The therapeutic effect of transcranial direct current stimulation combined with cognitive training on patients with unilateral neglect after stroke

Abstract

BACKGROUND:

Unilateral neglect (UN) is a frequent cognitive disability following a stroke. Additional research is needed to determine the most effective cognitive rehabilitation techniques.

OBJECTIVE:

Based on the unilateral neglect neural network, we aim to explore the effect of a new model of transcranial direct current stimulation (tDCS) combined with cognitive training on stroke patients with unilateral neglect.

METHODS:

Thirty stroke patients with UN after stroke were randomly divided into three groups. All patients received cognitive training for UN and transcranial direct current stimulation with an anode placed on the corresponding part of the right hemisphere for 2 weeks. Treatment group A received multi-site tDCS from the inferior parietal lobule, middle temporal gyrus to prefrontal lobe. Group B received single-site tDCS of the inferior parietal lobule. The improvement of UN symptoms was evaluated by the scores of the Deviation index and Behavioral Inattention Test conventional tests.

RESULTS:

All groups showed improvements in all tests, and the scores of the treatment groups were statistically significant compared with the control group.

CONCLUSION:

Both single-site tDCS and multi-site tDCS have therapeutic effects on UN after stroke, and the difference in the therapeutic effects of the two modes still needs to be further explored.

Keywords

Transcranial direct currentstimulation cognitive training stroke unilateral neglect

1 Introduction

Stroke is regarded as the important cause of disability in adults, which has burdened the family and society. Unilateral neglect (UN) is a cognitive disorder after a stroke defined as failure to report visual, auditory, tactile, or other stimuli from contralateral of the side of the lesion (Gammeri, Iacono, Ricci, & Salatino, 2020). As a predictor of functional independence of stroke patients and a powerful predictor of poor outcomes of activities of daily living, the UN seriously affects the rehabilitation process of stroke and the quality of life of patients (Tobler-Ammann et al., 2020). The pathogenesis of the UN is not clear. There are several hypotheses such as hemispheric network attention control (Corbetta & Shulman, 2011), attention lateralization (Heilman & Van Den Abell, 1980), and hemispheric conflict ( Kinsbourne, 1977). Among them, Kinsbourne’s inter-hemispheric conflict model pointed out that the parietal lobe can adjust the attention distribution between the bilateral hemispheres through the connection between the hemispheres, that is, the spatial attention dominated by the injured hemisphere will be inhibited by the healthy side, leading to the occurrence of UN.

Transcranial direct current stimulation (tDCS) is a neuromodulation technology that can adjust the resting membrane potential through subthreshold currents and change the excitability of the cerebral cortex. Anode stimulation has been demonstrated to increase cortical excitability, but cathodic stimulation has the opposite effect, according to studies (Nitsche & Paulus, 2001). Based on Kinsbourne’s inter-hemispheric conflict model, tDCS anode stimulation can increase the excitability of the affected side of the cortex, and cathodic stimulation can inhibit the healthy side so that patients can better pay attention to the space contralateral side of the lesion. Sparing et al. (2009) used anode stimulation of the posterior parietal lobules on the affected side of the hemisphere. Compared with tDCS sham stimulation, tDCS can help stroke patients with their neglect symptoms. Sunwoo et al. (2013) gave patients anode stimulation on the injured side hemisphere and cathodic stimulation on the posterior parietal lobule on the contralateral side. The findings suggested that dual-mode tDCS offers some treatment potential for the UN. At present, except for a few trials that locate the tDCS treatment electrode on the temporal lobe and motor cortex, most studies place the treatment electrode over the parietal posterior lobule (Meister et al., 2006; Bornheim, Maquet, Croisier, Crielaard, & Kaux, 2018).

Injuries in UN patients, however, do not just affect the parietal posterior lobules in a clinical setting. The lesions of the temporal-parietal junction, the middle temporal gyrus, the medial temporal lobe parahippocampal gyrus, and the interruption of the white matter fiber connection between the posterior parietal lobe, temporal lobe, and prefrontal lobe can all cause unilateral neglect (Wiesen, Sperber, Yourganov, Rorden, & Karnath, 2019; Mort et al., 2003). The UN neural attention network’s process emphasizes that damage to the cortical network, which regulates attention, rather than specific brain regions, is what leads to UN. Related review articles and meta-analyses show that the anatomical network may represent the basis of spatial unilateral neglect (Lunven & Bartolomeo, 2016; Mort et al., 2003). The ventral attention network mainly includes the inferior parietal lobule, the temporal parietal junction, the middle temporal gyrus, and the ventral cortex, participating in the bottom-up attention process, mainly goal-driven and stimulus-driven attention control (MangunBuonocore & Hopfinger, 2000; Shulman & Corbetta, 2002). In addition to the parietal lobe, damage to the frontal lobe, temporal lobe, temporal parietal junction, parietal-occipital junction, and insular lobe can also lead to the occurrence of UN (Halligan, Fink, Marshall, & Vallar, 2003; Ellison, Schindler, Pattison, & Milner, 2004; Hillis et al., 2005). Imaging studies have found that at the cortical level, the lesions associated with UN are the superior temporal gyrus, the middle temporal gyrus, the junction of the parietal-occipital cortex, and some areas of the insular lobe and frontal lobe (Wiesen, Sperber, Yourganov, Rorden, & Karnath, 2019). We also discovered other research that chose the treatment site other than the parietal lobe in transcranial direct current stimulation treatment with unilateral neglect. Bornheim et al. (2018) tried to locate the anode in the C4 motor area, and the results showed that the results of SCT and LBT in the experimental group were significantly better than those in the placebo group, which provided a new idea for the selection of therapeutic sites for tDCS in the treatment of UN. Transcranial magnetic stimulation in the temporoparietal junction can improve visual regression in patients with UN (Meister et al., 2006). A-tDCS on the right prefrontal lobe can improve the ability of visual sustained attention in patients with cognitive impairment (Stonsaovapak, Hemrungroj, Terachinda, & Piravej, 2020). The aforementioned study offers a fresh research concept for unilateral neglect treatment using transcranial direct current.

Based on the hemispheric conflict inhibition model and the UN attention network, our study first identified the UN neural network and then applied several tDCS therapy modalities in conjunction with cognitive training to provide rehabilitation for post-stroke patients with UN. To assess the improvement of neglect symptoms before and after therapy, we employ the Deviation Index (DI), the Behavioral Inattention Test conventional (BIT-c), and several paper-and-pencil exams. In this study, we aimed to explore the therapeutic effect of tDCS combined with cognitive training on UN after stroke, to formulate optimal stimulation protocol of tDCS to neglect.

2 Methods

2.1 Participants

We included patients who were admitted in XX Hospital from March 2019 to January 2021, met the diagnostic criteria of the Fourth National Cerebrovascular Conference, and had cerebral infarction or hemorrhage confirmed by CT or MRI. The inclusion criteria were: (1) right-handed, first-onset right hemisphere stroke patients; (2) disease duration from one to six months; (3) through Line crossing, Star cancellation test, and behavioral performance existing UN; (4) signed informed consent.

Patients were also disqualified if they fulfilled the following requirements: (1) Patients with contraindications to tDCS (e.g., patients with implantable electronic devices; patients with metal implants in the skull; patients with fever, electrolyte imbalance, or unstable vital signs; patients with local skin damage or inflammation; patients with bleeding propensity; serious cardiac disorders or other medical diseases, etc.); (2) patients with visual field defects such as hemianopia; (3) patients with severe cognitive impairment (MMSE < 10), severe dependence and communication impairment.

2.2 Equipment

The equipment used in the study included the Brain Rehabilitation System (Wispirit Tech, Nanjing, China) and the tDCS stimulator (IS200) (Sichuan Intelligent Electronic Industrial Co. Ltd, China).

2.3 Interventions

Filtering was based on the inclusion and exclusion standards. The patients were divided into three groups at random after giving their informed consent. Depending on their conditions, each patient underwent both standard rehabilitation therapy and cognitive rehabilitation training for the UN. Treatment group A received multi-site tDCS at the same time that group B received single-site tDCS and sham stimulation in the control group. For a total of 15 sessions, the treatment was administered five times per week for 30 minutes (tDCS 20 minutes per session). The study was approved by the Medical Ethics Committee of Hebei GeneralHospital.

In this study, the side of electrode pads is 5 cm x 7 cm. We soaked the pads with saturated warm salt water before stimulation and fixed the electrode pads at the therapeutic sites with an elastic band to ensure that it is fully attached to the scalp. In the Multi-site tDCS model, a total of 15 treatments were given to the patients, with every 5 sessions being a stage. In the three stages, the anode is placed on the right inferior parietal lobule, the right middle temporal gyrus, and the right prefrontal lobe in sequence, according to the International EEG 10–20 System, the anodes are respectively P4, T4, and F8. The cathode is placed on the opposite shoulder. In the single-site tDCS model, the anode is placed on the right parietal lobule, which is positioned as P4 according to the International EEG 10–20 system; the cathode is placed on the opposite shoulder of the patient. In these two models, the current intensity was 2 mA. While in the sham stimulation group, the anode is placed on the right parietal lobule, which is positioned as P4 according to International EEG 10–20 System; the cathode is also placed on the opposite shoulder. The current intensity is 2mA, and the power is turned off 10 s after the machine is turned on. All treatments were performed 5 times a week, 20 minutes each, and 15 times.

One-to-one cognitive training is performed by a professional cognitive therapist in a quiet environment without interference. Brain Rehabilitation System and conventional cognitive training were used for treatment, including left-side attention training, visual scanning training, visual search training, reading training, and so on. The conventional rehabilitation treatment consisted of 30 sessions of 45 min each, 1 session of physical therapy, and 1 occupational therapy daily, for 5 days per week.

2.4 Outcome measurements

In order to evaluate UN (HalliganCockburn & Wilson, 1991), we employed the traditional Part of the Behavioral Inattention Test, the Deviation index, and several paper-and-pencil test scores. All outcomes were assessed at baseline and after therapy.

2.4.1 Behavioral inattention test

The conventional part of the Behavioral Inattention Test (BIT-c) is a primary outcome of our study. It includes six pen and paper tests, namely Line Crossing Test (LC), Star Cancellation Test (SCT), Letter Cancellation Test (LCT), Line Bisection Test (LBT), Figure and Shape Copying(FSC), and Representational Drawing, (RD). The total score of BIT-c is 146 points. When the score is less than 129 points, it indicates the existence of the UN.

2.4.2 Deviation index

The deviation index (DI) is also a primary outcome. There are three 20 cm horizontal line segments arranged in a trapezoid, 1cm thick in the paper. Patients need to estimate and mark the midpoint of the horizontal line segment to calculate DI. The calculation method is (measured length on the left-true length on the left)/total length of the line segment multiplied by 100, and the deviation index of the three line segments is added together and the average value is taken. The higher the DI value, the more serious the neglect symptoms.

2.5 Statistical analysis

SPSS 21.0 software was used for the analysis in this study. The quantitative data were expressed by X±S. If these data conform to the normal distribution, a one-way analysis of variance was used for the comparison among three groups and the LSD-t test was used for the multiple comparisons. As for pre- and post-treatment, a paired-sample t-test was used. If these data do not follow a normal distribution, a non-parametric test was used. The qualitative data were expressed as the number of cases, and the chi-square test was used. The test level is α = 0.05, and the difference is statistically significant when P < 0.05.

3 Results

Finally, 30 patients from three groups were evaluated. There was no statistical difference in gender, age, education level, disease type, course of the disease, and pre-treatment MMSE score of patients in each group (P > 0.05) (Table 1).

Table 1
Comparison of demographic and baseline characteristics

Factor Group A Group B Control group P

Case (n) 10 10 10

Gender (n) 0.848

Male 8 7 7

Female 2 3 3

Lesions (n) 0.229

Hemorrhage 8 5 5

Infarction 2 5 5

Age (y) 52.10±10.61 56.90±9.55 58.50±13.70 0.438

The course of disease (d) 32.60±15.70 43.10±35.57 31.00±7.07 0.447

Educational level (y) 10.50±2.92 10.80±4.516 9.90±3.76 0.864

MMSE 23.30±2.87 21.70±2.63 20.7±2.63 0.115

Factor	Group A	Group B	Control group	P
Case (n)	10	10	10
Gender (n)				0.848
Male	8	7	7
Female	2	3	3
Lesions (n)				0.229
Hemorrhage	8	5	5
Infarction	2	5	5
Age (y)	52.10±10.61	56.90±9.55	58.50±13.70	0.438
The course of disease (d)	32.60±15.70	43.10±35.57	31.00±7.07	0.447
Educational level (y)	10.50±2.92	10.80±4.516	9.90±3.76	0.864
MMSE	23.30±2.87	21.70±2.63	20.7±2.63	0.115

All the outcomes of the three groups were not statistically different before treatment and were improved compared with post-treatment. For the primary outcomes, the total score of BIT-c of groups A and B were higher than those of the control group and the difference was statistically significant (P < 0.05). However, although the score of BIT-c of group A was higher than that of group B, the difference was not statistically significant (P > 0.05). Similarly, the DI values of the two treatment groups were lower than those of the control group with statistically different (P < 0.05). And DI score of group A was lower than B without a statistical difference (P > 0.05) (Table 2).

Table 2

Comparison of outcomes for all three groups

Outcomes	Group A (n = 10)	Group B (n = 10)	Control group (n = 10)	F	P
BIT-c
baseline	53.30±22.47	66.80±20.87	51.10±27.59	1.274	0.296
posttreatment	117.60±10.05*	115.00±12.66*	81.60±27.65	12.042	< 0.001
DI
baseline	23.94±13.10	21.81±7.88	27.57±12.01	0.673	0.518
posttreatment	7.45±4.94*	7.75±4.00*	16.56±7.46	8.367	0.001
LC
baseline	16.8±6.20	20.90±10.33	15.70±8.46	1.04	0.367
posttreatment	34.70±2.83*	34.00±2.11*	26.00±9.89	6.358	0.005
SCT
baseline	22.10±13.26	27.20±11.99	23.30±15.14	0.389	0.682
posttreatment	46.90±3.90*	46.20±6.11*	32.60±12.36	9.501	0.001
LCT
baseline	11.60±6.33	14.40±5.82	10.04±6.55	1.082	0.353
posttreatment	27.60±5.46*	26.40±6.08*	18.10±7.31	6.68	0.004
LBT
baseline	2.00±2.50	3.20±1.62	1.10±1.29	3.171	0.58
posttreatment	5.70±2.45*	5.10±1.52*	2.70±2.45	5.27	0.12
FSC
baseline	0.40±0.52	0.50±0.53	0.40±0.52	0.123	0.885
posttreatment	1.40±1.35	1.40±1.17	1.40±1.51	0.209	0.813
RD
baseline	0.40±0.52	0.6±0.52	0.20±0.42	1.688	0.204
posttreatment	1.30±1.16	1.9±0.738	0.80±1.03	3.079	0.062

^*Compare with the control group, P < 0.05

Additionally, the scores of all paper-and-pencil tests in the two treatment groups were higher than those of the control group, of which LC SCT, LCT, and LBT scores were statistically different (P < 0.05). Except for RD, although the scores of all tests in group A were higher than B, the difference was not statistically significant (P > 0.05) (Table 2).

4 Discussion

In this study, various tDCS therapeutic modalities were coupled with cognitive training. In the single-site therapy paradigm, we applied a-tDCS to the inferior parietal lobule of the injured hemisphere in accordance with Kinsbourne’s interhemispheric conflict model and attention network model (Corbetta & Shulman, 2011b; Kinsbourne, 1977). To increase the excitability of the entire attention network in patients with unilateral neglect, a-tDCS was applied to the ipsilateral inferior parietal lobule, temporal lobe, and prefrontal lobe in the multi-site therapy paradigm. The BIT-c scores of the two experimental groups were significantly higher than those of the control group after three weeks of therapy, and the DI of the two experimental groups was significantly lower. The outcomes demonstrated that the effect of single-site and multi-site tDCS combined with cognitive training was significantly better than that of simple cognitive training.

We have conducted further research to help in the selection of treatment locations. The parietal cortex is the most frequently injured area in unilateral neglect (Gammeri, Iacono, Ricci, & Salatino, 2020). The parietal cortex currently houses the majority of UN’s therapeutic sites. The stimulation patterns can be roughly divided into two types: single-site tDCS (ipsilateral parietal lobe anode stimulation and healthy side parietal lobe cathodic stimulation) and dual-site tDCS (ipsilateral parietal lobe anode stimulation and healthy side cathodic stimulation). The BITc and DI scores of the single site stimulation group were significantly better than those of the sham stimulation group, which is consistent with the findings of Sunwoo and Ladavas (Làdavas et al., 2015; Sunwoo et al., 2013). This indicates that the parietal cortex tDCS treatment could change the neglected symptoms of patients.

Based on the mechanism of the UN neural attention network ( & Shulman, 2011), we sequentially formed a treatment network of the right inferior parietal lobule, temporal lobe, and prefrontal lobe to better improve the symptoms of neglect. In our study, patients in group A received multi-site tDCS stimulation. After 15 sessions of treatment, BIT-c and DI scores were significantly higher than before treatment, and the results were statistically different, BIT-c and DI have a statistical difference compared with the control group after treatment, indicating that multi-site tDCS can effectively improve the symptoms of UN after stroke. Although the results of all evaluation indexes in experimental group A were better than those in experimental group B, there was no significant difference between the two groups (P > 0.05). Although this result did not show that the effect of multi-site tDCS in the treatment of UN was better than that of single-site tDCS, it also showed a certain trend. The lack of statistical difference may be related to the insufficient sample size, and the sample size can be expanded in future studies to further compare the two stimulationmodes.

This study had some limitations, due to the limited sample sizes, there was no significant difference in the results of the two stimulation modes. In addition, due to the short hospital stay, this study only compared the results before and after treatment and failed to conduct a longer-term observation of the efficacy. In future research, we will expand the sample size to further compare the therapeutic effects of the two stimulation modes, conduct more detailed grouping and research on the UN phenomenon, and pay attention to its long-term therapeutic effects. In terms of evaluation methods, combined with objective indicators such as diffusion tensor imaging and event-related potential, the treatment effect of UN is further evaluated.

5 Conclusions

Transcranial direct current stimulation combined with cognitive training can improve the neglect symptoms of stroke patients, and the effect is significantly better than pure cognitive training. Additionally, both single-site tDCS and multi-site tDCS have therapeutic effects on UN after stroke, and the difference in the therapeutic effects of the two modes still needs to be further explored.

Footnotes

Acknowledgments

The authors would like to thank the staff of the rehabilitation and neurology departments at Hebei General Hospital, Shijiazhuang, China for their support.

Conflict of interest

The authors declare no conflict of interest.

Funding

The study was funded by the Research Program of Hebei Provincial Administration of Traditional Chinese Medicine (2021168).

References

Bornheim,

, Maquet,

, Croisier,

J. L.

, Crielaard,

J. M.

, & Kaux,

J. F.

(2018). Motor cortex Transcranial Direct Current Stimulation (tDCS) improves acute stroke visuo-spatial neglect: A series of four case reports. Brain stimulation, 11(2), 459–461.

Cappon,

, Jahanshahi,

, & Bisiacchi,

(2016). Value and Efficacy of Transcranial Direct Current Stimulation in the Cognitive Rehabilitation: A Critical Review Since 2000. Front Neurosci, 10, 157.

Corbetta,

, & Shulman,

G. L.

(2011a). Spatial neglect and attention networks. Annu Rev Neurosci, 34, 569–599.

Corbetta,

, & Shulman,

G. L.

(2011b)Spatial neglect and attention networks. Annu Rev Neurosci, 34, 569–599.

ELLISON,

, SCHINDLER,

, PATTISON,

L. L.

, & MILNER,

A. D.

(2004). An exploration of the role of the superior temporal gyrus in visual search and spatial perception using TMS. Brain (London, England : 1878), 127(Pt 10), 2307–2315.

Gammeri,

, Iacono,

, Ricci,

, & Salatino,

(2020). Unilateral Spatial Neglect After Stroke: Current Insights. Neuropsychiatr Dis Treat, 16, 131–152.

Halligan,

P. W.

, Cockburn,

, & Wilson,

B. A.

(1991). The behavioural assessment of visual neglect. Neuropsychological Rehabilitation, 1(1), 5–32.

Halligan,

P. W.

, Fink,

G. R.

, Marshall,

J. C.

, & Vallar,

(2003). Spatial cognition: evidence from visual neglect. Trends in Cognitive Sciences, 7(3), 125–133.

Heilman,

K. M.

, & Van Den Abell,

(1980). Right hemisphere dominance for attention: the mechanism underlying hemispheric asymmetries of inattention (neglect). Neurology, 30(3), 327–330.

10.

Hillis,

A. E.

, Newhart,

, Heidler,

, Barker,

P. B.

, Herskovits,

E. H.

, & Degaonkar,

(2005). Anatomy of Spatial Attention: Insights from Perfusion Imaging and Hemispatial Neglect in Acute Stroke. The Journal of Neuroscience, 25(12), 3161–3167.

11.

Kinsbourne,

(1977). Hemi-neglect and hemisphere rivalry. Advances in Neurology, 18, 41.

12.

Làdavas,

, Giulietti,

, Avenanti,

, Bertini,

, Lorenzini,

, Quinquinio,

, et al. (2015). a-tDCS on theipsilesional parietal cortex boosts the effects of prism adaptationtreatment in neglect. Restorative Neurology and Neuroscience, 33(5), 647–662.

13.

Lunven,

, & Bartolomeo,

(2016). Attention and spatial cognition: Neural and anatomical substrates of visual neglect. Annals of Physical and Rehabilitation Medicine, 60(3), 124–129.

14.

Mangun,

G. R.

, Buonocore,

M. H.

, & Hopfinger,

J. B.

(2000). The neural mechanisms of top-down attentional control. Nature Neuroscience, 3(3), 284–291.

15.

Meister,

I. G.

, Wienemann,

, Buelte,

, Grünewald,

, Sparing,

, Dambeck,

, et al. (2006). Hemiextinction induced by transcranial magnetic stimulation over the right temporo-parietal junction. Neuroscience, 142(1), 119–123.

16.

Mort,

D. J.

, Malhotra,

, Mannan,

S. K.

, Rorden,

, Pambakian,

, Kennard,

, et al. (2003). The anatomy of visual neglect. American Journal of Ophthalmology, 136(6), 1200–1201.

17.

Nitsche,

M. A.

, & Paulus,

(2001). Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology, 57(10), 1899–1901.

18.

Nitsche,

M. A.

, & Paulus,

(2001). Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Neurology, 57(10), 1899–1901.

19.

Rossini,

P. M.

, Burke,

, Chen,

, Cohen,

L. G.

, Daskalakis,

, Di Iorio,

, et al. (2015). Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves:Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin Neurophysiol, 126(6), 1071–1107.

20.

Shulman,

G. L.

, & Corbetta,

(2002). Control of goal-directed and stimulus-driven attention in the brain. Nature reviews. Neuroscience, 3(3), 201–215.

21.

Sparing,

, Thimm,

, Hesse,

M. D.

, Kust,

, Karbe,

, & Fink,

G. R.

(2009). Bidirectional alterations of interhemispheric parietal balance by non-invasive cortical stimulation. Brain, 132(Pt 11), 3011–3020.

22.

Stonsaovapak,

, Hemrungroj,

, Terachinda,

, & Piravej,

(2020). Effect of Anodal Transcranial Direct Current Stimulation at the Right Dorsolateral Prefrontal Cortex on the Cognitive Function in Patients With Mild Cognitive Impairment: A Randomized Double-Blind Controlled Trial. Arch Phys Med Rehabil, 101(8), 1279–1287.

23.

Sunwoo,

, Kim,

, Chang,

W. H.

, Noh,

, Kim,

, & Ko,

(2013). Effects of dual transcranial direct current stimulation on post-stroke unilateral visuospatial neglect. Neuroscience Letters, 554, 94–98.

24.

Tobler-Ammann,

B. C.

, Weise,

, Knols,

R. H.

, Watson,

M. J.

, Sieben,

J. M.

, de Bie,

R. A.

, et al.(2020). Patients’ experiences of unilateral spatial neglect between stroke onset and discharge from inpatient rehabilitation: a thematic analysis of qualitative interviews. Disability and Rehabilitation, 42(11), 1578–1587.

25.

Wiesen,

, Sperber,

, Yourganov,

, Rorden,

, & Karnath,

(2019). Using machine learning-based lesion behavior mapping to identify anatomical networks of cognitive dysfunction: Spatial neglect and attention. NeuroImage (Orlando, Fla.), 201, 116000.