the control experiment was not possible.We therefore calculated the relative change in performance (i.e., the cTBS effectper se) in the two experiments for all the aforementioned parameters (CoC,leftmost x-position, and number of hit targets). For the two experiments, thereference value (i.e., the respective previous time point) varied: In the mainexperiment, the change in performance between the first run of SPT and thesecond run of SPT in conjunction with cTBS was calculated. In the controlexperiment, the change in performance between the time point ‘baseline’ andthe time point ‘cTBS alone’ was analysed. For the parameter ‘CoC’, the meandifference was calculated according to the formula: (score after intervention�scorein previous time point)/�1. For the parameter ‘leftmost x-position’, the percentagechange was calculated according to the formula: (score after intervention�score inprevious time point)/(total screen size in pixel)n100. Finally, for the parameter‘number of cancelled targets’, the percentage change was calculated according tothe formula: (score after intervention�score in previous time point)/(total numberof targets)n100.

All post-hoc analyses were conducted by means of Fisher least significantdifference (LSD)-corrected t-tests. For all statistical analyses, p-valueso .05 wereconsidered as statistically significant.

3. Results

3.1. Main experiment

3.1.1. Center of CancellationThe analysis of the CoC revealed no significant main effect of the

factor ‘stimulation’ (F(1, 11)¼ .246, p¼ .629) and a significant maineffect of the factor ‘time point’ (F(2, 22)¼29.271, po .001). Impor-tantly, there was a significant interaction ‘stimulation� time point’(F(2, 22)¼8.757, p¼ .002). In both sessions (cTBS or sham), patientsshowed a significant improvement in their performance (i.e., CoCscore nearer to zero) after the first run of SPT. However, a further,significant performance improvement after the second run of SPTwas observed only when cTBS (but not sham stimulation) waspreviously applied. The results concerning this interaction and thecorresponding post-hoc tests are depicted in Fig. 2.

3.1.2. x-position of the leftmost cancelled targetThe analysis of the x-position of the leftmost cancelled target

yielded no significant main effect of the factor ‘stimulation’ (F(1,11)¼ .694, p¼ .422) and a significant main effect of the factor ‘timepoint’ (F(2, 22)¼23.237, po .001). Importantly, the analysis revealed

Fig. 1. Apparatus and Bird Cancellation Task. Touchscreen monitor showing asubject performing the Bird Cancellation Task with its 64 targets and 96 distractors.

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a significant interaction ‘stimulation� time point’ (F(2, 22)¼10.990,po .001). In both sessions, patients showed a significant shift to theleft in their search performance (as indicated by the x-position of theleftmost cancelled target) after the first run of SPT. However, afurther, significant performance improvement after the second runof SPT was observed only when cTBS (but not sham stimulation) waspreviously applied. The results concerning this interaction and thecorresponding post-hoc tests are depicted in Fig. 3.

3.1.3. Number of cancelled targetsThe analysis of the number of cancelled targets revealed no

significant main effect of the factor ‘stimulation’ (F(1, 11)¼ .297,p¼ .596) and a significant main effect of the factor ‘time point’ (F(2,22)¼14.588, po .001). Importantly, the analysis yielded a significantinteraction ‘stimulation� time point’ (F(2, 22)¼18.033, po .001). Inthe cTBS session, patients showed a significant increase in perfor-mance after the first run of SPT, as displayed by a higher number ofcancelled targets. A further, significant improvement after the secondrun of SPT was observed only when cTBS (but not sham stimulation)was applied previously. The results concerning this interaction andthe corresponding post-hoc tests are depicted in Fig. 4. 3.2. Control experiment

3.2.1. Center of CancellationThe analysis of the CoC revealed no significant main effect of the

factor ‘stimulation’ (F(1, 5)¼3.005, p¼ .144) or of the factor ‘timepoint’ (F(1, 5)¼6.504, p¼ .051). Importantly, there was a significantinteraction ‘stimulation� time point’ (F(1, 5)¼22.622, p¼ .005). Inthe cTBS session, patients showed a significant increase in perfor-mance after the application of cTBS (baseline: m¼ .615, standarderror of the mean [SEM]¼ .083; cTBS: m¼ .446, SEM¼ .109). In thesham session, no significant change in the CoC score was observed(baseline: m¼ .423, SEM¼ .080; sham: m¼ .400, SEM¼ .106).

3.2.2. x-position of leftmost cancelled targetThe analysis of the x-position of the leftmost cancelled target

yielded no significant main effect of the factor ‘stimulation’ (F(1, 5)¼1.182, p¼ .327) and no significant main effect of the factor ‘time point’(F(1, 5)¼4.109, p¼ .098). Importantly, the analysis revealed a signifi-cant interaction ‘stimulation� time point’ (F(1, 5)¼10.735, p¼ .022).In the cTBS session, patients showed a significant shift to the left intheir search performance, as indicated by the x-position of theleftmost cancelled target (baseline:m¼927.041, SEM¼159.067; cTBS:m¼1231.25, SEM¼212.377). In the sham session, patients’ perfor-mance did not show any significant change (baseline: m¼1249.75,SEM¼156.766; sham: m¼1256.542, SEM¼215.487).

3.2.3. Number of cancelled targetsThe analysis of the number of cancelled targets revealed

no significant main effect of the factor ‘stimulation’ (F(1, 5)¼ .846,p¼ .400) or of the factor ‘time point’ (F(1, 5)¼6.289, p¼ .054).Importantly, the analysis yielded a significant interaction ‘stimula-tion� time point’ (F(1, 5)¼19.063, p¼ .007). In the cTBS session,patients showed a significant increase in performance after theapplication of cTBS, as indicated by a higher number of cancelledtargets (baseline:m¼23, SEM¼4.491; cTBS:m¼33.833, SEM¼6.340).In the sham session, no significant increase in performance observed(baseline: m¼32.166, SEM¼4.699; sham¼32.5, SEM¼5.709).

3.2.4. Comparison between the main and control experimentTo compare the effect of cTBS per se in the two experiments,

we calculated the change in performance in the three above-mentioned parameters. The comparison of the mean difference inthe CoC score, as well as the percentage change in the x-position of

Fig. 2. Mean Center of Cancellation (CoC) score. Mean CoC score in the two sessions(cTBS and sham) and the different time points. Error bars represent the standarderror of the mean (SEM). Asterisks depict significant post-hoc tests (npo .05;nnpo .01).

Fig. 3. Mean x-position of the leftmost cancelled target. Mean x-position of theleftmost cancelled target in the two sessions (cTBS and sham) and the differenttime points. Error bars represent the standard error of the mean (SEM). Asterisksdepict significant post-hoc tests (npo .05; nnpo .01).

Fig. 4. Mean number of cancelled targets. Mean number of cancelled target in thetwo sessions (cTBS and sham) and the different time points. Error bars representthe standard error of the mean (SEM). Asterisks depict significant post-hoc tests(npo .05; nnpo .01).

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the leftmost target and in the number of cancelled targets isdepicted in Table 2. The results show that cTBS triggered a similarimprovement in both the main and the control experiment.

4. Discussion

The present study shows that cTBS combined with SPT caninduce a significantly greater improvement of neglect than SPTalone. After the combined application of these two techniques,patients detected significantly more targets and their cancellationbehaviour presented a significantly greater shift towards thecontralesional hemispace, as evidenced by both the CoC and thex-position of the leftmost cancelled target.

SPT as a single therapeutic approach has been reliably shown tobe an important therapy of neglect. After SPT, patients improve inline bisection and cancellation tasks (Keller et al., 2009; Kerkhoffet al., 2006), text reading (Keller et al., 2009; Kerkhoff et al., 2006),tactile search tasks (Keller et al., 2009), and in an auditory midlinetask (Kerkhoff et al., 2012). Moreover, Kerkhoff et al. (2014) recentlyshowed that SPT not only improves neglect symptoms, but alsosignificantly reduces unawareness of the latter. Our results, showingthat 10 min of SPT significantly improve the cancellation behaviourin neglect patients, are thus well in line with previous findings.

The identification of a suitable combination of different thera-peutic approaches for the treatment of neglect seems to be challen-ging (see for an overview Saevarsson et al., 2011). From a theoreticpoint of view, the combined application of different therapeuticapproaches can result in a further improvement, a deterioration, orsimply not lead to any distinguishable additional effect as comparedto the application of a single therapeutic approach. The finding thata sequentially combined application of cTBS and SPT results in aneven larger improvement of neglect severity is thus novel and verypromising for the future of the therapy of neglect.

In a control experiment, we showed that the cTBS effect per sehad a comparable amplitude when: (a) cTBS was administered alone;or (b) cTBS was administered in conjunction with SPT. Although adirect comparison of the cTBS effect in the two experiments is notpossible due to the different patient populations, the analysissuggests that the effects of cTBS and SPT applied in conjunctionmight be additive rather than combinatory in a potentiation. If thelatter would pertain, the amplitude of the effect elicited by theapplication of cTBS in conjunction with SPT would be larger than theone elicited by cTBS alone. The finding that the effect of cTBS and SPTseem to be additive is encouraging, since previous results haveshown that combining SPT with other therapeutic approaches mightresult in no additional effect or even lead to a deterioration of neglectsymptoms. For instance, Pizzamiglio et al. (2004) investigatedwhether the combination of a standard spatial scanning trainingand SPT had superior effects as compared to the application of thespatial scanning training alone. Both approaches alone significantly

improved neglect severity. However, the combined application ofspatial scanning training and SPT did not result in any additionalimprovement when compared to spatial scanning training alone.Furthermore, Keller et al. (2009) showed that SPT combined withprism adaption did not result in any further improvement whencompared to SPT alone. More critically, a combined approachincluding SPT and arm movements from the ipsilesional to thecontralesional hemispace resulted in worse therapeutic effects thanSPT alone (Keller et al., 2009).

A further interesting finding of our study is that the effect oftwo consecutive runs of SPT was not significantly stronger thanthe effect of a single run. This suggests a‚ saturation phenom-enon’, i.e., once a positive effect is achieved by means of a firstSPT run, a further run does not seem to bring additional effect(at least when the two runs are conducted within a short timeperiod). This finding is different from what is known about theeffects of cTBS. There is strong evidence that the repeatedapplication of cTBS trains disproportionately increases the sti-mulation after-effects, putatively relying on long term depression(LTD)-like mechanisms (Huang et al., 2011) that can be consoli-dated by the repeated application (Goldsworthy et al., 2014).For instance, in an oculomotor paradigm in healthy subjects, asingle cTBS train applied over the frontal eye field increasedsaccade latency by up to 30%, whereas the application of a secondtrain 15 min later resulted in an increase of up to 50% (Nyffeleret al., 2006). This effect could also been shown for the motorcortex in healthy subjects, where one cTBS train decreasednormalized motor evoked potential amplitude by up to 30%,whereas two cTBS trains triggered a decrease of up to 60%(Goldsworthy et al., 2012). Additionally, in patients with neglect,four cTBS trains had a considerably stronger effect than two cTBStrains (Nyffeler et al., 2009).

The reason why some treatment combinations may evokeadditive effects, while others may not (or may even have detrimentaleffects) is yet unclear. One could hypothesize that different ther-apeutic approaches influence the attentional networks in specificand distinct ways, thereby activating different brain structures. Inkeeping with this consideration, some treatment combinationsmight be more beneficial because the single interventions compos-ing them activate different brain areas, thus resulting in an additionor even a potentiation of the effects. Other treatment combinationsmay have no additional effect because the single interventionscomposing them activate similar areas, thus resulting in no furthertherapeutic advantage.

cTBS targets the left PPC and thus directly interferes with the dorsalattention network (Corbetta et al., 2005; Corbetta and Shulman, 2011).In fact, cTBS has been shown to reduce the pathological hyperactivityof the left PPC observed in neglect patients (Koch et al., 2012) and toameliorate the dysbalance in the interhemispheric inhibition betweenthe left and the right PPC (Koch et al., 2011, 2012).

For SPT, different mechanisms of action are currently discussed(Doricchi et al., 2002; Keller et al., 2009; Kerkhoff et al., 2006).Generally, functional magnetic resonance imaging (fMRI) activa-tions linked to SPT seem to be more conspicuous in the posteriorand medial aspect of the dorsal attention network, particularly inthe precuneus (Konen et al., 2005; Sturm et al., 2006; Thimm et al.,2009; Zoccolotti et al., 1992). Hence, cTBS and SPT probably act ondifferent areas of the dorsal attentional network and their com-bined application might thus result in a potentiation of the effects,as observed in the present study.

Our study has a potential limitation, since different patientswere included in the main and in the control experiment and adirect comparison between the cTBS effect in the two experimentswas not possible. The reason was that several patients did not stayin hospital long enough to be tested on several occasions. Never-theless, relative scores (i.e., mean difference, percentage change)

Table 2Comparison of the cTBS alone effect in the main and the control experiment.

Mainexperiment

Controlexperiment

Significancetesting

n¼12 n¼6

Performance change m (SEM) m (SEM) pCenter ofCancellation

.177 (.026) .169 (.030) n.s.

Leftmost x-position(%)

17.392 (3.206) 15.844 (3.413) n.s.

Number of hits (%) 18.099 (2.251) 16.927 (3.364) n.s.

Note: m¼mean; SEM¼standard error of the mean; p¼significance value; n.s.¼notsignificant.

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Please cite this article as: Hopfner, S., et al., Enhancing treatment effects by combining continuous theta burst stimulation with smoothpursuit training. Neuropsychologia (2014), http://dx.doi.org/10.1016/j.neuropsychologia.2014.10.018i

were calculated to compare the isolated cTBS effect, and the twogroups were shown to be comparable.

In conclusion, the present study confirms that SPT and cTBSapplied alone can significantly reduce neglect symptoms, anddemonstrates – as a novel finding – that the two approaches appliedin conjunction (i.e., cTBS prior to SPT) have even stronger effects,most probably combining in an additive fashion. The sequentialapplication of cTBS and SPT is thus a promising new approach totreat neglect, and further studies are needed to evaluate thetemporal stability of such therapeutic effects.

Acknowledgements

This work was supported by the Swiss National Science Foundation(Grant no.320030_140696/1535 16-790).

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