Long-term effects of continuous theta-burst stimulation in visuospatial neglect

Abstract

Objective

To investigate whether the efficacy of continuous theta-burst stimulation (cTBS) for improving visuospatial neglect can be enhanced by providing more days of stimulation and more stimulation trains per day.

Methods

In a prospective study, right-handed patients with right hemisphere stroke and visuospatial neglect were randomized to cTBS or sham cTBS treatment for 2 weeks and were followed up for 4 weeks. The cTBS group received active cTBS over the posterior parietal cortex of the unaffected hemisphere, combined with conventional rehabilitation therapy. Changes in scores for two paper–pencil tests for visuospatial neglect (star cancellation and line bisection) were evaluated.

Results

In each group, 10 patients completed follow up. Compared with the sham group, star cancellation test scores in the cTBS group were improved by 37.03% at the end of treatment and by 47.21% after 4 weeks’ follow up, and the line bisection score improved by 21.37% at the end of treatment and by 35.99% after 4 weeks’ follow up.

Conclusions

These results suggest that the efficacy of cTBS in visuospatial neglect can be enhanced and prolonged by increasing the days of stimulation and the number of stimulation trains per day over the left posterior parietal cortex.

Keywords

Visuospatial neglect neurorehabilitation repetitive transcranial magnetic stimulation interhemispheric rivalry

Introduction

Visuospatial neglect is a common neurological syndrome following unilateral brain injury, particularly right hemispheric stroke:¹ it occurs in up to 43% of patients with acute right hemisphere stroke.² The most striking defining feature is failure to detect, respond or orient to stimuli – even one’s own body parts – in contralesional space.³ Visuospatial neglect is an independent predictor of poor outcome in terms of poststroke functional independence,⁴ therefore there is a compelling need for visuospatial neglect rehabilitation. Although several treatment methods have been developed,⁵ it is generally agreed that such approaches remain unsatisfactory.⁶

Methods of noninvasive brain stimulation, such as transcranial direct current stimulation⁷ or repetitive transcranial magnetic stimulation (TMS),⁸ are promising approaches to treat visuospatial neglect. One influential mechanism underlying these noninvasive stimulation methods is based on interhemispheric rivalry, or the competition model.^9,10 A classic theta-burst stimulation (TBS) protocol, which is used to induce long-term potentiation or long-term depression in brain slices, can be adapted to TMS, where it rapidly produces a long-lasting effect on the motor cortex.¹¹ In a sham-controlled study, 10 days of continuous theta-burst stimulation (cTBS) over the posterior parietal cortex (PPC) of the left hemisphere reduced visuospatial neglect for ≥2 weeks.^10, Another study showed a 37% improvement in the everyday behaviour of patients with visuospatial neglect for ≥3 weeks, after two consecutive days of continuous theta-burst stimulation.¹²

Here, we used a modified version of a cTBS protocol that is known to be effective in inducing long-term depression and long-lasting changes in the excitability of the stimulated cortex.¹¹ By increasing the number of stimulation days and the number of trains per day over the left PPC in poststroke patients, we investigated whether the efficacy of cTBS for visuospatial neglect rehabilitation could be enhanced. Visuospatial neglect was assessed with both the star cancellation test (SCT) and the line bisection test (LBT).¹³ The SCT is considered to be particularly sensitive for visuospatial neglect and is not subject to practice effects, therefore it is suitable for repeated measurements.¹⁴ The line bisection test, unlike the cancellation test, requires magnitude estimates that are influenced by attentional bias. Furthermore, a combination of neglect tests, rather than a single neglect test, might be more sensitive in detecting and defining the presence of visuospatial neglect.¹⁵

Patients and methods

Patients

This study enrolled consecutive right-handed patients with right hemisphere stroke and visuospatial neglect, attending the Department of Rehabilitation Medicine, Xuanwu Hospital, Capital Medical University between May 2011 and April 2013.

Patients were randomly allocated to left PPC cTBS treatment or sham treatment, using a computer-generated randomization schedule. Patients and therapists were blinded to the type of intervention. All patients received conventional rehabilitation training, based on visuospatial scanning, of 30 min twice daily for 2 weeks. Patients were also treated with programmes for motor rehabilitation when necessary.

All patients gave written informed consent for participation in the study. Experimental procedures were approved by the local Ethics Committee and were undertaken in accordance with the Declaration of Helsinki.

Inclusion/exclusion criteria

This study included patients with visuospatial neglect, with a history of a haemorrhagic or ischaemic lesion in the right hemisphere, which was confirmed by computed tomography or magnetic resonance imaging >2 weeks before the beginning of the study. The diagnosis of visuospatial neglect was based on the judgement of the clinician and on deficits in at least one out of two paper–pencil tests.¹² The applied paper–pencil tests were the SCT and LBT. The cut-off score of SCT was 51 (i.e. four omissions was defined as an impairment score).¹⁶ In the LBT, patients were included if they scored a deviation ≥12% to the right of centre.¹⁵ All patients had normal or corrected-to-normal acuity.

Exclusion criteria for this study were based on the accepted safety guidelines for TMS, which included an assessment of the history of epilepsy, previous head trauma, drug and alcohol abuse and psychiatric disorders.¹⁷ Moreover, patients were excluded for any of the following reasons: recurrent stroke, obvious aphasia and communication obstacles, family history of seizures, ever use of tricyclic antidepressants or antipsychotic drugs, in vivo diamagnetic metal implants such as cardiac pacemakers and age <30 years or >80 years. Also, patients with visual field defects detected by the confrontation method were excluded.

Continuous theta-burst stimulation and sham protocols

Continuous theta-burst stimulation and sham treatments were performed immediately before visuospatial scanning training. The site of cTBS or sham stimulation was set over P5, according to the International 10/10 EEG system: this site overlies the left PPC in proximity of the intraparietal sulcus.¹⁸ Each day, four trains of left PPC cTBS or sham stimulation were applied, with an interval of 15 min. Treatment was given for 14 consecutive days.

Continuous theta-burst stimulation was delivered using a Super Rapid 2 magnetic stimulator (Magstim, Whitland, UK) with 2.0-Tesla maximum field strength, connected with a figure-of-eight coil (diameter of outside loop, 87 mm). For each train, a three-pulse burst was delivered at 30 Hz and repeated every 200 ms (i.e. 5 Hz; the frequency that mimics the theta wave of a spontaneous neural rhythm) for 40 s. ¹¹ The stimulus intensity was 80% of the resting motor threshold of the resting abductor pollicis brevis muscles.¹⁹

Sham stimulation was delivered with the same set up as cTBS but with the coil perpendicular to the patient’s scalp, with only one edge of the coil resting on the scalp.²⁰

Clinical evaluation of visuospatial neglect

Visuospatial neglect was assessed with the SCT and LBT, which were administered by blinded raters (Y.Z., S.H. and R.Z) at three time points: 1 h before starting the first session of stimulation (baseline), at the end of stimulation (Post 1) and after a follow up of 4 weeks (Post 2).

The SCT consisted of an A4 sheet of paper on which there were 56 small stars randomly interspersed with a variety of distracts (52 large stars, 10 short words and 13 letters). The patients were instructed to cross out all of the small stars. The percentage of small stars not crossed out was calculated.²¹

The LBT consisted of a landscape-oriented A4 sheet of paper on which there were five horizontal lines distributed with equal vertical spacing. The line lengths (L) were 16, 14, 12, 10 and 8 cm. Patients were asked to mark the midpoint of each line. The distance between the marked midpoint and the corresponding true midpoint were measured (R). A positive value indicated deviation towards the right of the true midpoint, while a negative value indicated deviation towards the left. The percentage severity of visuospatial neglect was calculated as 100 × R/(L/2).²²

Statistical analyses

Data are presented as mean ± SD. SPSS® version 17.0 (SPSS Inc., Chicago, IL, USA) was used to process the data. A repeated-measure analysis of variance (ANOVA) was performed to calculate the differences in SCT score and LBT score, with group (cTBS versus Sham) as the between-subject main factor and time (baseline versus Post 1 versus Post 2) as the within-subject main factor. The Greenhouse–Geisser test was used to correct the P-value if the Mauchly’s test of sphericity was significant. If a significant effect was observed, post hoc tests were carried out for multiple comparisons (least significant difference or Student–Newman–Keuls). For all statistical analyses, a P-value < 0.05 was considered to be significant.

Results

Twenty-two right-handed patients with right hemisphere stroke and visuospatial neglect were enrolled in this study. Of these, 11 were assigned to cTBS and 11 to sham treatment. One patient in each group did not finish the follow-up testing and these two patients were excluded from the study. Therefore, each group included full data from 10 patients for analysis. The treatment groups did not differ in sex, age or time between stroke onset and beginning of testing (Table 1).

Table 1.

Clinical and demographic data for right-handed patients with right hemisphere stroke and visuospatial neglect, listed by treatment group.

Patient	Sex	Age, years	Type of stroke (brain lesion)	Time between stroke and testing, days
Continuous theta-burst stimulation
1	Male	42	Haemorrhage (R fronto-temporal)	93
2	Male	63	Infarction (R parieto-occipital)	22
3	Male	52	Haemorrhage (R BG)	38
4	Male	66	Infarction (R fronto-parietal, BG)	21
5	Female	78	Infarction (R BG, corona radiata)	42
6	Female	65	Haemorrhage (R paraventricular)	76
7	Male	37	Infarction (R fronto-parietal, BG)	19
8	Male	37	Haemorrhage (R BG)	52
9	Male	63	Infarction (R temporal-occipital, insula)	26
10	Male	48	Haemorrhage (R thalamus)	114
Sham treatment
1	Male	63	Haemorrhage (R BG)	42
2	Male	71	Infarction (R MCA, BG)	20
3	Male	72	Haemorrhage (R parietal)	42
4	Female	52	Infarction (R BG)	17
5	Male	56	Haemorrhage (R thalamus)	46
6	Female	65	Haemorrhage (R BG)	17
7	Male	53	Haemorrhage (R temporal)	37
8	Male	33	Haemorrhage (R BG)	36
9	Male	54	Infarction (R temporal-parieto-occipital)	63
10	Male	76	Infarction (R MCA)	29

There were no significant differences between the treatment groups (post hoc tests: least significant difference or Student–Newman–Keuls).

BG, basal ganglia; MCA, middle cerebral artery; R, right.

There were no significant differences between the groups in baseline SCT scores (mean ± SD for SCT scores in the two groups were 53.47 ± 7.07% and 52.14 ± 7.07%, in the cTBS and sham treatment groups, respectively). There were significant differences between the groups in Post 1 SCT scores (cTBS, 16.43 ± 7.03%; sham, 50.00 ± 7.03%; P = 0.030) and Post 2 SCT scores (cTBS, 6.25 ± 5.94%; sham, 45.29 ± 5.94%; P < 0.001; Figure 1). Compared with sham treatment, cTBS over the left PPC resulted in an improvement in SCT scores between baseline and Post 2, as revealed by ANOVA, showing a group × time effect (F_2,18 = 44.499; P < 0.001) and a group × time interaction (F_2,18 = 27.582; P < 0.001). Within the cTBS group, there were significant improvements between baseline and Post 1 SCT scores (by 37.03%; P < 0.001) and between baseline and Post 2 scores (by 47.21%; P < 0.001). There was no significant within-group difference between Post 1 and Post 2 scores.

Figure 1.

Star cancellation test (SCT) scores obtained in the continuous theta-burst stimulation (cTBS) and sham treatment groups of visuospatial neglect patients before treatment (baseline), at the end of the 2-week treatment period (Post 1) and after 4-week follow up (Post 2). Error bars indicate standard deviation. Asterisks indicate results that were significant using post hoc tests: *P < 0.05; **P < 0.01.

There were no significant differences between the groups in baseline LBT scores (cTBS, 47.16 ± 23.65%; sham, 46.03 ± 22.82%) or Post 1 scores (cTBS, 25.79 ± 27.32%; sham, 32.79 ± 13.12%). There was a significant difference between the groups in Post 2 LBT scores (cTBS, 11.17 ± 14.27%; sham, 35.79 ± 18.65%; P = 0.004; Figure 2). Compared with sham treatment, cTBS over the left PPC resulted in an improvement in LBT score between baseline and Post 2, as revealed by ANOVA analysis showing a group × time effect (F_2,18 = 13.522; P < 0.001) and a group × time interaction (F_2,18 = 4.050; P = 0.045). Within the cTBS group, there were significant differences between baseline and Post 1 LBT scores (21.37%; P = 0.042) and between baseline and Post 2 scores (35.99%; P = 0.001). There was no significant within-group difference between Post 1 and Post 2 scores.

Figure 2.

Line bisection test (LBT) scores obtained in the continuous theta-burst stimulation (cTBS) and sham treatment groups of visuospatial neglect patients before treatment (baseline), at the end of the 2-week treatment period (Post 1) and after 4-week follow up (Post 2). Error bars indicate standard deviation. Asterisks indicate results that were significant using post hoc tests: **P < 0.01.

No study participant experienced any severe adverse event. Two patients reported a slight headache when they received the real cTBS stimulation.

Discussion

The present study findings showed that our modified cTBS protocol, administered over the unaffected PPC for 2 weeks, combined with conventional rehabilitation training, reduced visuospatial neglect significantly. The improvement persisted for ≥4 weeks after the discontinuation of cTBS. Furthermore, for the LBT task, efficacy at the end of 4 weeks’ follow up was significantly better than at the end of 2 weeks’ stimulation. No significant improvement was observed with sham treatment combined with conventional rehabilitation therapy. Our device was only able to deliver 30-Hz magnetic pulses if we also wanted to adjust the output (stimulation intensity), which we did in the present study; hence, we used a modified protocol. Furthermore, 4–7-Hz rhythms are in the range of the theta band, according to electroencephalograph systems.

The method of how to achieve powerful, long-lasting and stable efficacy for visuospatial neglect is still open to debate. Our observation of a reduction in visuospatial neglect after cTBS over the unaffected PPC is in line with other noninvasive brain stimulation studies, which used single-pulse TMS and paired TMS as a ‘virtual lesion’ technique,^23,24 low-frequency (≤1 Hz) repetitive TMS,^17,24,25 cathodal transcranial direct current stimulation²⁶ or continuous TBS.^10,12 Koch et al.¹⁰ applied left PPC TBS in two sessions per day with an interval of 15 min every day for 2 weeks (10 days), which reduced hemispatial neglect for up to 2 weeks after treatment: behavioural inattention test scores improved by 16.3% at the end of treatment and 22.6% at 2-week follow up. Cazzoli et al.¹² applied more trains per day (four trains), but for fewer days (2 days): their results showed a 37% improvement in everyday behaviour of hemispatial neglect patients for ≥3 weeks. In the current study, we applied more trains per day (four trains) and more stimulation days (14 consecutive days) and showed that the efficacy of cTBS can be enhanced and can persist for ≥4 weeks after discontinuation of stimulation. The mean ± SD SCT score in the cTBS group improved by 37.03% at the end of stimulation and 47.21% at 4 weeks’ follow up. However, no significant effect was observed in the sham group. Patients in the cTBS group maintained their relatively stable beneficial outcome, or even kept improving, after discontinuation of stimulation. This finding suggests that the approach applied in this study – four trains daily and 14 consecutive days – might be particularly promising for therapeutic application.

It has been suggested that the suppression of pathological hyperexcitability of the structurally intact PPC, which also leads to a reduced interhemispheric inhibition from the unaffected towards the affected hemisphere, is an important mechanism resulting in visuospatial neglect remission.²⁷ It is highly possible that the build up of cumulative effects may account for the disproportionately longer-lasting effect of repeated trains of cTBS compared with a single train: cumulative effects can be achieved after a long conditioning phase involving periodic stimulation sessions at intervals ≤24 h, which build up a lasting ‘memory’ and result in increased facilitation of subsequent stimulation effects.²⁸ Another interpretation for the long-lasting effect of cTBS considers consolidation mechanisms, as proposed in the cascade model of animals, where repeated trains of TBS can extend the lifetime of plastic modifications in the human brain. Similar to results in animal studies, the number of applied theta-burst trains determines the lifetime of changes in the neural network of the human brain.¹⁹ The lasting reduction in visuospatial neglect observed in this study supports the idea that one or more of these mechanisms is active in the human brain.

A strength of the present study is the blinding of the patients, therapists and the test raters. Also, the stimulus intensity for the sham stimulation was the same as for cTBS, and all patients had the same acoustic sensation during treatment. Notable limitations of the present study are that there was no stratification by patient age, lesion location or subtype of visuospatial neglect, all of which may influence the recovery of visuospatial neglect,¹² therefore stratification studies are needed. Further studies should also investigate whether the number of stimulation days or the number of trains per day has the greater effect. In addition, we note that our study also excluded patients with visual field defects, which may have resulted in less-impaired patients being included in the cohort. Whether the extent of visuospatial neglect in stroke patients affects the efficacy of cTBS should be considered in further studies. Finally, further studies should include a control group.

In conclusion, the present study supports previous findings that multiple sessions of cTBS over the unaffected PPC, combined with conventional rehabilitation therapy, can lead to efficient and long-lasting improvement in visuospatial neglect. Compared with other studies,^10,12 the present study also found initial evidence that efficacy of cTBS for visuospatial neglect may be enhanced and prolonged by increasing the number of stimulation days and the number of trains per day. We base this conclusion following comparison of our findings with those from other published studies, and we note that the efficacy of conventional rTMS or TBS often is considered to be short lasting.

Footnotes

Acknowledgements

The authors would like to thank Dr Di Wu for his help in preparation of manuscript and useful suggestions.

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This work was supported by National Natural Science Foundation of China (grant no. 81171024).

References

Cassidy

Lewis

Gray

. Recovery from visuospatial neglect in stroke patients. J Neurol Neurosurg Psychiatry 1998; 64: 555–557.

Ringman

Saver

Woolson

. Frequency, risk factors, anatomy, and course of unilateral neglect in an acute stroke cohort. Neurology 2004; 63: 468–474.

Parton

Malhotra

Husain

. Hemispatial neglect. J Neurol Neurosurg Psychiatry 2004; 75: 13–21.

Gillen

Tennen

McKee

. Unilateral spatial neglect: Relation to rehabilitation outcomes in patients with right hemisphere stroke. Arch Phys Med Rehabil 2005; 86: 763–767.

Kerkhoff

Schenk

. Rehabilitation of neglect: An update. Neuropsychologia 2012; 50: 1072–1079.

Cappa

. Neglect rehabilitation in stroke: Not to be neglected. Eur J Neurol 2008; 15: 883–884.

Utz

Dimova

Oppenländer

. Electrified minds: Transcranial direct current stimulation (tDCS) and galvanic vestibular stimulation (GVS) as methods of non-invasive brain stimulation in neuropsychology – a review of current data and future implications. Neuropsychologia 2010; 48: 2789–2810.

Cazzoli

Müri

Hess

. Treatment of hemispatial neglect by means of rTMS – a review. Restor Neurol Neurosci 2010; 28: 499–510.

Kinsbourne

. Mechanisms of neglect: Implications for rehabilitation. Neuropsychol Rehabil 1994; 4: 151–153.

10.

Koch

Bonnì

Giacobbe

. θ-burst stimulation of the left hemisphere accelerates recovery of hemispatial neglect. Neurology 2012; 78: 24–30.

11.

Huang

Edwards

Rounis

. Theta burst stimulation of the human motor cortex. Neuron 2005; 45: 201–206.

12.

Cazzoli

Müri

Schumacher

. Theta burst stimulation reduces disability during the activities of daily living in spatial neglect. Brain 2012; 135: 3426–3439.

13.

Ferber

Karnath

. How to assess spatial neglect–line bisection or cancellation tasks? J Clin Exp Neuropsychol 2001; 23: 599–607.

14.

Bailey

Riddoch

Crome

. Treatment of visual neglect in elderly patients with stroke: A single-subject series using either a scanning and cueing strategy or a left-limb activation strategy. Phys Ther 2002; 82: 782–797.

15.

Lee

Kang

Park

. The character-line bisection task: A new test for hemispatial neglect. Neuropsychologia 2004; 42: 1715–1724.

16.

Nurmi

Kettunen

Laihosalo

. Right hemisphere infarct patients and healthy controls: Evaluation of starting points in cancellation tasks. J Int Neuropsychol Soc 2010; 16: 902–909.

17.

Song

. Low-frequency transcranial magnetic stimulation for visual spatial neglect: A pilot study. J Rehabil Med 2009; 41: 162–165.

18.

Oliveri

Bisiach

Brighina

. rTMS of the unaffected hemisphere transiently reduces contralesional visuospatial hemineglect. Neurology 2001; 57: 1338–1340.

19.

Nyffeler

Wurtz

Lüscher

. Extending lifetime of plastic changes in the human brain. Eur J Neurosci 2006; 24: 2961–2966.

20.

Lisanby

Gutman

Luber

. Sham TMS: Intracerebral measurement of the induced electrical field and the induction of motor-evoked potentials. Biol Psychiatry 2001; 49: 460–463.

21.

Grimsen

Hildebrandt

Fahle

. Dissociation of egocentric and allocentric coding of space in visual search after right middle cerebral artery stroke. Neuropsychologia 2008; 46: 902–914.

22.

Sarri

Greenwood

Kalra

. Prism adaptation aftereffects in stroke patients with spatial neglect: Pathological effects on subjective straight ahead but not visual open-loop pointing. Neuropsychologia 2008; 46: 1069–1080.

23.

Oliveri

Rossini

Traversa

. Left frontal transcranial magnetic stimulation reduces contralesional extinction in patients with unilateral right brain damage. Brain 1999; 122: 1731–1739.

24.

Oliveri

Rossini

Filippi

. Time-dependent activation of parieto-frontal networks for directing attention to tactile space. A study with paired transcranial magnetic stimulation pulses in right-brain-damaged patients with extinction. Brain 2000; 123: 1939–1947.

25.

Koch

Oliveri

Cheeran

. Hyperexcitability of parietal-motor functional connections in the intact left-hemisphere of patients with neglect. Brain 2008; 131: 3147–3155.

26.

Sparing

Thimm

Hesse

. Bidirectional alterations of interhemispheric parietal balance by non-invasive cortical stimulation. Brain 2009; 132: 3011–3020.

27.

Grefkes

Fink

. Reorganization of cerebral networks after stroke: New insights from neuroimaging with connectivity approaches. Brain 2011; 134: 1264–1276.

28.

Valero-Cabré

Pascual-Leone

Rushmore

. Cumulative sessions of repetitive transcranial magnetic stimulation (rTMS) build up facilitation to subsequent TMS-mediated behavioural disruptions. Eur J Neurosci 2008; 27: 765–774.