Spatial neglect is a strong and negative predictor of general functional outcome after stroke, and its therapy remains a challenge. Whereas inhibitory non-invasive brain stimulation (NIBS) over the contralesional, intact hemisphere has generally been shown to ameliorate neglect on a group level, a conspicuous variability of the effects at the individual level is typically observed. We aimed to comprehensively assess the characteristics and determinants of the effects of inhibitory NIBS in neglect, identifying which patients would respond to this therapeutic approach and which not. To this end, we prospectively included sixty patients with a subacute right-hemispheric stroke. In thirty patients with spatial neglect, continuous Theta Burst Stimulation (cTBS) was applied over the left posterior parietal cortex (PPC) in a randomized clinical trial, either in 8 or 16 trains, or as sham stimulation. Thirty patients without neglect served as control group. Neglect severity was measured with a neuropsychological test battery and the Catherine Bergego Scale (CBS), at admission to and at discharge from inpatient neurorehabilitation, as well as at 3 months follow-up. General functional outcome was assessed by means of the Functional Independent Measurement (FIM) and the Lucerne ICF-based Multidisciplinary Observation Scale (LIMOS). The impact of clinical and demographic factors was evaluated, and the influence of lesion location and extension was assessed by means of voxel-based lesionsymptom mapping (VLSM). On a group level, both cTBS protocols (i.e., 8 and 16 trains) significantly reduced neglect severity in both the CBS and the neuropsychological tests, at discharge and 3 months later. Furthermore, cTBS significantly improved general functional outcome. On an individual level, hierarchical cluster and VLSM analyses revealed that the variability in the responses to cTBS is determined by the integrity of inter-hemispheric connections within the corpus callosum, in particular parieto-parietal connections. In cTBS responders, in whom neglect and general functional outcome were significantly improved, the corpus callosum was intact, whereas this was not the case in cTBS non-responders. Moreover, analyses based on the Proportional recovery rule and the Maugeri predictive stroke recovery model showed that the recovery ! ! 3! ! of neglect and of the activities of daily living (ADL) was accelerated only in cTBS responders. Furthermore, the level of ADL recovery of these neglect patients was brought close to the one of right-hemispheric control patients without neglect. Hence, in neglect patients with intact interhemispheric connectivity, cTBS over the contralesional PPC significantly improves and accelerates neglect recovery and, associated with it, general functional outcome.

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Background: Unilateral spatial neglect is an attention disorder frequently occurring after a right-hemispheric stroke. Neglect results in a reduction in quality of life and performance in activities of daily living. With current technical improvements in virtual reality (VR) technology, training with stereoscopic head-mounted displays (HMD) has become a promising new approach for the assessment and the rehabilitation of neglect. The focus of this pilot study was to develop and evaluate a simple visual search task in VR for HMD. The VR system was tested regarding feasibility, acceptance, and potential adverse effects in healthy controls and right-hemispheric stroke patients with and without neglect. Methods: The VR system consisted of two main components, a head-mounted display to present the virtual environment, and a hand-held controller for the interaction with the latter. The task followed the rationale of diagnostic paper-pencil cancellation tasks; i.e., the participants were asked to search targets among distractors. However, instead of a two-dimensional setup, the targets and distractors were arranged in three dimensions, in a sphere around the subject inside its field of view. Usability and acceptance of the task, as well as the performance in the latter, were tested in 15 right-hemispheric subacute stroke patients (10 of whom with and five of whom without unilateral spatial neglect; mean age: 67.1 ± 10.5 years) and 35 age-matched healthy controls. Results: System usability and acceptance were rated as high both in stroke patients and healthy controls, close to the maximum score of the questionnaire scale. No relevant adverse effects occurred. There was a high correlation (r = 0.854, p = 0.002) between the Center of Cancellation [an objective neglect measure) calculated from a paperpencil cancellation task (Sensitive Neglect Test (SNT)] and the newly developed VR cancellation task. Conclusion: Overall, the developed visual search task in the tested VR system is feasible, well-accepted, enjoyable, and does not evoke any significant negative effects, both for