Definition of hemineglect and functional repercussions

Hemineglect involves a difficulty in attending to the hemifield contralateral (usually the left) to the injured brain area, and can range from an omission of objects that are located in the left hemifield of space to a lack of attention, recognition and even denial of parts of one’s own body. At the functional level, hemineglect results in severe difficulties in the independence of the affected person, both in basic activities of daily living (grooming, dressing, eating, etc.) and instrumental (handling money, food preparation, public transportation or independent ambulation).

In addition, the presence of hemineglect has been associated with longer hospital admission and rehabilitation times, increased risk of falls, and poor motor and functional recovery (Chen et al., 2015; Jehkonen et al., 2006; Wilkinson et al., 2012).

Recovery from hemineglect

Regarding the prognosis of hemineglect recovery, in studies conducted 8 to 12 months after stroke with the presence of hemineglect, they found that hemineglect persisted in one-third of cases (Colombo et al., 1982; Karnath et al., 2011) or little recovery from hemineglect occurred (Kalra et al., 1997; Katz et al., 1999; Luukkainen-Markkula et al., 2014; Paolucci et al., 2001).

Current therapies

Today, available therapeutic approaches for the rehabilitation of hemineglect, e.g. prismatic adaptation, visuospatial training, mental imagery therapy or optokinetic stimulation, have limited and sometimes short-lived clinical effectiveness (Azouvi et al., 2017; Fasotti & van Kessel, 2013).Due to the persistence of the symptomatology and the impact it has on the patient’s independence, it is essential to develop new treatment methods and address the underlying brain dysfunctions in an appropriate manner. In this regard, interventions based on non-invasive brain stimulation techniques are a promising therapeutic intervention.

Improvement of hemineglect by neuromodulation

At the brain injury unit of the Beata María Ana Hospital in Madrid, a study is being carried out focused on the improvement of hemineglect by means of neuromodulation through direct current electrical stimulation (tDCS) aimed at improving hemineglect secondary to stroke in order to enhance the benefits that both interventions have independently.

The research, carried out together with the Universitat Oberta de Catalunya and the Universidad Francisco de Vitoria, is co-directed by Dr. Juan Pablo Romero, director of the Brain Injury Neurorehabilitation research group, neurologist at the Brain Injury Unit of the Beata María Ana Hospital and professor at the Universidad Francisco de Vitoria, and Dr. Elena Muñoz Marrón, director of the Cognitive NeuroLab research group, professor at the UOC’s Faculty of Health Sciences and director of the University Master’s Degree in Neuropsychology. Also participating in the project are Dr. Marcos Ríos-Lago, coordinator of the brain damage unit of the Beata María Ana Hospital, Begoña González Rodríguez and David de Noreña Martínez, neuropsychologists of the Unit, and the predoctoral researchers of the Francisco de Vitoria University, Francisco Sánchez, Yeray González and Aida Arroyo.

Objective

The aim of this project is to validate a neuromodulation protocol aimed at the treatment of hemineglect secondary to ischemic stroke in patients who are in the subacute phase (3 to 12 months after the injury). This technique seeks an improvement in symptomatology by reducing the pathological hyperactivity developed by the non-damaged hemisphere after a stroke located in the right medial cerebral artery, through the application of a multisite tDCS stimulation program.

Neuromodulatory techniques

Noninvasive brain stimulation refers to different neurophysiological techniques that allow modulation of brain activity in a safe and noninvasive manner (Bikson et al., 2016). Through these techniques we can both increase the excitability of the cerebral cortex and decrease it. The most commonly used noninvasive brain stimulation techniques today are transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS), for which there is sufficient empirical evidence supporting their potential to modulate brain activity in the short and long term (Hummel & Cohen, 2006).

Transcranial direct current stimulation (tDCS)

tDCS allows the modulation of cortical activity by applying a low intensity electric current (generally between 1 mA and 2 mA) by placing two or more electrodes on the patient’s scalp. In this way, the electric current flows between the electrodes, from the anode to the cathode, increasing cortical excitability below the anode and decreasing it below the cathode. On the other hand, multisite, or high-definition tDCS, allows a more precise and localized stimulation of the selected brain area.

Also, tDCS has proven to be an effective technique as a complementary therapeutic approach to more conventional treatments in post-stroke rehabilitation (Edwards & Fregni, 2008), showing promising results in the rehabilitation of visuospatial hemineglect (e.g., Bang & Bong, 2015; Ladavas et al., 2015; Yi et al., 2016).

Based on Kinsbourne’s interhemispheric rivalry model (Kinsbourne, 1977) and depending on the stimulation parameters, different stimulation approaches are possible, such as increasing brain activity in the injured hemisphere, inhibiting pathological hyperactivity in the healthy hemisphere, or a combination of both (Zebhauser et al., 2019).

Rehabilitation project with tDCS

In this project we applied a tDCS protocol with a duration of 20 minutes daily for 10 consecutive days (Monday to Friday), being its intensity of 2 mA. The stimulation is applied with the cathode positioned at P3 (following the international 10/20 system for EEG electrode placement), being the return electrodes distributed at C3, CP5, CP1, Pz, PO3, PO7, P7. The aim of this setup is to reduce the pathological hyperactivation of the parietal cortex of the healthy hemisphere (P3), in order to get the injured hemisphere (right) to increase its level of activation and participation of attention towards the left hemifield, by reducing the hyperactivity of the healthy contralateral hemisphere, which frees the damaged hemisphere from the inhibition exerted on it by the healthy one.

Interventions based on non-invasive brain stimulation, such as tDCS, constitute a very promising therapeutic approach, with minimal adverse effects and encouraging results described in various reviews and meta-analyses (Fan et al., 2018; Kashiwagi et al., 2018; Salazar et al., 2018; Zebhauser et al., 2019).

NeuronUP: a neurorehabilitation platform

The neuropsychological rehabilitation program aimed at the rehabilitation of hemineglect is based on the use of the NeuronUP rehabilitation platform, a platform aimed at the rehabilitation and stimulation of cognitive functions.

We have chosen this platform because it has a large bank of activities that can be performed both interactively and with pencil and paper. The ease of use and the wide adaptability to the characteristics of each of the users allows to design in a simple and adjusted way the personalized intervention programs for each person.

Nine specific exercises aimed at the stimulation and rehabilitation of hemineglect have been selected and combined throughout the 10 intervention sessions (4 tasks in each session), with a duration of 30 minutes each. The configuration of the platform allows programming the sessions in order to progressively increase the difficulty of the tasks according to the achievements reached by the participant. Thus, in each session, the difficulty of the activities is adjusted according to the previous day’s performance.

The ease of programming, the recording of user performance in each task and the wide and innovative bank of activities specifically designed to treat specific cognitive functions, means that the application of the intervention sessions can be carried out systematically and without errors in their design, which guarantees homogeneity in the application of the treatment to all participants.

tDCS-Neglect Project

In order to participate in the research project, participants must meet a series of requirements; among them we can cite:

• Having suffered a hemorrhagic or ischemic stroke in the right hemisphere.
• Time since injury between 3 months and 12 months.
• Be older than 18 years old.
• Have a neuroimaging study performed.
• Absence of previous stroke.
• Functional capacity to remain seated and active for one hour.
• Right-handed dominance.
• Show heminegligence in objective tests to assess it.
• Informed consent signed by the affected person or his/her legal guardian.

Neuropsychological assessment and EEG

All participants underwent a neuropsychological assessment and an electroencephalogram (EEG) at the beginning of the study. The neuropsychological assessment is aimed at identifying the presence of hemineglect and the severity of the symptomatology, also assessing the functional impact of this alteration in their daily functioning and the alteration or preservation of other cognitive functions, such as attention and working memory. The neuropsychological assessment and EEG will be performed three days before the start of the intervention with tDCS and NeuronUP. The same assessment protocol will be repeated three days after the end of the intervention, in order to analyze the cognitive improvements that may have occurred, the changes in physiological measures (EEG), and the correlation between both measures.

Content

Participants are assigned to one of two intervention groups; the intervention program consists of 10 sessions of neuropsychological rehabilitation with NeuronUP over two weeks (Monday to Friday). One of the groups (active group) receives neuropsychological rehabilitation for 30 min combined with active tDCS for 20 min (starting 5 min after the start of NeuronUP). The other group (placebo group) performs the same neuropsychological rehabilitation program but combined with placebo tDCS (called sham tDCS) for the same time. In all cases, the participants, the evaluators and the neuropsychologists responsible for carrying out the intervention program are blind to the experimental conditions assigned, i.e. they do not know to which group each participant has been assigned.

The novelty of this study lies in the combination of two tools aimed at the stimulation and improvement of a disorder with a high prevalence and serious repercussions on the functional independence of the person, such as hemineglect. The combination of both therapeutic approaches will enhance the improvement of hemineglect symptomatology, so that the benefits will be superior to those achieved by the techniques separately.

In the following video (In Spanish with English subtitles available) we present a more detailed explanation of the project and its objectives.

Participation

The study is currently open to any person affected by a stroke who presents symptoms of hemineglect, meets the aforementioned inclusion criteria and wishes to participate voluntarily in the study. Individuals or centers interested in participating can contact the principal investigators of the project:

Dr. Juan Pablo Romero

Email: [email protected]

Dr. Elena Muñoz Marrón

Email: [email protected]

This article has been carried out by Begoña González, Elena Muñoz and Juan Pablo Romero. You can consult more projects of the research groups involved at: https://www.ufv.es/neurorrehabilitacion-dano-cerebral/ (Spanish)

Bibliographic References

Azouvi, P., Jacquin-Courtois, S., & Luauté, J. (2017). Rehabilitation of unilateral neglect: Evidence-based medicine. Annals of Physical and Rehabilitation Medicine, 60(3), 191-197. https://doi.org/10.1016/j.rehab.2016.10.006

Bang, D.-H., & Bong, S.-Y. (2015). Effect of a combination of transcranial direct current stimulation and feedback training on visuospatial neglect in patients with subacute stroke: A pilot randomized controlled trial. Journal of physical therapy science, 27(9), 2759‐2761.

Bikson, M., Grossman, P., Thomas, C., Zannou, A. L., Jiang, J., Adnan, T., Mourdoukoutas, A. P., Kronberg, G., Truong, D., Boggio, P., Brunoni, A. R., Charvet, L., Fregni, F., Fritsch, B., Gillick, B., Hamilton, R. H., Hampstead, B. M., Jankord, R., Kirton, A., … Woods, A. J. (2016). Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimulation, 9(5), 641-661. https://doi.org/10.1016/j.brs.2016.06.004

Chen, P., Hreha, K., Kong, Y., & Barrett, A. M. (2015). Impact of spatial neglect on stroke rehabilitation: Evidence from the setting of an inpatient rehabilitation facility. Archives of Physical Medicine and Rehabilitation, 96(8), 1458-1466. https://doi.org/10.1016/j.apmr.2015.03.019

Colombo, A., De Renzi, E., & Gentilini, M. (1982). The time course of visual hemi-inattention. Archiv Für Psychiatrie Und Nervenkrankheiten, 231(6), 539-546. https://doi.org/10.1007/BF00343997

Edwards, D., & Fregni, F. (2008). Modulating the healthy and affected motor cortex with repetitive transcranial magnetic stimulation in stroke: Development of new strategies for neurorehabilitation. NeuroRehabilitation, 23(1), 3-14.

Fan, J., Li, Y., Yang, Y., Qu, Y., & Li, S. (2018). Efficacy of Noninvasive Brain Stimulation on Unilateral Neglect After Stroke: A Systematic Review and Meta-analysis. American Journal of Physical Medicine & Rehabilitation, 97(4), 261-269. https://doi.org/10.1097/PHM.0000000000000834

More references on rehabilitation of hemineglect after stroke

Fasotti, L., & van Kessel, M. (2013). Novel insights in the rehabilitation of neglect. Frontiers in Human Neuroscience, 7, 780. https://doi.org/10.3389/fnhum.2013.00780

Hummel, F. C., & Cohen, L. G. (2006). Non-invasive brain stimulation: A new strategy to improve neurorehabilitation after stroke? The Lancet Neurology, 5(8), 708-712. https://doi.org/10.1016/S1474-4422(06)70525-7

Jehkonen, M., Laihosalo, M., & Kettunen, J. E. (2006). Impact of neglect on functional outcome after stroke: A review of methodological issues and recent research findings. Restorative Neurology and Neuroscience, 24(4-6), 209-215.

Kalra, L., Perez, I., Gupta, S., & Wittink, M. (1997). The influence of visual neglect on stroke rehabilitation. Stroke, 28(7), 1386-1391.

Karnath, H.-O., Rennig, J., Johannsen, L., & Rorden, C. (2011). The anatomy underlying acute versus chronic spatial neglect: A longitudinal study. Brain: A Journal of Neurology, 134(Pt 3), 903-912. https://doi.org/10.1093/brain/awq355

Kashiwagi, F. T., El Dib, R., Gomaa, H., Gawish, N., Suzumura, E. A., da Silva, T. R., Winckler, F. C., de Souza, J. T., Conforto, A. B., Luvizutto, G. J., & Bazan, R. (2018). Noninvasive Brain Stimulations for Unilateral Spatial Neglect after Stroke: A Systematic Review and Meta-Analysis of Randomized and Nonrandomized Controlled Trials. Neural Plasticity, 2018. https://doi.org/10.1155/2018/1638763

Katz, N., Hartman-Maeir, A., Ring, H., & Soroker, N. (1999). Functional disability and rehabilitation outcome in right hemisphere damaged patients with and without unilateral spatial neglect. Archives of Physical Medicine and Rehabilitation, 80(4), 379-384.

Ladavas, E., Giulietti, S., Avenanti, A., Bertini, C., Lorenzini, E., Quinquinio, C., & Serino, A. (2015). A-tDCS on the ipsilesional parietal cortex boosts the effects of prism adaptation treatment in neglect. Restorative neurology and neuroscience, 33(5), 647‐662. https://doi.org/10.3233/RNN-140464

More documentation about heminegligence and stroke

Kinsbourne, M. (1977). Hemineglect and hemisphere rivalry. Advances in neurology, 18, 41-49.

Luukkainen-Markkula, R., Eng, N., & Tarkka, I. (2014). Recovery from neglect after right hemisphere stroke. International journal of neurorehabilitation, 1. https://doi.org/10.4172/ijn.1000103

Paolucci, S., Antonucci, G., Grasso, M. G., & Pizzamiglio, L. (2001). The role of unilateral spatial neglect in rehabilitation of right brain-damaged ischemic stroke patients: A matched comparison. Archives of Physical Medicine and Rehabilitation, 82(6), 743-749.

Salazar, A. P. S., Vaz, P. G., Marchese, R. R., Stein, C., Pinto, C., & Pagnussat, A. S. (2018). Noninvasive Brain Stimulation Improves Hemispatial Neglect After Stroke: A Systematic Review and Meta-Analysis. Archives of Physical Medicine and Rehabilitation, 99(2), 355-366.e1. https://doi.org/10.1016/j.apmr.2017.07.009

Wilkinson, D., Sakel, M., Camp, S.-J., & Hammond, L. (2012). Patients with hemispatial neglect are more prone to limb spasticity, but this does not prolong their hospital stay. Archives of Physical Medicine and Rehabilitation, 93(7), 1191-1195. https://doi.org/10.1016/j.apmr.2012.01.010

Yi, Y. G., Chun, M. H., Do, K. H., Sung, E. J., Kwon, Y. G., & Kim, D. Y. (2016). The Effect of Transcranial Direct Current Stimulation on Neglect Syndrome in Stroke Patients. Annals of Rehabilitation Medicine-Arm, 40(2), 223-229. https://doi.org/10.5535/arm.2016.40.2.223

Zebhauser, P. T., Vernet, M., Unterburger, E., & Brem, A.-K. (2019). Visuospatial Neglect-a Theory-Informed Overview of Current and Emerging Strategies and a Systematic Review on the Therapeutic Use of Non-invasive Brain Stimulation. Neuropsychology Review, 29(4), 397-420. https://doi.org/10.1007/s11065-019-09417-4