NOVEL INSIGHTS IN REHABILITATION OF NEGLECT, 2nd EDITION Topic Editors Tanja Nijboer and Stefan Van der Stigchel HUMAN NEUROSCIENCE Frontiers in Human Neuroscience December 2014 | Novel Insights in Rehabilitation of Neglect, 2nd Edition | 1 ABOUT FRONTIERS Frontiers is more than just an open-access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. FRONTIERS JOURNAL SERIES The Frontiers Journal Series is a multi-tier and interdisciplinary set of open-access, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. 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Cover image provided by Ibbl sarl, Lausanne CH ISSN 1664-8714 ISBN 978-2-88919-409-4 DOI 10.3389/978-2-88919-409-4 Frontiers in Human Neuroscience December 2014 | Novel Insights in Rehabilitation of Neglect, 2nd Edition | 2 Topic Editors: Tanja Nijboer, Utrecht University, Netherlands Stefan Van der Stigchel, Utrecht University, Netherlands Hemispatial neglect is the failure to report, respond to, or orient to novel or meaningful stimuli presented in the contralesional visual field. It constitutes one of the most invalidating neurological disorders that can occur after stroke. It is therefore important to treat neglect as adequate as possible and much of the research dedicated to neglect therefore focuses on rehabilitation. In this special topic, you will find 29 articles on the rehabilitation of neglect. This Research Topic has opened new perspectives, and has given us an indication of where the field is going. Although some of the current rehabilitation techniques have proven to be beneficial, there is limited agreement on the most valuable technique or the mechanisms underlying the ameliorating effects. NOVEL INSIGHTS IN REHABILITATION OF NEGLECT, 2nd EDITION Frontiers in Human Neuroscience December 2014 | Novel Insights in Rehabilitation of Neglect, 2nd Edition | 3 Table of Contents 06 Introduction to the Research Topic Novel Insights in Rehabilitation of Neglect Stefan Van der Stigchel and Tanja C. W. Nijboer 09 Predicting Functional Outcome after Stroke: The Influence of Neglect on Basic Activities in Daily Living Tanja Nijboer, Ingrid van de Port, Vera Schepers, Marcel Post and Anne Visser-Meily 15 Hemispatial Neglect: Computer-Based Testing Allows More Sensitive Quantification of Attentional Disorders and Recovery and Might Lead to Better Evaluation of Rehabilitation Mario Bonato and Leon Y. Deouell 19 Advancing the Science of Spatial Neglect Rehabilitation: An Improved Statistical Approach with Mixed Linear Modeling Kelly M. Goedert, Raymond C. Boston and A. M. Barrett 34 Long-Lasting Amelioration of Walking Trajectory in Neglect After Prismatic Adaptation Marco Rabuffetti, Alessia Folegatti, Lucia Spinazzola, Raffaella Ricci, Maurizio Ferrarin, Anna Berti and Marco Neppi-Modona 47 The Feasibility of Computer-Based Prism Adaptation to Ameliorate Neglect in Sub-Acute Stroke Patients Admitted to a Rehabilitation Center Miranda Smit, Stefan Van der Stigchel, Johanna M. A. Visser-Meily, Mirjam Kouwenhoven, Anja L. H. Eijsackers and Tanja C. W. Nijboer 55 Exploring the Effects of Ecological Activities During Exposure to Optical Prisms in Healthy Individuals Paola Fortis, Roberta Ronchi, Elena Calzolari, Marcello Gallucci and Giuseppe Vallar 66 Prismatic Adaptation in the Rehabilitation of Neglect Patients: Does the Specific Procedure Matter? Alessio Facchin, Roberta Daini and Alessio Toraldo 69 A Note on Striemer and Danckert's Theory of Prism Adaptation in Unilateral Neglect Styrmir Saevarsson and Árni Kristjánsson 74 Spatial Compression Impairs Prism-Adaptation in Healthy Individuals Rachel J. Scriven and Roger Newport 82 Early Visual Processing is Affected by Clinical Subtype in Patients with Unilateral Spatial Neglect: A Magnetoencephalography Study Katsuhiro Mizuno, Tetsuya Tsuji, Yves Rossetti, Laure Pisella, Hisao Ohde and Meigen Liu Frontiers in Human Neuroscience December 2014 | Novel Insights in Rehabilitation of Neglect, 2nd Edition | 4 90 Now You Feel Both: Galvanic Vestibular Stimulation Induces Lasting Improvements in the Rehabilitation of Chronic Tactile Extinction Lena Schmidt, Kathrin S. Utz, Lena Depper, Michaela Adams, Anna-Katharina Schaadt, Stefan Reinhart and Georg Kerkhoff 101 Transcutaneous Electrical Nerve Stimulation Effects on Neglect: A Visual- Evoked Potential Study Sabrina Pitzalis, Donatella Spinelli, Giuseppe Vallar and Francesco Di Russo 110 Harnessing Motivation to Alleviate Neglect Charlotte Russell, Korina Li and Paresh A. Malhotra 117 Visual Scanning Training for Neglect after Stroke With and Without a Computerized Lane Tracking Dual Task M. E. van Kessel, A. C. H. Geurts, W. H. Brouwer and L. Fasotti 128 Combined Space and Alertness Related Therapy of Visual Hemineglect: Effect of Therapy Frequency Walter Sturm, M. Thimm, F . Binkofski, H. Horoufchin, G. R. Fink, J. Küst, H. Karbe and K. Willmes 140 Is Two Better than One? Limb Activation Treatment Combined with Contralesional Arm Vibration to Ameliorate Signs of Left Neglect Marco Pitteri, Giorgio Arcara, Laura Passarini, Francesca Meneghello and Konstantinos Priftis 150 Effects of Pro-Cholinergic Treatment in Patients Suffering From Spatial Neglect N. Lucas, A. Saj, S. Schwartz, R. Ptak, A. Schnider, C. Thomas, P . Conne, R. Leroy, S. Pavin, K. Diserens and Patrik Vuilleumier 165 Dissociation in Optokinetic Stimulation Sensitivity Between Omission and Substitution Reading Errors in Neglect Dyslexia Roberta Daini, Andrea Albonico, Manuela Malaspina, Marialuisa Martelli, Silvia Primativo and Lisa S. Arduino 175 Visual Scanning Training, Limb Activation Treatment, and Prism Adaptation for Rehabilitating Left Neglect: Who is the Winner? Konstantinos Priftis, Laura Passarini, Cristina Pilosio, Francesca Meneghello and Marco Pitteri 187 Motor Neglect and Future Directions for Research Dimitrios S. Sampanis and Jane Riddoch 189 Videogame Based Neglect Rehabilitation: A Role for Spatial Remapping and Multisensory Integration? N. A. Borghese, G. Bottini and A. Sedda 190 The Influence of Prism Adaptation on Perceptual and Motor Components of Neglect: A Reply to Saevarsson and Kristjansson Christopher L. Striemer and James Danckert 192 Novel Insights in the Rehabilitation of Neglect Luciano Fasotti and Marlies van Kessel 200 Rehabilitation Interventions for Unilateral Neglect After Stroke: A Systematic Review From 1997 Through 2012 Nicole Y. H. Yang, Dong Zhou, Raymond C. K. Chung, Cecilia W. P . Li-Tsang and Kenneth N. K. Fong Frontiers in Human Neuroscience December 2014 | Novel Insights in Rehabilitation of Neglect, 2nd Edition | 5 203 Non-Invasive Brain Stimulation in Neglect Rehabilitation: An Update René Martin Müri, Dario Cazzoli, Tobias Nef, Urs P . Mosimann, Simone Hopfner and Thomas Nyffeler 213 Effect of Eye Patching in Rehabilitation of Hemispatial Neglect Nicola Smania, Cristina Fonte, Alessandro Picelli, Marialuisa Gandolfi and Valentina Varalta 231 Spatial Working Memory Deficits Represent a Core Challenge for Rehabilitating Neglect Christopher L. Striemer, Susanne Ferber and James Danckert 242 Statistical Learning as a Tool for Rehabilitation in Spatial Neglect Albulena Shaqiri, Britt Anderson and James Danckert 257 Motor Extinction: A Deficit of Attention or Intention? T. David Punt, M. Jane Riddoch and Glyn W. Humphreys HUMAN NEUROSCIENCE EDITORIAL published: 14 April 2014 doi: 10.3389/fnhum.2014.00233 Introduction to the ResearchTopic Novel Insights in Rehabilitation of Neglect Stefan Van der Stigchel 1 * and Tanja C. W. Nijboer 1,2 * 1 Department of Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, Netherlands 2 Brain Center Rudolf Magnus and Center of Excellence for Rehabilitation Medicine, University Medical Center Utrecht and De Hoogstraat Rehabilitation Center, Utrecht, Netherlands *Correspondence: s.vanderstigchel@uu.nl ; t.c.w.nijboer@uu.nl Edited and reviewed by: Hauke R. Heekeren, Freie Universität Berlin, Germany Keywords: neglect, rehabilitation, treatment, prism adaptation, stroke Hemispatial neglect is the failure to report, respond to, or orient to novel or meaningful stimuli presented in the contralesional visual field. This failure cannot be attributed to motor or sensory defects (Heilman andValenstein,1979). It constitutes one of the most inval- idating neurological disorders that can occur after stroke. As dis- cussed in this Research Topic, patients with neglect are less inde- pendent in various activities of daily living compared to patients without neglect (Nijboer et al., 2013). It is therefore important to treatneglectasadequatelyaspossibleandmuchof theresearchdedi- cated to neglect therefore focuses on rehabilitation. Here we provide a brief overview of the 29 articles featured in this Research Topic. This Research Topic points to a number of promising tech- nological innovations. For instance, it is argued that computer- based testing allows more sensitive quantification of attentional disorders and recovery than paper-and-pencil tests (Bonato and Deouell, 2013). These innovations are likely to result in improved diagnosis and more tailor-made rehabilitation trajectories. Fur- thermore, future studies will hopefully take into account improved statistical approaches, like mixed linear modeling, which are more appropriate than ANOVAs to assess change over time when mea- suring recovery patterns (Goedert et al., 2013). Also innovations are proposed with respect to treatment of neglect. Prism adapta- tion (PA) is currently the most profoundly studied rehabilitation technique for neglect. New insights are reported in this Research Topic. First, the effect of PA extends to walking trajectories: PA when applied to the upper right limb improved the walking trajec- tory of a neglect patient, and this effect remained up to 15 months after treatment (Rabuffetti et al., 2013). Second, in line with the technological innovations mentioned above, computer-based PA is shown to be feasible, yet no improvement of neglect has been found on neuropsychological neglect tests (Smit et al., 2013). Third, two studies aimed to unravel the specific conditions in which the beneficial effects of PA are optimal. One of the arti- cles discusses an effective novel adaptation procedure, which is more ecologically valid and regarded as more pleasant by patients (Fortis et al., 2013). The success of this new procedure is also highlighted in a review on different PA procedures, which revealed that the different available PA procedures are equally effective (Facchin et al., 2013). The results of these studies indicate that one can choose the best fitting or most suitable procedure for a given patient, without lowering the efficacy of the PA adaptation itself. The underlying mechanism of PA is currently unclear. In this Research Topic, there was a debate on which aspect of neglect is part of the successful PA treatment: the perceptual or visual aspect or the motor aspect (Saevarsson and Kristjansson, 2013; Striemer and Danckert, 2013), whereas another research proposes that a distortion of visual space explains neglect performance while adapting to prisms (Scriven and Newport, 2013). This debate is still ongoing and will hopefully be resolved in the coming years, perhaps by using relatively novel measures like visually evoked magnetic fields (Mizuno et al., 2013). Besides PA, a wide range of rehabilitation techniques tapping into various domains underlying hemispatial neglect, such as gal- vanic vestibular stimulation (Schmidt et al., 2013), transcutaneous electrical nerve stimulation (Pitzalis et al., 2013), motivational manipulations (Russell et al., 2013), visual scanning training (Van Kessel et al., 2013), space- and alertness-related training (Sturm et al., 2013), limb activation training (Pitteri et al., 2013), pro- cholinergic treatments (Lucas et al., 2013), and optokinetic stimu- lation (Daini et al., 2013), are described. From this list, it becomes clear that there is a wealth of different techniques, although effec- tiveness was shown to be quite diverse. One study directly com- pares the beneficial effects of visual scanning training, PA, and limb activation and reveals that all three treatments can be consid- ered as comparably effective rehabilitation interventions (Priftis et al., 2013). There are also newly proposed techniques, such as noradrenergic stimulation to improve motor neglect (Sampanis and Riddoch, 2013) and videogame based neglect rehabilitation due to their high flexibility (Borghese et al., 2013). Systematic reviews of the different techniques point to major shortcomings of the current literature on rehabilitation methods of neglect. The effectiveness of almost all techniques has not been investigated thoroughly enough to allow firm conclusions (Fasotti and van Kessel, 2013). For instance, when looking at the studies that used the behavioral inattention test as the primary outcome, the conclusion was drawn that all these studies had low power and suffered from limitations in the blinding of the design (Yang et al., 2013). With respect to upcoming non-invasive brain stimulations, such as TMS and tDCS, only few studies are reported, which are too heterogenous in methodology and outcome measures to draw firm conclusions on effectiveness from them (Muri et al., 2013). The same conclusion holds for eye patching, for which there is a great need for randomized controlled trials (Smania et al., 2013). Frontiers in Human Neuroscience www.frontiersin.org April 2014 | Volume 8 | Article 233 | 6 Van der Stigchel and Nijboer Novel insights in neglect rehabilitation One of the factors that might contribute to the lack of con- sistent findings on the different rehabilitation techniques is the heterogeneity of the neglect syndrome. One of the proposals in this Research Topic is that a deficit in spatial working memory is one of the possible components of neglect. With respect to treat- ment, it is known that for example PA has no influence on spatial working memory deficits, which might explain why some patients benefit from PA whereas others do not (Striemer et al., 2013). Oth- ers characterize neglect as a disorder in representational updating, which reflects our ability to build mental models and adapt those models to changing experience (Shaqiri et al., 2013). Furthermore, neglect might be related to the motor system as reflected by a case description of a patient with motor extinction (Punt et al., 2013). CONCLUSION This Research Topic has opened new perspectives, and has given us an indication of where the field is going. Although some of the current rehabilitation techniques have proven to be benefi- cial, there is limited agreement on the most valuable technique or the mechanisms underlying the ameliorating effects. Future studies should focus on the heterogeneous nature of the neglect syndrome. There is a need for a better link between the various primary components of neglect and a more sensitive diagno- sis (e.g., using computer-based testing) in future rehabilitation studies. ACKNOWLEDGMENTS This research was supported by the grant 451-10-013 from the Netherlands Organization for Scientific Research (NWO) to Tanja C. W. Nijboer. REFERENCES Bonato, M., and Deouell, L. Y. (2013). Hemispatial neglect: computer-based testing allows more sensitive quantification of attentional disorders and recovery and might lead to better evaluation of rehabilitation. Front. Hum. Neurosci. 7:162. doi:10.3389/fnhum.2013.00162 Borghese, N. A., Bottini, G., and Sedda, A. (2013). Videogame based neglect rehabil- itation: a role for spatial remapping and multisensory integration? Front. Hum. Neurosci. 7:116. doi:10.3389/fnhum.2013.00116 Daini, R., Albonico, A., Malaspina, M., Martelli, M., Primativo, S., and Arduino, L. S. (2013). 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Predicting functional outcome after stroke: the influence of neglect on basic activities in daily life. Front. Hum. Neurosci. 7:182. doi:10.3389/fnhum. 2013.00182 Pitteri, M., Arcara, G., Passarini, L., Meneghello, F., and Priftis, K. (2013). Is two better than one? Limb activation treatment combined with contralesional arm vibration to ameliorate signs of left neglect. Front. Hum. Neurosci. 7:460. doi:10.3389/fnhum.2013.00460 Pitzalis, S., Spinelli, D., Vallar, G., and Di Russo, F. (2013). Transcutaneous electrical nerve stimulation effects on neglect: a visual-evoked potential study. Front. Hum. Neurosci. 7:111. doi:10.3389/fnhum.2013.00111 Priftis, K., Passarini, L., Pilosio, C., Meneghello, F., and Pitteri, M. (2013). Visual scanning training, limb activation treatment, and prism adaptation for rehabili- tating left neglect: who is the winner? Front. Hum. Neurosci. 7:360. doi:10.3389/ fnhum.2013.00360 Punt, T. D., Riddoch, M. J., and Humphreys, G. W. (2013). Motor extinction: a deficit of attention or intention. Front. Hum. Neurosci. 7:644. doi:10.3389/fnhum.2013. 00644 Rabuffetti, M., Folegatti, A., Spinazzola, L., Ricci, R., Ferrarin, M., Berti, A., et al. (2013). Long-lasting amelioration of walking trajectory in neglect after prismatic adaptation. Front. Hum. Neurosci. 7:382. doi:10.3389/fnhum.2013.00382 Russell, C., Li, K., and Malhotra, P. (2013). Harnessing motivation to alleviate neglect. Front. Hum. Neurosci. 7:230. doi:10.3389/fnhum.2013.00230 Saevarsson, S., and Kristjansson, A. (2013). A note on Striemer and Danckert’s theory of prism adaptation in unilateral neglect. Front. Hum. Neurosci. 7:44. doi:10.3389/fnhum.2013.00044 Sampanis, D. S., and Riddoch, J. (2013). Motor neglect and future directions for research. Front. Hum. Neurosci. 7:110. doi:10.3389/fnhum.2013.00110 Schmidt, L., Utz, K. S., Depper, L., Adams, M., Schaadt, A.-K., Reinhart, S., et al. (2013). Now you feel both: galvanic vestibular stimulation induces lasting improvements in the rehabilitation of chronic tactile extinction. Front. Hum. Neurosci. 7:90. doi:10.3389/fnhum.2013.00090 Scriven, R. J., and Newport, R. (2013). Spatial compression impairs prism adap- tation in healthy individuals. Front. Hum. Neurosci. 7:165. doi:10.3389/fnhum. 2013.00165 Shaqiri, A., Anderson, B., and Danckert, J. (2013). Statistical learning as a tool for rehabilitation in spatial neglect. Front. Hum. Neurosci. 7:224. doi:10.3389/fnhum. 2013.00224 Smania, N., Fonte, C., Picelli, A., Gandolfi, M., and Varalta, V. (2013). Effect of eye patching in rehabilitation of hemispatial neglect. Front. Hum. Neurosci. 7:527. doi:10.3389/fnhum.2013.00527 Smit, M.,Van Der Stigchel, S.,Visser-Meily,A., Kouwenhoven, M., Eijsackers,A. L. H., and Nijboer, T. C. W. (2013). The feasibility of computer-based prism adaptation to ameliorate neglect in sub-acute stroke patients admitted to a rehabilitation center. Front. Hum. Neurosci. 7:353. doi:10.3389/fnhum.2013.00353 Striemer, C. L., and Danckert, J. (2013). The influence of prism adaptation on per- ceptual and motor components of neglect: a reply to Saevarsson and Kristjans- son. Front. Hum. Neurosci. 7:255. doi:10.3389/fnhum.2013.00255 Striemer, C. L., Ferber, S., and Danckert, J. (2013). Spatial working memory deficits represent a core challenge for rehabilitating neglect. Front. Hum. Neurosci. 7:334. doi:10.3389/fnhum.2013.00334 Sturm, W., Thimm, M., Binkofski, F., Horoufchin, H., Fink, G. R., Kust, J., et al. (2013). Combined space and alertness related therapy of visual hemineglect: effect of therapy frequency. Front. Hum. Neurosci. 7:373. doi:10.3389/fnhum. 2013.00373 Van Kessel, M. E., Geurts, A. C. H., Brouwer, W. H., and Fasotti, L. (2013). Visual scanning training for neglect after stroke with and without a computerized lane tracking dual task. Front. Hum. Neurosci. 7:358. doi:10.3389/fnhum.2013. 00358 Yang, N. Y. H., Zhou, D., Chung, R. C. K., Li-Tsang, C. W. P., and Fong, K. N. K. (2013). Rehabilitation interventions for unilateral neglect after stroke: a systematic review from 1997 through 2012. Front. Hum. Neurosci. 7:187. doi:10.3389/fnhum.2013.00187 Frontiers in Human Neuroscience www.frontiersin.org April 2014 | Volume 8 | Article 233 | 7 Van der Stigchel and Nijboer Novel insights in neglect rehabilitation Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received: 07 March 2014; accepted: 01 April 2014; published online: 14 April 2014. Citation: Van der Stigchel S and Nijboer TCW (2014) Introduction to the Research Topic Novel Insights in Rehabilitation of Neglect. Front. Hum. Neurosci. 8 :233. doi: 10.3389/fnhum.2014.00233 This article was submitted to the journal Frontiers in Human Neuroscience. Copyright © 2014 Van der Stigchel and Nijboer. This is an open-access arti- cle distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, pro- vided the original author(s) or licensor are credited and that the original publi- cation in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Frontiers in Human Neuroscience www.frontiersin.org April 2014 | Volume 8 | Article 233 | 8 HUMAN NEUROSCIENCE ORIGINAL RESEARCH ARTICLE published: 09 May 2013 doi: 10.3389/fnhum.2013.00182 Predicting functional outcome after stroke: the influence of neglect on basic activities in daily living Tanja Nijboer 1,2 *, Ingrid van de Port 3 , Vera Schepers 2 , Marcel Post 2 and Anne Visser-Meily 2 1 Experimental Psychology, Helmholtz Institute, Utrecht University, Utrecht, Netherlands 2 Rudolf Magnus Institute of Neuroscience, Center of Excellence for Rehabilitation Medicine, University Medical Center Utrecht and De Hoogstraat Rehabilitation, Utrecht, Netherlands 3 Revant Revalidatiecentrum, Breda, Netherlands Edited by: Hauke R. Heekeren, Freie Universität Berlin, Germany Reviewed by: Bianca De Haan, University of Tuebingen, Germany James Danckert, University of Waterloo, Canada *Correspondence: Tanja Nijboer , Experimental Psychology, Helmholtz Institute, Utrecht University, Heidelberglaan 2, 3584 CS Utrecht, Netherlands. e-mail: t.c.w.nijboer@uu.nl One prominent deficit resulting from stroke is visuo-spatial neglect, which has been asso- ciated with slower and more attenuated recovery patterns of sensory-motor impairment as well as limitations in activities of daily living (ADL). The aim of the current study was to further specify the relationship between neglect and recovery of different domains of ADL. One hundred eighty four patients were assessed with the Functional Independence Measure in the first week of inpatient rehabilitation, and again at 6, 12, and 36 months post- stroke. On average, neglect patients scored significantly lower on Self-care, Transfers, and Locomotion compared to non-neglect patients, but these differences became smaller with progress of time. Overall, no differences between groups were found for Sphincter control and Cognition. Patients with more severe neglect scored significantly lower on Self-care and Transfers compared to patients with mild neglect. During rehabilitation, it would be of importance to test for independence in ADL domains in neglect in order to define realistic treatment goals. The current findings could be taken into account in early multidisciplinary intervention planning in the sub-acute phase, to optimize regaining ADL. Keywords: stroke, neglect, recovery, ADL INTRODUCTION One prominent deficit resulting from stroke is visuo-spatial neglect, commonly referred to as neglect; about 25–30% of all stroke patients show impaired or lost awareness for events and (visual, auditory, and/or tactile) stimuli located at the side oppo- site of the brain lesion (Appelros et al., 2002; Buxbaum et al., 2004). Neglect can result from a lesion to either hemisphere, but is more severe and enduring after right hemisphere damage (Stone et al., 1993). The time course of spontaneous neurologi- cal recovery of neglect shows a natural logistic curve up to the first 12–14 weeks post-stroke, after which neglect severity becomes invariant (Nijboer et al., 2012). Neglect has been associated with slower and more attenuated recovery patterns of sensory-motor impairment (Katz et al., 1999) as well as limitations in activi- ties of daily living (ADL) (Katz et al., 1999; Cherney et al., 2001; Di Monaco et al., 2011; Verhoeven et al., 2011) compared to non-neglect patients. None of the previous studies, however, dif- ferentiated between the different domains of ADL, whereas there is general consensus that some of these domains are more complex (e.g., Self-care, Transfers, Locomotion) than others (e.g., bowel management) (Granger et al., 1993; Grimby et al., 1996). Addi- tionally, skills that easily allow for compensation strategies (e.g., grooming), improve earlier compared to more complex skills (e.g., dressing and climbing stairs) (Kwakkel and Kollen, 2013). The aim of the current study was to further specify the rela- tionship between neglect and recovery of different domains of ADL. Knowledge about factors that determine the final outcome in terms of post-stroke activities is important for early stroke management, in order to set suitable rehabilitation goals, enable early discharge planning, and psycho-education (Kwakkel and Kollen, 2013). One of the most widely used functional outcomes measures in rehabilitation facilities is the Functional Independence Measure (FIM), which measures degree of disability. Performance on the five domains of the FIM (i.e., Self-care, Sphincter control, Transfers, Locomotion, and Cognition) were compared between neglect and non-neglect patients in a repeated measures design up to 3 years post-stroke. Additionally, the relation between neglect severity and functional independence was investigated, as strong associations between severity of neurological deficits and final basic ADL outcomes have been described (Kwakkel and Kollen, 2013). MATERIALS AND METHODS PARTICIPANTS The “Functional Prognostication and disability study on stroke” (FuPro-stroke) database was used for the current study. The aim of FuPro-stroke was twofold: first, to determine which functional outcome measures are most effective in a stroke population; and second, to investigate prognostic factors of functional outcome and recovery up to 3 years post-stroke onset. In FuPro-stroke, 318 patients were selected from stroke patients consecutively admitted to four Dutch rehabilitation centers for an inpatient rehabilitation program in the period April 2000–July 2002. The inclusion criteria were: (1) first-ever stroke, as revealed by CT or MRI; (2) a one- sided supratentorial lesion; (3) age above 18; and (4) written or verbal informed consent. Exclusion criteria for the FuPro-stroke Frontiers in Human Neuroscience www.frontiersin.org May 2013 | Volume 7 | Article 182 | 9 Nijboer et al. Relation between neglect and ADL were: (1) disabling comorbidity [pre-stroke Barthel Index (BI) below 18 (range 0–20)]; (2) premorbid inability to speak Dutch. Exclusion criteria for the present study were: (1) subarachnoid hemorrhage ( n = 34); (2) no letter cancelation at start of the study ( n = 100). PROCEDURE Patients were included at the start of rehabilitation. Informed consent was obtained. Personal and stroke characteristics were recorded at the first assessment. The scoring of ADL indepen- dency and neglect was assessed in the first week of inpatient rehabilitation, and again at 6, 12, and 36 months post-stroke. The study was approved by the Ethics Review Boards of the Univer- sity Medical Center Utrecht and all participating rehabilitation centers. OUTCOME MEASURES The FIM (Linacre et al., 1994; Marshall et al., 1999; Schepers et al., 2006) consists of 18 items assessing level of independence at 5 domains: Self-care [i.e., eating, grooming, bathing, dressing (upper and lower body), toileting], Sphincter control (i.e., bladder and bowel management), Transfers (i.e., bed/chair/wheelchair, toilet, tub/shower), Locomotion (i.e., walk/wheelchair, stairs), and Cog- nition (i.e., comprehension, expression, social interaction, prob- lem solving, and memory). Each item is scored on a seven-point Likert scale, and the score indicates the amount of observed assis- tance required to perform each item (1, total assistance, 7, total independence), resulting in a final summed score ranging from 18 up to 126. Additionally, the patient’s medical record was reviewed. The following admission to rehabilitation data were captured: age, gender, time post-stroke, hemisphere and subtype of stroke, BI, Motricity Index (MI), Center of Epidemiologic Studies Depres- sion Scale (CES-D), Mini Mental State Examination (MMSE), and sensory deficit in the arm as determined by the Thumb Finding Test (TFT). The BI (Collin et al., 1988) measures the extent to which stroke patients can function independently in their ADL (i.e., feeding, bathing, grooming, dressing, bowel and bladder control, toileting, chair transfer, ambulation, and stair climbing). Scores range from 0 (completely dependent) up to 20 (completely independent). The MI (Collin and Wade, 1990) was used to determine the motor functions. There are three items for the arms (i.e., pinch grip, elbow flexion, shoulder abduction) as well as three items for the legs (i.e., ankle dorsiflexion, knee extension, hip flexion). Scores range from 0 (no activity, paralysis) up to 33 [maximum (normal) muscle force] for each dimension, with a maximum total score of 100. The CES-D (Shinar et al., 1986; Parikh et al., 1988) was used to determine the magnitude of depressive symptomatology. Scores range from 0 (no depressive symptoms) up to 60 (many depressive symptoms). It investigates mood over the past 7 days. Cognitive status was measured with the MMSE (Folstein et al., 1975). It is a 30-point questionnaire used for screening orientation, memory, attention, calculation, language, and construction func- tions. Scores vary from 0 (severe cognitive impairments) up to 30 (no cognitive impairments). A score of less than 24 is considered as cognitive impairment. In the TFT (Kalra and Crome, 1993; Rieck and Moreland, 2005), the patient is asked to find his thumb with his unaffected hand, while the affected arm supported in front and eyes are closed. Scores vary from 0 (unable) up to 3 (no deficit). The Letter Cancelation Test (LCT, Lezak, 1995) was used to categorize patients as neglect or non-neglect. In the LCT, patients need to cancel O’s among other letters to demonstrate presence and severity of neglect. Patients were requested to cross all O’s on a sheet of A4 paper containing 20 O’s on the left side and 20 O’s on the right, among 425 distractor letters in total. Both target and distractor letters were arranged in random order throughout the page. The difference in number of crossed letters on the con- tralesional and ipsilesional side was used to indicate neglect [i.e., an asymmetry of at least two omissions 1 between contralesional and ipsilesional sides (Kelley and Kovacs, 1986)] and hence, cate- gorize patients as neglect or non-neglect. Severity of neglect was indicated by the magnitude of this asymmetry. STATISTICAL ANALYSES Demographics and stroke characteristics of the neglect and no-neglect patients were compared using Mann–Whitney U tests. The extent of recovery of dependency for functional activi- ties explained by time was estimated using random coefficient analysis with MLWin (Rasbash et al., 2009a,b,c). The advantages of using random coefficient analysis in this case are, first, the explicit “time” variable and second, the efficiency when number of time-dependent measures across individuals varies. As such, information about change within an individual as well as across individuals will be taken into account. Observed differences in change across individuals can be associated with individual char- acteristics (i.e., important predictors of change over time) (Singer and Willet, 2003). The iterative generalized least-squares (IGLS) was used to estimate the regression coefficient (Singer and Willet, 2003). Regression coefficients were calculated for the association between outcome (FIM domains: Self-care, Sphincter control, Transfers, Locomotion, and Cognition) and neglect at admission and time, corrected for motor impairment (MI), sensory deficits (TFT), dependence (BI), and magnitude of depressive symptomatology (CES-D) at admission, to certify that potential differences between groups are attributable to neglect and not to other group differ- ences. In addition, interaction terms (neglect × time) were fitted to determine if the post-stroke relationship between neglect at admis- sion (with non-neglect as reference) and outcome was dependent upon the time of measurement. Additionally, regression coefficients were calculated (neglect patients only) for the association between outcome (FIM domains: Self-care, Sphincter control, Transfers, Locomotion, and Cogni- tion) and neglect severity (i.e., magnitude of asymmetry in left versus right sided omissions on the LCT). The Wald-test was used to obtain p -values for the regression coefficients (Twisk, 2006). For all tests, a two-tailed significance level of 0.05 was used. 1 One might argue that this cut-off value is rather liberal. Therefore we also grouped patients with a less liberal asymmetry (4); this did not change the results. Therefore, we chose to keep the asymmetry of 2 as criterion for neglect, in line with the norms of the test. Frontiers in Human Neuroscience www.frontiersin.org May 2013 | Volume 7 | Article 182 | 10 Nijboer et al. Relation between neglect and ADL RESULTS DEMOGRAPHIC AND STROKE CHARACTERISTICS In the present aim, 184 patients (mean age: 57.42, SD: 11.09) were included from the original FuPro-stroke database. In general, patients were relatively young and infarctions were more frequent than hemorrhages. Neglect was present at admission in 28.80%. An overview of all demographics and stroke characteristics of the neglect and no-neglect patients is given in Table 1 . The groups did not differ with