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This review discusses the neurophysiology and neuroanatomy of the cortical control of reflexive and volitional saccades in humans. The main focus is on classical lesion studies and studies using the interference method of transcranial magnetic stimulation (TMS). To understand the behavioural function of a region, it is essential to assess oculomotor deficits after a focal lesion using a variety of oculomotor paradigms, and to study the oculomotor consequences of the lesion in the chronic phase. Saccades are controlled by different cortical regions, which could be partially specialised in the triggering of a specific type of saccade. The division of saccades into reflexive visually guided saccades and intentional or volitional saccades corresponds to distinct regions of the neuronal network, which are involved in the control of such saccades. TMS allows to specifically interfere with the functioning of a region within an intact oculomotor network. TMS provides advantages in terms of temporal resolution, allowing to interfere with brain functioning in the order of milliseconds, thereby allowing to define the time course of saccade planning and execution. In the first part of the paper, we present an overview of the cortical structures important for saccade control, and discuss the pro's and con's of the different methodological approaches to study the cortical oculomotor network. In the second part, the functional network involved in reflexive and volitional saccades is presented. Finally, studies concerning recovery mechanisms after a lesion of the oculomotor cortex are discussed. [ABSTRACT FROM AUTHOR]

Background and Purpose: Patients with postural tachycardia syndrome report position-dependent visual symptoms. Despite their impact on daily life, these symptoms have remained largely unexplored in research. The aim of this study was to investigate the nature of visual symptoms in postural tachycardia syndrome and possible underlying pathophysiological mechanisms., Methods: Fifteen patients with postural tachycardia syndrome and 15 healthy controls were included in the study. Through a comprehensive array of measurements, including haemodynamics, subjective symptom assessments, eye movement tracking and pupil diameter analysis, participants were assessed during free image exploration in both supine and 60° head-up tilt positions., Results: During head-up tilt, patients showed a decreased number and duration of fixations, as well as a decreased number, peak velocity and amplitude of saccades compared to the supine position and the control group. This reduction in visual exploration occurred primarily in the peripheral field of view and coincided with the occurrence of subjective visual symptoms. No significant differences in the saccade main sequence were observed between the two groups in either body position., Conclusions: Patients with postural tachycardia syndrome have a reduced exploration of the peripheral field of view when in an upright body position, potentially leading to tunnel vision. Since the normality of the saccade main sequence in patients combined with the focus on the centre of the field of view and the lower saccade amplitudes points to an intact brainstem function, the decrease in peripheral visual exploration may be attributed to a position-dependent dysfunction of the frontal eye field., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Introduction: There is currently a lack of easy-to-use and effective robotic devices for upper-limb rehabilitation after stroke. Importantly, most current systems lack the provision of somatosensory information that is congruent with the virtual training task. This paper introduces a novel haptic robotic system designed for upper-limb rehabilitation, focusing on enhancing sensorimotor rehabilitation through comprehensive haptic rendering., Methods: We developed a novel haptic rehabilitation device with a unique combination of degrees of freedom that allows the virtual training of functional reach and grasp tasks, where we use a physics engine-based haptic rendering method to render whole-hand interactions between the patients' hands and virtual tangible objects. To evaluate the feasibility of our system, we performed a clinical mixed-method usability study with seven patients and seven therapists working in neurorehabilitation. We employed standardized questionnaires to gather quantitative data and performed semi-structured interviews with all participants to gain qualitative insights into the perceived usability and usefulness of our technological solution., Results: The device demonstrated ease of use and adaptability to various hand sizes without extensive setup. Therapists and patients reported high satisfaction levels, with the system facilitating engaging and meaningful rehabilitation exercises. Participants provided notably positive feedback, particularly emphasizing the system's available degrees of freedom and its haptic rendering capabilities. Therapists expressed confidence in the transferability of sensorimotor skills learned with our system to activities of daily living, although further investigation is needed to confirm this., Conclusion: The novel haptic robotic system effectively supports upper-limb rehabilitation post-stroke, offering high-fidelity haptic feedback and engaging training tasks. Its clinical usability, combined with positive feedback from both therapists and patients, underscores its potential to enhance robotic neurorehabilitation., (© 2024. The Author(s).)

Developing motor and cognitive skills is needed to achieve expert (motor) performance or functional recovery from a neurological condition, e.g., after stroke. While extensive practice plays an essential role in the acquisition of good motor performance, it is still unknown whether certain person-specific traits may predetermine the rate of motor learning. In particular, learners' functional brain organisation might play an important role in appropriately performing motor tasks. In this paper, we aimed to study how two critical cognitive brain networks-the Attention Network (AN) and the Default Mode Network (DMN)-affect the posterior motor performance in a complex visuomotor task: virtual surfing. We hypothesised that the preactivation of the AN would affect how participants divert their attention towards external stimuli, resulting in robust motor performance. Conversely, the excessive involvement of the DMN-linked to internally diverted attention and mind-wandering-would be detrimental for posterior motor performance. We extracted seven widely accepted microstates-representing participants mind states at rest-out of the Electroencephalography (EEG) resting-state recordings of 36 healthy volunteers, prior to execution of the virtual surfing task. By correlating neural biomarkers (microstates) and motor behavioural metrics, we confirmed that the preactivation of the posterior DMN was correlated with poor posterior performance in the motor task. However, we only found a non-significant association between AN preactivation and the posterior motor performance. In this EEG study, we propose the preactivation of the posterior DMN-imaged using EEG microstates-as a neural trait related to poor posterior motor performance. Our findings suggest that the role of the executive control system is to preserve an homeostasis between the AN and the DMN. Therefore, neurofeedback-based downregulation of DMN preactivation could help optimise motor training., (© 2022. The Author(s).)

Pareidolia are perceptions of recognizable images or meaningful patterns where none exist. In recent years, this phenomenon has been increasingly studied in healthy subjects and patients with neurological or psychiatric diseases. The current study examined pareidolia production in a group of 53 stroke patients and 82 neurologically healthy controls who performed a natural images task. We found a significant reduction of absolute pareidolia production in left- and right-hemispheric stroke patients, with right-hemispheric patients producing overall fewest pareidolic output. Responses were categorized into 28 distinct categories, with 'Animal', 'Human', 'Face', and 'Body parts' being the most common, accounting for 72% of all pareidolia. Regarding the percentages of the different categories of pareidolia, we found a significant reduction for the percentage of "Body parts" pareidolia in the left-hemispheric patient group as compared to the control group, while the percentage of this pareidolia type was not significantly reduced in right-hemispheric patients compared to healthy controls. These results support the hypothesis that pareidolia production may be influenced by local-global visual processing with the left hemisphere being involved in local and detailed analytical visual processing to a greater extent. As such, a lesion to the right hemisphere, that is believed to be critical for global visual processing, might explain the overall fewest pareidolic output produced by the right-hemispheric patients., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Gait abnormalities in older adults are linked to increased risks of falls, institutionalization, and mortality, necessitating accurate and frequent gait assessments beyond traditional clinical settings. Current methods, such as pressure-sensitive walkways, often lack the continuous natural environment monitoring needed to understand an individual's gait fully during their daily activities. To address this gap, we present a Lidar-based method capable of unobtrusively and continuously tracking human leg movements in diverse home-like environments, aiming to match the accuracy of a clinical reference measurement system. We developed a calibration-free step extraction algorithm based on mathematical morphology to realize Lidar-based gait analysis. Clinical gait parameters of 45 healthy individuals were measured using Lidar and reference systems (a pressure-sensitive walkway and a video recording system). Each participant participated in three predefined ambulation experiments by walking over the walkway. We observed linear relationships with strong positive correlations (R2>0.9) between the values of the gait parameters (step and stride length, step and stride time, cadence, and velocity) measured with the Lidar sensors and the pressure-sensitive walkway reference system. Moreover, the lower and upper 95% confidence intervals of all gait parameters were tight. The proposed algorithm can accurately derive gait parameters from Lidar data captured in home-like environments, with a performance not significantly less accurate than clinical reference systems.

Background: Promoting cognitive health is key to maintaining cognitive and everyday functions and preventing the risk of cognitive impairment or dementia. Existing scientific evidence shows the benefits of various training modalities on cognition. One way to promote cognitive health is through engagement in cognitive activities (eg, board and video games)., Objective: This study aims to investigate the benefits of dynamic adaptive casual puzzle games on cognitive function and well-being in healthy adults and older people., Methods: A total of 12 adults and older people (female participants: n=6; mean age 58.92, SD 10.28 years; range 46-75 years) were included in this pilot randomized controlled trial. This study used a crossover design with two phases (8 weeks each) and three measurement waves (pretest, midtest, and posttest). The participants were randomly allocated either to the control or experimental group. In the control group, participants read newspapers between the pre- and midtest, then switched to cognitive training with puzzle games. In the experimental group, the interventions were reversed. Baseline measurements (pretest) were collected before the intervention. The interventions were delivered on tablet computers and took place unsupervised at participants' homes., Results: The outcome measures included global cognitive function, higher cognitive function, and emotional well-being at 3 time points (pretest, midtest, and posttest) using standardized neuropsychological tests. The participants showed improvements in their visual attention and visuospatial measures after the puzzle game intervention., Conclusions: The study showed that digital games are a feasible way to train cognition in healthy adults and older people. The algorithm-based dynamic adaption allows accommodations for persons with different cognitive levels of skill. The results of the study will guide future prevention efforts and trials in high-risk populations., (© Prabitha Urwyler, Rajnish Kumar Gupta, Michael Falkner, Joel Niklaus, René Martin Müri, Tobias Nef. Originally published in JMIR Aging (https://aging.jmir.org).)

Background: Sensory overload and sensory deprivation have both been associated with negative health outcomes in critically ill patients. While there is a lack of any clear treatment or prevention strategies, immersive virtual reality is a promising tool for addressing such problems, but which has not been repetitively tested in random samples. Therefore, this study aimed to determine how critically ill patients react to repeated sessions of immersive virtual reality., Methods: This exploratory study was conducted in the mixed medical-surgical intermediate care unit of the University Hospital of Bern (Inselspital). Participants ( N  = 45; 20 women, 25 men; age = 57.73 ± 15.92 years) received two immersive virtual reality sessions via a head-mounted display and noise-canceling headphones within 24 h during their stay in the unit. Each session lasted 30-min and showed a 360-degree nature landscape. Physiological data were collected as part of the participants' standard care, while environmental awareness, cybersickness, and general acceptance were assessed using a questionnaire designed by our team (1 = not at all, 10 = extremely)., Results: During both virtual reality sessions, there was a significant negative linear relationship found between the heart rate and stimulation duration [first session: r (43) = -0.78, p  < 0.001; second session: r (38) = -0.81, p  < 0.001] and between the blood pressure and stimulation duration [first session: r (39) = -0.78, p  < 0.001; second session: r (30) = -0.78, p  < 0.001]. The participants had a high comfort score [median (interquartile range {IQR}) = 8 (7, 10); mean = 8.06 ± 2.31], did not report being unwell [median (IQR) = 1 (1, 1); mean = 1.11 ± 0.62], and were not aware of their real-world surroundings [median (IQR) = 1 (1, 5); mean = 2.99 ± 3.22]., Conclusion: The subjectively reported decrease in environmental awareness as well as the decrease in the heart rate and blood pressure over time highlights the ability of immersive virtual reality to help critically ill patients overcome sensory overload and sensory deprivation. Immersive virtual reality can successfully and repetitively be provided to a randomly selected sample of critically ill patients over a prolonged duration., Competing Interests: 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., (Copyright © 2023 Naef, Gerber, Single, Müri, Haenggi, Jakob, Jeitziner and Nef.)

Reduplicative paramnesia refers to the delusional belief that there are identical places in different locations. In this case-control study we investigated the clinical, phenomenological, neuropsychological and neuroanatomical data of eleven patients with reduplicative paramnesia and compared them against a control group of eleven patients with severe spatial disorientation without signs of reduplicative paramnesia. We show that most patients with reduplicative paramnesia report that a current place is reduplicated and/or relocated to an other familiar place. Patients with reduplicative paramnesia show a higher prevalence of deficits in the executive functions compared to the control patients, while mnestic and visuo-spatial deficits were both frequent in patients with reduplicative paramnesia and the control group. Patients with reduplicative paramnesia mostly suffer from right hemispheric lesions with a maximal overlap in the dorsolateral prefrontal cortex. Using lesion network mapping we show that lesions causing reduplicative paramnesia are connected to bilateral anterior insula and the right cingulate cortex. We argue that patients with reduplicative paramnesia fail to integrate the actual context with visuo-spatial memories and personal relevant emotional information due to a disruption of the neural network within the anterior temporal lobe, the cingulate cortex and the anterior insula. Also patients with reduplicative paramnesia are not able to resolve this conflict due to the lesion of the dorsolateral prefrontal cortex and executive dysfunction., Competing Interests: Declaration of competing interest The authors report no conflicts of interest and no financial relationships relevant to the manuscript., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The use of virtual reality (VR) stimulation in clinical settings has increased in recent years. In particular, there has been increasing interest in the use of VR stimulation for a variety of purposes, including medical training, pain therapy, and relaxation. Unfortunately, there is still a limited amount of real-world 360-degree content that is both available and suitable for these applications. Therefore, this tutorial paper describes a pipeline for the creation of custom VR content. It covers the planning and designing of content; the selection of appropriate equipment; the creation and processing of footage; and the deployment, visualization, and evaluation of the VR experience. This paper aims to provide a set of guidelines, based on first-hand experience, that readers can use to help create their own 360-degree videos. By discussing and elaborating upon the challenges associated with making 360-degree content, this tutorial can help researchers and health care professionals anticipate and avoid common pitfalls during their own content creation process., (©Aileen C Naef, Marie-Madlen Jeitziner, Stephan M Jakob, René M Müri, Tobias Nef. Originally published in JMIR Medical Education (https://mededu.jmir.org), 14.09.2023.)

Background: Exposure to elevated sound pressure levels within the intensive care unit is known to negatively affect patient and staff health. In the past, interventions to address this problem have been unsuccessful as there is no conclusive evidence on the severity of each sound source and their role on the overall sound pressure levels. Therefore, the goal of the study was to perform a continuous 1 week recording to characterize the sound pressure levels and identify negative sound sources in this setting., Methods: In this prospective, systematic, and quantitative observational study, the sound pressure levels and sound sources were continuously recorded in a mixed medical-surgical intensive care unit over 1 week. Measurements were conducted using four sound level meters and a human observer present in the room noting all sound sources arising from two beds., Results: The mean 8 h sound pressure level was significantly higher during the day (52.01 ± 1.75 dBA) and evening (50.92 ± 1.66 dBA) shifts than during the night shift (47.57 ± 2.23; F (2, 19) = 11.80, p  < 0.001). No significant difference was found in the maximum and minimum mean 8 h sound pressure levels between the work shifts. However, there was a significant difference between the two beds in the based on location during the day ( F (3, 28) = 3.91, p  = 0.0189) and evening ( F (3, 24) = 5.66, p  = 0.00445) shifts. Cleaning of the patient area, admission and discharge activities, and renal interventions (e.g., dialysis) contributed the most to the overall sound pressure levels, with staff talking occurring most frequently., Conclusion: Our study was able to identify that continuous maintenance of the patient area, patient admission and discharge, and renal interventions were responsible for the greatest contribution to the sound pressure levels. Moreover, while staff talking was not found to significantly contribute to the sound pressure levels, it was found to be the most frequently occurring activity which may indirectly influence patient wellbeing. Overall, identifying these sound sources can have a meaningful impact on patients and staff by identifying targets for future interventions, thus leading to a healthier environment., Competing Interests: M-MJ, BZ, and JS report grants from Orion Pharma, Abbott Nutrition International, B. Braun Medical AG, CSEM AG, Edwards Lifesciences Services GmbH, Kenta Biotech Ltd., Maquet Critical Care AB, Omnicare Clinical Research AG, Nestle, Pierre Fabre Pharma AG, Pfizer, Bard Medica S.A., Abbott AG, Anandic Medical Systems, Pan Gas AG Healthcare, Bracco, Hamilton Medical AG, Fresenius Kabi, Getinge Group Maquet AG, Dräger AG, Teleflex Medical GmbH, Glaxo Smith Kline, Merck Sharp and Dohme AG, Eli Lilly, and Company, Baxter, Astellas, Astra Zeneca, CSL Behring, Novartis, Covidien, Hemotune, Phagenesis, Philips Medical, Prolong Pharmaceuticals, and Nycomed outside the submitted work. The money received was paid into departmental funds. No personal financial gain was applied. The remaining 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., (Copyright © 2023 Naef, Knobel, Ruettgers, Rossier, Jeitziner, Zante, Müri, Schefold, Nef and Gerber.)

Parallel test versions require a comparable degree of difficulty and must capture the same characteristics using different items. This can become challenging when dealing with multivariate items, which are for example very common in language or image data. Here, we propose a heuristic to identify and select similar multivariate items for the generation of equivalent parallel test versions. This heuristic includes: 1. inspection of correlations between variables; 2. identification of outlying items; 3. application of a dimension-reduction method, such as for example principal component analysis (PCA); 4. generation of a biplot, in case of PCA of the first two principal components (PC), and grouping the displayed items; 5. assigning of the items to parallel test versions; and 6. checking the resulting test versions for multivariate equivalence, parallelism, reliability, and internal consistency. To illustrate the proposed heuristic, we applied it exemplarily on the items of a picture naming task. From a pool of 116 items, four parallel test versions were derived, each containing 20 items. We found that our heuristic can help to generate parallel test versions that meet requirements of the classical test theory, while simultaneously taking several variables into account., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Göbel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In everyday life, information from different cognitive domains-such as visuospatial attention, alertness and inhibition-needs to be integrated between different brain regions. Early models suggested that completely segregated brain networks control these three cognitive domains. However, more recent accounts, mainly based on neuroimaging data in healthy participants, indicate that different tasks lead to specific patterns of activation within the same, higher-order and 'multiple-demand' network. If so, then a lesion to critical substrates of this common network should determine a concomitant impairment in all three cognitive domains. The aim of the present study was to critically investigate this hypothesis, i.e. to identify focal stroke lesions within the network that can concomitantly affect visuospatial attention, alertness and inhibition. We studied an unselected sample of 60 first-ever right-hemispheric, subacute stroke patients using a data-driven, bottom-up approach. Patients performed 12 standardized neuropsychological and oculomotor tests, four per cognitive domain. A principal component analysis revealed a strong relationship between all three cognitive domains: 10 of 12 tests loaded on a first, common component. Analysis of the neuroanatomical lesion correlates using different approaches (i.e. voxel-based and tractwise lesion-symptom mapping, disconnectome maps) provided convergent evidence on the association between severe impairment of this common component and lesions at the intersection of superior longitudinal fasciculus II and III, frontal aslant tract and, to a lesser extent, the putamen and inferior fronto-occipital fasciculus. Moreover, patients with a lesion involving this region were significantly more impaired in daily living cognition, which provides an ecological validation of our results. A probabilistic functional atlas of the multiple-demand network was performed to confirm the potential relationship between patients' lesion substrates and observed cognitive impairments as a function of the multiple-demand network connectivity disruption. These findings show, for the first time, that a lesion to a specific white matter crossroad can determine a concurrent breakdown in all three considered cognitive domains. Our results support the multiple-demand network model, proposing that different cognitive operations depend on specific collaborators and their interaction, within the same underlying neural network. Our findings also extend this hypothesis by showing (i) the contribution of superior longitudinal fasciculus and frontal aslant tract to the multiple-demand network; and (ii) a critical neuroanatomical intersection, crossed by a vast amount of long-range white matter tracts, many of which interconnect cortical areas of the multiple-demand network. The vulnerability of this crossroad to stroke has specific cognitive and clinical consequences; this has the potential to influence future rehabilitative approaches., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Virtual reality (VR) is a promising tool to promote motor (re)learning in healthy users and brain-injured patients. However, in current VR-based motor training, movements of the users performed in a three-dimensional space are usually visualized on computer screens, televisions, or projection systems, which lack depth cues (2D screen), and thus, display information using only monocular depth cues. The reduced depth cues and the visuospatial transformation from the movements performed in a three-dimensional space to their two-dimensional indirect visualization on the 2D screen may add cognitive load, reducing VR usability, especially in users suffering from cognitive impairments. These 2D screens might further reduce the learning outcomes if they limit users' motivation and embodiment, factors previously associated with better motor performance. The goal of this study was to evaluate the potential benefits of more immersive technologies using head-mounted displays (HMDs). As a first step towards potential clinical implementation, we ran an experiment with 20 healthy participants who simultaneously performed a 3D motor reaching and a cognitive counting task using: (1) (immersive) VR (IVR) HMD, (2) augmented reality (AR) HMD, and (3) computer screen (2D screen). In a previous analysis, we reported improved movement quality when movements were visualized with IVR than with a 2D screen. Here, we present results from the analysis of questionnaires to evaluate whether the visualization technology impacted users' cognitive load, motivation, technology usability, and embodiment. Reports on cognitive load did not differ across visualization technologies. However, IVR was more motivating and usable than AR and the 2D screen. Both IVR and AR rea ched higher embodiment level than the 2D screen. Our results support our previous finding that IVR HMDs seem to be more suitable than the common 2D screens employed in VR-based therapy when training 3D movements. For AR, it is still unknown whether the absence of benefit over the 2D screen is due to the visualization technology per se or to technical limitations specific to the device., Competing Interests: Conflicts of interestThe authors declare no conflict of interest in this work., (© The Author(s) 2021.)

Background: The relearning of movements after brain injury can be optimized by providing intensive, meaningful, and motivating training using virtual reality (VR). However, most current solutions use two-dimensional (2D) screens, where patients interact via symbolic representations of their limbs (e.g., a cursor). These 2D screens lack depth cues, potentially deteriorating movement quality and increasing cognitive load. Head-mounted displays (HMDs) have great potential to provide naturalistic movement visualization by incorporating improved depth cues, reduce visuospatial transformations by rendering movements in the space where they are performed, and preserve eye-hand coordination by showing an avatar-with immersive VR (IVR)-or the user's real body-with augmented reality (AR). However, elderly populations might not find these novel technologies usable, hampering potential motor and cognitive benefits., Methods: We compared movement quality, cognitive load, motivation, and system usability in twenty elderly participants (>59 years old) while performing a dual motor-cognitive task with different visualization technologies: IVR HMD, AR HMD, and a 2D screen. We evaluated participants' self-reported cognitive load, motivation, and usability using questionnaires. We also conducted a pilot study with five brain-injured patients comparing the visualization technologies while using an assistive device., Results: Elderly participants performed straighter, shorter duration, and smoother movements when the task was visualized with the HMDs than screen. The IVR HMD led to shorter duration movements than AR. Movement onsets were shorter with IVR than AR, and shorter for both HMDs than the screen, potentially indicating facilitated reaction times due to reduced cognitive load. No differences were found in the questionnaires regarding cognitive load, motivation, or usability between technologies in elderly participants. Both HMDs proved high usability in our small sample of patients., Conclusions: HMDs are a promising technology to be incorporated into neurorehabilitation, as their more naturalistic movement visualization improves movement quality compared to conventional screens. HMDs demonstrate high usability, without decreasing participants' motivation, and might potentially lower cognitive load. Our preliminary clinical results suggest that brain-injured patients may especially benefit from more immersive technologies. However, larger patient samples are needed to draw stronger conclusions.*., (© 2022. The Author(s).)

Stress is a part of everyday life which can be counteracted by evoking the relaxation response via nature scenes presented using immersive virtual reality (VR). The aim of this study was to determine which sensory aspect of immersive VR intervention is responsible for the greatest relaxation response. We compared four conditions: auditory and visual combined (audiovisual), auditory only, visual only, and no artificial sensory input. Physiological changes in heart rate, respiration rate, and blood pressure were recorded, while participants reported their preferred condition and awareness of people, noise, and light in the real-world. Over the duration of the stimulation, participants had the lowest heart rate during the audiovisual and visual only conditions. They had the steadiest decrease in respiration rate and the lowest blood pressure during the audiovisual condition, compared to the other conditions, indicating the greatest relaxation. Moreover, ratings of awareness indicated that participants reported being less aware of their surroundings (i.e., people, noise, light, real environment) during the audiovisual condition versus the other conditions (p < 0.001), with a preference for audiovisual inputs. Overall, the use of audiovisual VR stimulation is more effective at inducing a relaxation response compared to no artificial sensory inputs, or the independent inputs., (© 2022. The Author(s).)

Mental imagery is a powerful capability that engages similar neurophysiological processes that underlie real sensory and motor experiences. Previous studies show that motor cortical excitability can increase during mental imagery of actions. In this study, we focused on possible inhibitory effects of mental imagery on motor functions. We assessed whether imagined arm paralysis modulates motor cortical excitability in healthy participants, as measured by motor evoked potentials (MEPs) of the hand induced by near-threshold transcranial magnetic stimulation (TMS) over the primary motor cortex hand area. We found lower MEP amplitudes during imagined arm paralysis when compared to imagined leg paralysis or baseline stimulation without paralysis imagery. These results show that purely imagined bodily constraints can selectively inhibit basic motor corticospinal functions. The results are discussed in the context of motoric embodiment/disembodiment., (© 2022 The Authors. Psychophysiology published by Wiley Periodicals LLC on behalf of Society for Psychophysiological Research.)

Using connected sensing devices to remotely monitor health is a promising way to help transition healthcare from a rather reactive to a more precision medicine oriented proactive approach, which could be particularly relevant in the face of rapid population ageing and the challenges it poses to healthcare systems. Sensor derived digital measures of health, such as digital biomarkers or digital clinical outcome assessments, may be used to monitor health status or the risk of adverse events like falls. Current research around such digital measures has largely focused on exploring the use of few individual measures obtained through mobile devices. However, especially for long-term applications in older adults, this choice of technology may not be ideal and could further add to the digital divide. Moreover, large-scale systems biology approaches, like genomics, have already proven beneficial in precision medicine, making it plausible that the same could also hold for remote-health monitoring. In this context, we introduce and describe a zero-interaction digital exhaust: a set of 1268 digital measures that cover large parts of a person's activity, behavior and physiology. Making this approach more inclusive of older adults, we base this set entirely on contactless, zero-interaction sensing technologies. Applying the resulting digital exhaust to real-world data, we then demonstrate the possibility to create multiple ageing relevant digital clinical outcome assessments. Paired with modern machine learning, we find these assessments to be surprisingly powerful and often on-par with mobile approaches. Lastly, we highlight the possibility to discover novel digital biomarkers based on this large-scale approach., (© 2022. The Author(s).)

Background: Brain fog is a common and highly disturbing symptom for patients with neuropathic postural tachycardia syndrome (POTS). Cognitive deficits have been measured exclusively in the upright body position and mainly comprised impairments of higher cognitive functions. The cause of brain fog is still unclear today. This study aimed to investigate whether increased autonomic activation might be an underlying mechanism for the occurrence of brain fog in neuropathic POTS. We therefore investigated cognitive function in patients with neuropathic POTS and a healthy control group depending on body position and in relation to catecholamine release as a sensitive indicator of acute stress. The second aim was to test the effect of water intake on cardiovascular regulation, orthostatic symptoms, cognitive function and catecholamine release., Methods: Thirteen patients with neuropathic POTS and 15 healthy control subjects were included. All participants completed a total of four rounds of cognitive testing: two before and two after the intake of 500 ml still water, each first in the supine position and then during head-up tilt. At the end of each cognitive test, a blood sample was collected for determination of plasma catecholamines. After each head-up tilt phase participants were asked to rate their current symptoms on a visual analogue scale., Results: Working memory performance in the upright body position was impaired in patients, which was associated with self-reported symptom severity. Patients had elevated plasma norepinephrine independent of body position and water intake that increased excessively in the upright body position. The excessive increase of plasma norepinephrine was related to heart rate and symptom severity. Water intake in patients decreased norepinephrine concentrations and heart rate, and improved symptoms as well as cognitive performance., Conclusion: Brain fog and symptom severity in neuropathic POTS are paralleled by an excessive norepinephrine secretion. Bolus water drinking down-regulates norepinephrine secretion and improves general symptom severity including brain fog., Competing Interests: 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., (Copyright © 2022 Rodriguez, Hochstrasser, Eugster, Grouzmann, Müri and Z’Graggen.)

Background: Virtual reality (VR) devices are increasingly being used in medicine and other areas for a broad spectrum of applications. One of the possible applications of VR involves the creation of an environment manipulated in a way that helps patients with disturbances in the spatial allocation of visual attention (so-called hemispatial neglect). One approach to ameliorate neglect is to apply cross-modal cues (ie, cues in sensory modalities other than the visual one, eg, auditory and tactile) to guide visual attention toward the neglected space. So far, no study has investigated the effects of audio-tactile cues in VR on the spatial deployment of visual attention in neglect patients., Objective: This pilot study aimed to investigate the feasibility and usability of multimodal (audio-tactile) cueing, as implemented in a 3D VR setting, in patients with neglect, and obtain preliminary results concerning the effects of different types of cues on visual attention allocation compared with noncued conditions., Methods: Patients were placed in a virtual environment using a head-mounted display (HMD). The inlay of the HMD was equipped to deliver tactile feedback to the forehead. The task was to find and flag appearing birds. The birds could appear at 4 different presentation angles (lateral and paracentral on the left and right sides), and with (auditory, tactile, or audio-tactile cue) or without (no cue) a spatially meaningful cue. The task usability and feasibility, and 2 simple in-task measures (performance and early orientation) were assessed in 12 right-hemispheric stroke patients with neglect (5 with and 7 without additional somatosensory impairment)., Results: The new VR setup showed high usability (mean score 10.2, SD 1.85; maximum score 12) and no relevant side effects (mean score 0.833, SD 0.834; maximum score 21). A repeated measures ANOVA on task performance data, with presentation angle, cue type, and group as factors, revealed a significant main effect of cue type (F 30,3 =9.863; P<.001) and a significant 3-way interaction (F 90,9 =2.057; P=.04). Post-hoc analyses revealed that among patients without somatosensory impairment, any cue led to better performance compared with no cue, for targets on the left side, and audio-tactile cues did not seem to have additive effects. Among patients with somatosensory impairment, performance was better with both auditory and audio-tactile cueing than with no cue, at every presentation angle; conversely, tactile cueing alone had no significant effect at any presentation angle. Analysis of early orientation data showed that any type of cue triggered better orientation in both groups for lateral presentation angles, possibly reflecting an early alerting effect., Conclusions: Overall, audio-tactile cueing seems to be a promising method to guide patient attention. For instance, in the future, it could be used as an add-on method that supports attentional orientation during established therapeutic approaches., (©Samuel Elia Johannes Knobel, Brigitte Charlotte Kaufmann, Nora Geiser, Stephan Moreno Gerber, René M Müri, Tobias Nef, Thomas Nyffeler, Dario Cazzoli. Originally published in JMIR Serious Games (https://games.jmir.org), 25.05.2022.)

With growing use of machine learning algorithms and big data in health applications, digital measures, such as digital biomarkers, have become highly relevant in digital health. In this paper, we focus on one important use case, the long-term continuous monitoring of cognitive ability in older adults. Cognitive ability is a factor both for long-term monitoring of people living alone as well as a relevant outcome in clinical studies. In this work, we propose a new potential digital biomarker for cognitive abilities based on location eigenbehaviour obtained from contactless ambient sensors. Indoor location information obtained from passive infrared sensors is used to build a location matrix covering several weeks of measurement. Based on the eigenvectors of this matrix, the reconstruction error is calculated for various numbers of used eigenvectors. The reconstruction error in turn is used to predict cognitive ability scores collected at baseline, using linear regression. Additionally, classification of normal versus pathological cognition level is performed using a support-vector machine. Prediction performance is strong for high levels of cognitive ability but grows weaker for low levels of cognitive ability. Classification into normal and older adults with mild cognitive impairment, using age and the reconstruction error, shows high discriminative performance with an ROC AUC of 0.94. This is an improvement of 0.08 as compared with a classification with age only. Due to the unobtrusive method of measurement, this potential digital biomarker of cognitive ability can be obtained entirely unobtrusively-it does not impose any patient burden. In conclusion, the usage of the reconstruction error is a strong potential digital biomarker for binary classification and, to a lesser extent, for more detailed prediction of inter-individual differences in cognition.

Spatial neglect after right-hemispheric stroke, characterized by the failure to attend or respond to the contralesional space, is a strong negative outcome predictor. Neglect is a supramodal syndrome affecting not only the visual but also the auditory modality. Preliminary studies used this audio-visual cross-modal effect to show short-lasting effects on attention towards the neglected space. The aim of the present study was to introduce a new technique of auditory stimulation combining the unspecific effect of music (i.e., patients choose their preferred music) with the effects of auditory spatial cueing (i.e., the music is presented dynamically as moving from right to left). The effect of this new auditory stimulation technique was investigated in two proof-of-concept experiments using repeated-measures, cross-over designs including 21 patients with visual neglect after a first right-hemispheric stroke. In Experiment I (n = 9), neglect patients showed a significantly larger improvement in Letter Cancellation after listening to preferred music with than without auditory spatial cueing. After granting the feasibility of this new auditory stimulation technique, we investigated the long-term aftereffects in Experiment II (n = 12). Herefore, we used video-oculography during Free Visual Exploration, a sensitive and reliable tool to assess spatial attention over time. Listening to music with auditory spatialcueing - as compared to music without auditory spatialcueing - significantly improved neglect severity in terms of visual exploration behaviour for up to 3h. A voxel-based-lesion-symptom mapping analysis over all patients revealed that the response variability in listening to music with auditory spatial cueing is determined by the integrity of the right inferior parietal lobule, the second branch of the superior longitudinal fascicle, and parieto-parietal callosal fibres. Our study shows that listening to music with auditory spatial cueing significantly reduces neglect severity and has the potential to be used as an add-on in the neurorehabilitation of neglect., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

To offer engaging neurorehabilitation training to neurologic patients, motor tasks are often visualized in virtual reality (VR). Recently introduced head-mounted displays (HMDs) allow to realistically mimic the body of the user from a first-person perspective (i.e., avatar) in a highly immersive VR environment. In this immersive environment, users may embody avatars with different body characteristics. Importantly, body characteristics impact how people perform actions. Therefore, alternating body perceptions using immersive VR may be a powerful tool to promote motor activity in neurologic patients. However, the ability of the brain to adapt motor commands based on a perceived modified reality has not yet been fully explored. To fill this gap, we "tricked the brain" using immersive VR and investigated if multisensory feedback modulating the physical properties of an embodied avatar influences motor brain networks and control. Ten healthy participants were immersed in a virtual environment using an HMD, where they saw an avatar from first-person perspective. We slowly transformed the surface of the avatar (i.e., the "skin material") from human to stone. We enforced this visual change by repetitively touching the real arm of the participant and the arm of the avatar with a (virtual) hammer, while progressively replacing the sound of the hammer against skin with stone hitting sound via loudspeaker. We applied single-pulse transcranial magnetic simulation (TMS) to evaluate changes in motor cortical excitability associated with the illusion. Further, to investigate if the "stone illusion" affected motor control, participants performed a reaching task with the human and stone avatar. Questionnaires assessed the subjectively reported strength of embodiment and illusion. Our results show that participants experienced the "stone arm illusion." Particularly, they rated their arm as heavier, colder, stiffer, and more insensitive when immersed with the stone than human avatar, without the illusion affecting their experienced feeling of body ownership. Further, the reported illusion strength was associated with enhanced motor cortical excitability and faster movement initiations, indicating that participants may have physically mirrored and compensated for the embodied body characteristics of the stone avatar. Together, immersive VR has the potential to influence motor brain networks by subtly modifying the perception of reality, opening new perspectives for the motor recovery of patients., Competing Interests: 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., (Copyright © 2022 Buetler, Penalver-Andres, Özen, Ferriroli, Müri, Cazzoli and Marchal-Crespo.)

Transcranial Direct Current Stimulation (tDCS) has been employed to modulate visuo-spatial attentional asymmetries, however, further investigation is needed to characterize tDCS-associated variability in more ecological settings. In the present research, we tested the effects of offline, anodal conventional tDCS (Experiment 1) and HD-tDCS (Experiment 2) delivered over the posterior parietal cortex (PPC) and Frontal Eye Field (FEF) of the right hemisphere in healthy participants. Attentional asymmetries were measured by means of an eye tracking-based, ecological paradigm, that is, a Free Visual Exploration task of naturalistic pictures. Data were analyzed from a spatiotemporal perspective. In Experiment 1, a pre-post linear mixed model (LMM) indicated a leftward attentional shift after PPC tDCS; this effect was not confirmed when the individual baseline performance was considered. In Experiment 2, FEF HD-tDCS was shown to induce a significant leftward shift of gaze position, which emerged after 6 s of picture exploration and lasted for 200 ms. The present results do not allow us to conclude on a clear efficacy of offline conventional tDCS and HD-tDCS in modulating overt visuospatial attention in an ecological setting. Nonetheless, our findings highlight a complex relationship among stimulated area, focality of stimulation, spatiotemporal aspects of deployment of attention, and the role of individual baseline performance in shaping the effects of tDCS.

Neurorehabilitation research suggests that not only high training intensity, but also somatosensory information plays a fundamental role in the recovery of stroke patients. Yet, there is currently a lack of easy-to-use robotic solutions for sensorimotor hand rehabilitation. We addressed this shortcoming by developing a novel clinical-driven robotic hand rehabilitation device, which is capable of fine haptic rendering, and that supports physiological full flexion/extension of the fingers while offering an effortless setup. Our palmar design, based on a parallelogram coupled to a principal revolute joint, introduces the following novelties: (1) While allowing for an effortless installation of the user's hand, it offers large range of motion of the fingers (full extension to 180° flexion). (2) The kinematic design ensures that all fingers are supported through the full range of motion and that the little finger does not lose contact with the finger support in extension. (3) We took into consideration that a handle is usually comfortably grasped such that its longitudinal axis runs obliquely from the metacarpophalangeal joint of the index finger to the base of the hypothenar eminence. (4) The fingertip path was optimized to guarantee physiologically correct finger movements for a large variety of hand sizes. Moreover, the device possesses a high mechanical transparency, which was achieved using a backdrivable cable transmission. The transparency was further improved with the implementation of friction and gravity compensation. In a test with six healthy participants, the root mean square of the human-robot interaction force was found to remain as low as 1.37 N in a dynamic task. With its clinical-driven design and easy-to-use setup, our robotic device for hand sensorimotor rehabilitation has the potential for high clinical acceptance, applicability and effectiveness., Competing Interests: FC is currently employed by Force Dimension (Switzerland), which provided the motors and drivers for the mechanical realization of the prototype as part of their engagement as industrial partner in the Innosuisse project 32213.1 IP-CT “Novel Clinical-Driven Robot-Assisted Sensorimotor Therapy.” The involvement of FC was limited to the development of the prototype and verification of the technical correctness of the manuscript. Our work does neither evaluate, nor promote any commercial devices of Force Dimension. The remaining 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., (Copyright © 2021 Rätz, Conti, Müri and Marchal-Crespo.)

Learning a new motor task is a complex cognitive and motor process. Especially early during motor learning, cognitive functions such as attentional engagement, are essential, e.g., to discover relevant visual stimuli. Drawing participant's attention towards task-relevant stimuli-e.g., with task instructions using visual cues or explicit written information-is a common practice to support cognitive engagement during training and, hence, accelerate motor learning. However, there is little scientific evidence about how visually cued or written task instructions affect attentional brain networks during motor learning. In this experiment, we trained 36 healthy participants in a virtual motor task: surfing waves by steering a boat with a joystick. We measured the participants' motor performance and observed attentional brain networks using alpha-band electroencephalographic (EEG) activity before and after training. Participants received one of the following task instructions during training: (1) No explicit task instructions and letting participants surf freely (implicit training; IMP); (2) Task instructions provided through explicit visual cues (explicit-implicit training; E-IMP); or (3) through explicit written commands (explicit training; E). We found that providing task instructions during training (E and E-IMP) resulted in less post-training motor variability-linked to enhanced performance-compared to training without instructions (IMP). After training, participants trained with visual cues (E-IMP) enhanced the alpha-band strength over parieto-occipital and frontal brain areas at wave onset. In contrast, participants who trained with explicit commands (E) showed decreased fronto-temporal alpha activity. Thus, providing task instructions in written (E) or using visual cues (E-IMP) leads to similar motor performance improvements by enhancing activation on different attentional networks. While training with visual cues (E-IMP) may be associated with visuo-attentional processes, verbal-analytical processes may be more prominent when written explicit commands are provided (E). Together, we suggest that training parameters such as task instructions, modulate the attentional networks observed during motor practice and may support participant's cognitive engagement, compared to training without instructions., Competing Interests: 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., (Copyright © 2021 Penalver-Andres, Buetler, Koenig, Müri and Marchal-Crespo.)

When humans visually explore an image, they typically tend to start exploring its left side. This phenomenon, so-called pseudoneglect, is well known, but its time-course has only sparsely been studied. Furthermore, it is unclear whether age influences pseudoneglect, and the relationship between visuo-spatial attentional asymmetries in a free visual exploration task and a classical line bisection task has not been established. To address these questions, 60 healthy participants, aged between 22 and 86, were assessed by means of a free visual exploration task with a series of naturalistic, colour photographs of everyday scenes, while their gaze was recorded by means of a contact-free eye-tracking system. Furthermore, a classical line bisection task was administered, and information concerning handedness and subjective alertness during the experiment was obtained. The results revealed a time-sensitive window during visual exploration, between 260 and 960 ms, in which age was a significant predictor of the leftward bias in gaze position, i.e., of pseudoneglect. Moreover, pseudoneglect as assessed by the line bisection task correlated with the average gaze position throughout a time-window of 300-1490 ms during the visual exploration task. These results suggest that age influences visual exploration and pseudoneglect in a time-sensitive fashion, and that the degree of pseudoneglect in the line bisection task correlates with the average gaze position during visual exploration in a time-sensitive manner., (© 2021. The Author(s).)

In Parkinson's disease (PD) patients, visual misperceptions are a major problem within the non-motor symptoms. Pareidolia, i.e., the tendency to perceive a specific, meaningful image in an ambiguous visual pattern, is a phenomenon that occurs also in healthy subjects. Literature suggests that the perception of face pareidolia may be increased in patients with neurodegenerative diseases. We aimed to examine, within the same experiment, face perception and the production of face pareidolia in PD patients and healthy controls (HC). Thirty participants (15 PD patients and 15 HC) were presented with 47 naturalistic photographs in which faces were embedded or not. The likelihood to perceive the embedded faces was modified by manipulating their transparency. Participants were asked to decide for each photograph whether a face was embedded or not. We found that PD patients were significantly less likely to recognize embedded faces than controls. However, PD patients also perceived faces significantly more often in locations where none were actually present than controls. Linear regression analyses showed that gender, age, hallucinations, and Multiple-Choice Vocabulary Intelligence Test (MWT) score were significant predictors of face pareidolia production in PD patients. Montreal Cognitive Assessment (MoCA) was a significant predictor for pareidolia production in PD patients in trials in which a face was embedded in another region [ F (1, 13) = 24.4, p = <0.001]. We conclude that our new embedded faces paradigm is a useful tool to distinguish face perception performance between HC and PD patients. Furthermore, we speculate that our results observed in PD patients rely on disturbed interactions between the Dorsal (DAN) and Ventral Attention Networks (VAN). In photographs in which a face is present, the VAN may detect this as a behaviourally relevant stimulus. However, due to the deficient communication with the DAN in PD patients, the DAN would not direct attention to the correct location, identifying a face at a location where actually none is present., Competing Interests: 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., (Copyright © 2021 Göbel, Möller, Hollenstein, Binder, Oechsner, Ide, Urwyler, Cazzoli and Müri.)

Background: Theta burst stimulation (TBS) is a non-invasive brain stimulation method. Various stimulation protocols have been proposed, for instance, stimulation at 50 Hz with pattern at 5 Hz, or at 30 Hz with pattern at 6 Hz. To identify better stimulation parameters for behavioral applications, we investigated the effects of 50-Hz continuous TBS (cTBS) on the sense of agency (SoA), and compared them with a previously published study with 30-Hz cTBS., Methods: Based on power analysis from a previous sample using two applications of 30-Hz cTBS, we recruited 20 healthy subjects in a single-blind, Vertex-controlled, randomized, crossover trial. Participants were stimulated with one application of 50-Hz cTBS over the right posterior parietal cortex (rPPC), a key area for agency processing, and the vertex, in a random order. A behavioral task targeting the SoA was done before and after stimulation. After controlling for baseline differences across samples, we studied the effect of stimulation in the two protocols separately., Results: Compared to the previously published 30-Hz protocol, 50-Hz cTBS over the rPPC did not reveal significant changes in the SoA, similar to sham Vertex stimulation., Conclusion: One application of 50-Hz cTBS was not sufficient to elicit behavioral effects, compared to two applications of 30-Hz cTBS, as previously described. This may be due to a mechanism of synaptic plasticity, consolidated through consecutive stimulation cycles. Our results are relevant for future studies aiming at modulating activity of the rPPC in cognitive domains other than agency, and in patients affected by abnormal agency, who could benefit from treatment options based on TBS., Competing Interests: 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., (Copyright © 2021 Zito, Worbe, Lamy, Kälin, Bühler, Weber, Müri and Aybek.)

Background: Serious games are gaining increasing importance in neurorehabilitation since they increase motivation and adherence to therapy, thereby potentially improving its outcome. The benefits of serious games, such as the possibility to implement adaptive feedback and the calculation of comparable performance measures, can be even further improved by using immersive virtual reality (iVR), allowing a more intuitive interaction with training devices and higher ecological validity., Objective: This study aimed to develop a visual search task embedded in a serious game setting for iVR, including self-adapting difficulty scaling, thus being able to adjust to the needs and ability levels of different groups of individuals., Methods: In a two-step process, a serious game in iVR (bird search task) was developed and tested in healthy young (n=21) and elderly (n=23) participants and in a group of patients with impaired visual exploration behavior (ie, patients with hemispatial neglect after right-hemispheric stroke; n=11). Usability, side effects, game experience, immersion, and presence of the iVR serious game were assessed by validated questionnaires. Moreover, in the group of stroke patients, the performance in the iVR serious game was also considered with respect to hemispatial neglect severity, as assessed by established objective hemispatial neglect measures., Results: In all 3 groups, reported usability of the iVR serious game was above 4.5 (on a Likert scale with scores ranging from 1 to 5) and reported side effects were infrequent and of low intensity (below 1.5 on a Likert scale with scores ranging from 1 to 4). All 3 groups equally judged the iVR serious game as highly motivating and entertaining. Performance in the game (in terms of mean search time) showed a lateralized increase in search time in patients with hemispatial neglect that varied strongly as a function of objective hemispatial neglect severity., Conclusions: The developed iVR serious game, "bird search task," was a motivating, entertaining, and immersive task, which can, due to its adaptive difficulty scaling, adjust and be played by different populations with different levels of skills, including individuals with cognitive impairments. As a complementary finding, it seems that performance in the game is able to capture typical patterns of impaired visual exploration behavior in hemispatial neglect, as there is a high correlation between performance and neglect severity as assessed with a cancellation task., (©Samuel Elia Johannes Knobel, Brigitte Charlotte Kaufmann, Stephan Moreno Gerber, Prabitha Urwyler, Dario Cazzoli, René M Müri, Tobias Nef, Thomas Nyffeler. Originally published in JMIR Serious Games (https://games.jmir.org), 02.07.2021.)

Background: Population aging is posing multiple social and economic challenges to society. One such challenge is the social and economic burden related to increased health care expenditure caused by early institutionalizations. The use of modern pervasive computing technology makes it possible to continuously monitor the health status of community-dwelling older adults at home. Early detection of health issues through these technologies may allow for reduced treatment costs and initiation of targeted preventive measures leading to better health outcomes. Sleep is a key factor when it comes to overall health and many health issues manifest themselves with associated sleep deteriorations. Sleep quality and sleep disorders such as sleep apnea syndrome have been extensively studied using various wearable devices at home or in the setting of sleep laboratories. However, little research has been conducted evaluating the potential of contactless and continuous sleep monitoring in detecting early signs of health problems in community-dwelling older adults., Objective: In this work we aim to evaluate which contactlessly measurable sleep parameter is best suited to monitor perceived and actual health status changes in older adults., Methods: We analyzed real-world longitudinal (up to 1 year) data from 37 community-dwelling older adults including more than 6000 nights of measured sleep. Sleep parameters were recorded by a pressure sensor placed beneath the mattress, and corresponding health status information was acquired through weekly questionnaires and reports by health care personnel. A total of 20 sleep parameters were analyzed, including common sleep metrics such as sleep efficiency, sleep onset delay, and sleep stages but also vital signs in the form of heart and breathing rate as well as movements in bed. Association with self-reported health, evaluated by EuroQol visual analog scale (EQ-VAS) ratings, were quantitatively evaluated using individual linear mixed-effects models. Translation to objective, real-world health incidents was investigated through manual retrospective case-by-case analysis., Results: Using EQ-VAS rating based self-reported perceived health, we identified body movements in bed-measured by the number toss-and-turn events-as the most predictive sleep parameter (t score=-0.435, P value [adj]=<.001). Case-by-case analysis further substantiated this finding, showing that increases in number of body movements could often be explained by reported health incidents. Real world incidents included heart failure, hypertension, abdominal tumor, seasonal flu, gastrointestinal problems, and urinary tract infection., Conclusions: Our results suggest that nightly body movements in bed could potentially be a highly relevant as well as easy to interpret and derive digital biomarker to monitor a wide range of health deteriorations in older adults. As such, it could help in detecting health deteriorations early on and provide timelier, more personalized, and precise treatment options., (©Narayan Schütz, Hugo Saner, Angela Botros, Bruno Pais, Valérie Santschi, Philipp Buluschek, Daniel Gatica-Perez, Prabitha Urwyler, René M Müri, Tobias Nef. Originally published in JMIR mHealth and uHealth (https://mhealth.jmir.org), 11.06.2021.)

Spatial neglect has been shown to occur in 17-65% of patients after acute left-hemispheric stroke. One reason for this varying incidence values might be that left-hemispheric stroke is often accompanied by aphasia, which raises difficulties in assessing attention deficits with conventional neuropsychological tests entailing verbal instructions. Video-oculography during free visual exploration (FVE) requires only little understanding of simple non-verbal instruction and has been shown to be a sensitive and reliable tool to detect spatial neglect in patients with right-hemispheric stroke. In the present study, we aimed to investigate the feasibility of FVE to detect neglect in 10 left-hemispheric stroke patients with mild to severe aphasia as assessed by means of the Token Test, Boston Naming Test and Aachener Aphasie Test. The patient's individual deviation between eye movement calibration and validation was recorded and compared to 20 age-matched healthy controls. Furthermore, typical FVE parameters such as the landing point of the first fixation, the mean gaze position (in ° of visual angle), the number and duration of visual fixations and the mean visual exploration area were compared between groups. In addition, to evaluate for neglect, the Bells cancellation test was performed and neglect severity in daily living was measured by means of the Catherine Bergego Scale (CBS). Our results showed that the deviation between calibration and validation did not differ between aphasia patients and healthy controls highlighting its feasibility. Furthermore, FVE revealed the typical neglect pattern with a significant leftward shift in visual exploration bahaviour, which highly correlated with neglect severity as assessed with CBS. The present study provides evidence that FVE has the potential to be used as a neglect screening tool in left-hemispheric stroke patients with aphasia in which compliance with verbal test instructions may be compromised by language deficits., Competing Interests: 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., (Copyright © 2021 Kaufmann, Cazzoli, Koenig-Bruhin, Müri, Nef and Nyffeler.)

Background: Delirium has been long considered as a major contributor to cognitive impairments and increased mortality following a critical illness. Pharmacologic and non-pharmacologic strategies are used against delirium in the intensive care unit (ICU), despite these strategies remaining controversial. Previous studies have shown the feasibility of using virtual reality within the ICU setting, and we propose to use this technology to investigate the effect of immersive virtual reality stimulation on the incidence of delirium in the ICU. Moreover, we propose to use motion sensors to determine if patient movement patterns can lead to early prediction of delirium onset., Methods: This study is conducted as a randomized clinical trial. A total of 920 critically ill patients in the ICU will participate. The control group will receive standard ICU care, whereas the intervention group will, in addition to the standard ICU care, receive relaxing 360-degree immersive virtual reality content played inside a head-mounted display with noise-cancelling headphones, three times a day. The first 100 patients, regardless of their group, will additionally have their movement patterns recorded using wearable and ambient sensors. Follow-up measurements will take place 6 months after discharge from the ICU., Discussion: Delirium is widely present within the ICU setting but lacks validated prevention and treatment strategies. By providing patients with virtual reality stimulation presented inside a head-mounted display and noise-cancelling headphones, participants may be isolated from disturbances on an ICU. It is believed that by doing so, the incidence of delirium will be decrease among these patients. Moreover, identifying movement patterns associated with delirium would allow for early detection and intervention, which may further improve long-term negative outcomes associated with delirium during critical care., Trial Registration: ClinicalTrials.gov NCT04498585 . Registered on August 3, 2020.

Passive infrared motion sensors are commonly used in telemonitoring applications to monitor older community-dwelling adults at risk. One possible use case is quantification of in-home physical activity, a key factor and potential digital biomarker for healthy and independent aging. A major disadvantage of passive infrared sensors is their lack of performance and comparability in physical activity quantification. In this work, we calibrate passive infrared motion sensors for in-home physical activity quantification with simultaneously acquired data from wearable accelerometers and use the data to find a suitable correlation between in-home and out-of-home physical activity. We use data from 20 community-dwelling older adults that were simultaneously provided with wireless passive infrared motion sensors in their homes, and a wearable accelerometer for at least 60 days. We applied multiple calibration algorithms and evaluated results based on several statistical and clinical metrics. We found that using even relatively small amounts of wearable based ground-truth data over 7-14 days, passive infrared based wireless sensor systems can be calibrated to give largely better estimates of older adults' daily physical activity. This increase in performance translates directly to stronger correlations of measured physical activity levels with a variety of age relevant health indicators and outcomes known to be associated with physical activity., Competing Interests: PB was employed by Domo-Safety SA, which is the manufacturer of the displayed sensor system. The remaining 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., (Copyright © 2021 Schütz, Saner, Botros, Buluschek, Urwyler, Müri and Nef.)

The clinical link between spatial and non-spatial attentional aspects in patients with hemispatial neglect is well known; in particular, an increase in alerting can transitorily help to allocate attention towards the contralesional side. In models of attention, this phenomenon is postulated to rely on an interaction between ventral and dorsal cortical networks, subtending non-spatial and spatial attentional aspects, respectively. However, the exact neural underpinnings of the interaction between these two networks are still poorly understood. In the present study, we included 80 right-hemispheric patients with subacute stroke (50% women; age range: 24-96), 33 with and 47 without neglect, as assessed by paper-pencil cancellation tests. The patients performed a computerized task in which they were asked to respond as quickly as possible by button-press to central targets, which were either preceded or not preceded by non-spatial, auditory warning tones. Reaction times in the two different conditions were measured. In neglect patients, a warning tone, enhancing activity within the ventral attentional 'alerting' network, could boost the reaction (in terms of shorter reaction times) of the dorsal attentional network to a visual stimulus up to the level of patients without neglect. Critically, using voxel-based lesion-symptom mapping analyses, we show that this effect significantly depends on the integrity of the right anterior insula and adjacent inferior frontal gyrus, i.e., right-hemispheric patients with lesions involving these areas were significantly less likely to show shorter reaction times when a warning tone was presented prior to visual target appearance. We propose that the right anterior insula and inferior frontal gyrus are a critical hub through which the ventral attentional network can 'alert' and increase the efficiency of the activity of the dorsal attentional network., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Pneumococcal meningitis (PM) causes damage to the hippocampus, a brain structure critically involved in learning and memory. Hippocampal injury-which compromises neurofunctional outcome-occurs as apoptosis of progenitor cells and immature neurons of the hippocampal dentate granule cell layer thereby impairing the regenerative capacity of the hippocampal stem cell niche. Repetitive transcranial magnetic stimulation (rTMS) harbours the potential to modulate the proliferative activity of this neuronal stem cell niche. In this study, specific rTMS protocols-namely continuous and intermittent theta burst stimulation (cTBS and iTBS)-were applied on infant rats microbiologically cured from PM by five days of antibiotic treatment. Following two days of exposure to TBS, differential gene expression was analysed by whole transcriptome analysis using RNAseq. cTBS provoked a prominent effect in inducing differential gene expression in the cortex and the hippocampus, whereas iTBS only affect gene expression in the cortex. TBS induced polarisation of microglia and astrocytes towards an inflammatory phenotype, while reducing neurogenesis, neuroplasticity and regeneration. cTBS was further found to induce the release of pro-inflammatory cytokines in vitro. We conclude that cTBS intensified neuroinflammation after PM, which translated into increased release of pro-inflammatory mediators thereby inhibiting neuroregeneration., Competing Interests: The authors have declared that no competing interests exist.

Neglect after stroke is most accurately diagnosed by a systematic, ecological observation during everyday behaviour using the Catherine Bergego Scale (CBS). However, the CBS is time-consuming and often omitted in clinical settings, especially stroke units. In this study, we aimed to explore if video-oculography during free visual exploration (FVE), which can be performed in few minutes, is sensitive in mirroring neglect in everyday behaviour and whether it is more sensitive than conventional neuropsychological paper-pencil tests. In this retrospective, observational, multicentre study, we identified 78 patients in our database with subacute right-hemispheric stroke, with and without neglect in everyday behaviour, diagnosed by the CBS, who also performed FVE. 40 age-matched healthy participants served as controls. The sensitivity to detect neglect was compared between FVE (i.e., mean gaze position on the horizontal axis) and conventional neuropsychological paper-pencil tests, i.e., Random Shape Cancellation, Line Bisection, Two-Part Picture, Bells, Star Cancellation, Letter Cancellation, Sensitive Neglect, and Five-Point. FVE correctly identified neglect in 85%of patients, with an AUC-value of .922 in ROC-analysis. Conventional neuropsychological paper-pencil tests, considered alone or in combination, showed heterogeneous results, and identified neglect significantly less often (21.74%-68.75%). Moreover, there was a significant correlation between mean gaze position and CBS scores, providing evidence for the relationship between FVE and neglect in everyday behaviour. Furthermore, VLSM analyses suggested that the absence of a pathological rightward bias in FVE might depend on the integrity of the second branch of the right Superior Longitudinal Fascicle (SLF II), a white-matter tract connecting cortical areas critical for visual attention. Video-oculography during FVE has a high sensitivity and specificity to diagnose neglect after stroke and it is more sensitive than conventional neuropsychological paper-pencil tests. It can be performed in short time and has the potential to be used as a fast and accurate screening tool that allows the initiation of comprehensive neuropsychological diagnostics and therapy from early on., Competing Interests: Declaration of competing interest None declared., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Noise levels on intensive care units (ICUs) are typically elevated. While many studies reported negative effects of ICU ambient sounds on patients, only few investigated noise as a factor to influence well-being or performance in healthcare professionals., Methods: An online survey in the German-speaking part of Switzerland was conducted to assess how ICU soundscapes are subjectively perceived by healthcare professionals. The questionnaire was answered by 348 participants. Additionally, effects of noise on working memory performance were evaluated in an experimental noise exposure setting. Twenty-six healthcare professionals and 27 healthy controls performed a 2-back object-location task while being exposed to either ICU or pink noise., Results: Survey results demonstrate that a majority of participants was aware of heightened noise levels. Participants reported that mostly well-being, performance, and attention could be reduced, along with subjective annoyance and fatigue by ICU ambient sounds. Although no significant effects of noise exposure on working memory performance was observed, self-assessments revealed significantly higher stress levels, increased annoyance and distraction ratings as well as decreased confidence in performance after ICU-noise exposure., Conclusion: Subjective assessments indicate that heightened noise levels on ICUs induce annoyance, with heightened stress levels, impaired well-being, and reduced performance being potential consequences. Empirical evidence with objective and physiological measures is warranted.

The Mean gaze position during free visual exploration (FVE) is a sensitive tool to detect neglect in patients after a right-hemispheric stroke. Here we investigated the test-retest-reliability of mean gaze position during FVE in 23 patients with left-sided neglect after a first-ever sub-acute right-hemispheric stroke. We analyzed the reliability between different test sets administered within 11 days (test sets A and B, each including different images and their mirrored versions), and between repeated measures using the same test set administered three times within 2 days (test set C, including the same images and their mirrored versions). The intra-class correlation coefficient (ICC) showed good reliability between the two different test sets (test sets A and B; ICC = 0.819), and excellent reliability for the repeated measures with the same test set C (ICC = 0.964). FVE can therefore be recommended for the longitudinal assessments of patients' neglect severity during neurorehabilitation as well as in treatment trials., (Copyright © 2020 Kaufmann, Cazzoli, Müri, Nef and Nyffeler.)

Clinical, neuroimaging, and non-invasive brain stimulation studies have associated the dorsolateral prefrontal cortex (DLPFC) with the multilingual language control system. Here, we investigated if this role is increased during the processing of the non-dominant language due to the higher cognitive/attentional demands. We used an inhibitory repetitive transcranial magnetic stimulation (rTMS) protocol over the left DLPFC and investigated the behavioral and electrophysiological effects on (i) picture naming in the mother tongue and second language, (ii) forward and backward translation and (iii) non-verbal inhibition. To this end, we compared the effects of inhibitory rTMS (cTBS) vs sham-rTMS using a single-blind within-subject design including 22 late bilinguals. Behaviorally, response times were longer after cTBS compared to sham-rTMS in the picture naming task independent of language, while response times were not affected for the word translation task. These results were mirrored on the electrophysiological level showing an effect of stimulation in the picture naming task starting at 547 ms post-stimulus onset, but not in the translation task. This late time range is likely associated with processes of conflict resolution and initiation of the articulation of the word rather than processes related to lexical selection or language switching. For the non-verbal inhibition task, behavioral outcome was not affected despite electrophysiological stimulation-induced changes. Overall, the results suggest that the DLPFC plays a role in top-down cognitive control in language production, but that this role is not increased with higher cognitive demand such as naming in a second language or in language switching during word translation.

Background: The sense of agency is an important aspect of motor control. Impaired sense of agency has been linked to several medical conditions, including schizophrenia and functional neurological disorders. A complex brain network subserves the sense of agency, and the right temporoparietal junction is one of its main nodes. In this paper, we tested whether transcranial magnetic stimulation over the right temporoparietal junction elicited behavioural changes in the sense of agency., Methods: In experiment 1, 15 healthy participants performed a behavioural task during functional MRI, with the goal of localizing the area relevant for the sense of agency in the right temporoparietal junction. In the task, the movement of a cursor (controlled by the participants) was artificially manipulated, and the sense of agency was either diminished (turbulence) or enhanced (magic). In experiment 2, we applied transcranial magnetic stimulation in 20 healthy participants in a sham-controlled, crossover trial with excitatory, inhibitory or sham (vertex) stimulation. We measured the summary agency score, an indicator of the sense of agency (lower values correspond to diminished sense of agency)., Results: Experiment 1 revealed a peak of activation during agency manipulation in the right temporoparietal junction (Montreal Neurological Institute coordinates x, y, z: 68, -26, 34). Experiment 2 showed that inhibition of the right temporoparietal junction significantly reduced the summary agency score in both turbulence (from -14.4 ± 11.4% to -22.5 ± 8.9%), and magic (from -0.7 ± 5.8% to -4.4 ± 4.4%)., Limitations: We found no excitatory effects, possibly because of a ceiling effect (because healthy participants have a normal sense of agency) or noneffectiveness of the excitatory protocol., Conclusion: Our experiments showed that the network subserving the sense of agency was amenable to neuromodulation in healthy participants. This sets the ground for further research in patients with impaired sense of agency. Clinical trial identification: DRKS00012992 (German clinical trials registry)., Competing Interests: R. Müri declares funding from the Swiss National Foundation, outside of the submitted work. No other competing interests were declared., (© 2020 Joule Inc. or its licensors.)

Adjustment disorders (AjD) with depressive symptoms following an acquired brain injury (ABI) is a common phenomenon. Although brain injuries are increasing more and more, research on psychological therapies is comparably scarce. The present study compared, by means of a randomized controlled trial (RCT), a newly developed integrative treatment (Standard PLUS) to a standard neuropsychological treatment (Standard). Primary outcomes were depressive symptoms assessed with the Beck Depression Inventory (BDI-II) at post-treatment and 6-month follow-up assessment. In total, 25 patients (80% after a stroke) were randomized to one of the two conditions. Intention-to-treat analyses showed that the two groups did not significantly differ either at post-treatment nor at follow-up assessment regarding depressive symptoms. Both treatments showed large within-group effect sizes on depressive symptoms. Regarding secondary outcomes, patients in the Standard PLUS condition reported more emotion regulation skills at post-assessment than in the control condition. However, this difference was not present anymore at follow-up assessment. Both treatments showed medium to large within-group effects sizes on most measures for patients suffering from an AjD after ABI. More research with larger samples is needed to investigate who profits from which intervention.

Background: We developed a standardized, comprehensive, ambulatory, hospital-based neurorehabilitation program ("MS-Fit") to improve disability, activities of daily living and quality of life in people with multiple sclerosis (PwMS)., Aim: The aim of this study was to assess feasibility, adherence and satisfaction of the training intervention., Design: Prospective multicenter cohort study analysis., Setting: Ambulatory, hospital-based study., Population: PwMS, aged 18 to 75 years, complaining about multiple sclerosis-related disability affecting activities of daily living and/or quality of life., Methods: A standardized, ambulatory, hospital-based circuit training consisting of six workstations (aerobic exercise training, strength upper limbs, balance, manual dexterity, reactivity, strength and flexibility lower limbs) was performed two hours, twice weekly, for two months in groups of two to six participants supervised by experienced physiotherapists. Physiotherapists adapted the type and intensity of training according to the participants' individual performance using a training booklet. Program satisfaction and adherence were evaluated using a questionnaire and the attendance rate (clinicaltrials.gov Identifier: NCT02440516)., Results: Fifty-five participants started (mean age 52.82 years±10.68 standard deviation, range 29-74; 69% female; median Expanded Disability Status Scale 3.5, range 1.0-7.0) and 49 (89%) finished the training program. Main reasons to drop out during the training were lack of time, travel problems, social issues or Uthoff's phenomenon during the summer. All participants finalizing the training achieved >80% (mean 92.26%, ±7.59) attendance rate and sent back the questionnaire. Overall participant's satisfaction was high with a median of 9 points (range 4-10) on a Likert Scale from 0-10. Program quality was rated "good" with an overall median score of 39/50 points (range 26-50) and 95% of the participants would recommend the program to others., Conclusions: MS-Fit is a feasible training program with high patient satisfaction and adherence. It enables high intensity ambulatory training and can be easily reproduced due to its standardized nature., Clinical Rehabilitation Impact: MS-FIT enables a standardized ambulatory high intensity training that is easily reproducible. Participants benefit from group training and from individual adaption of the training through professional supervision.

This study investigated the role of the left dorsolateral prefrontal cortex (DLPFC) in language switching using theta burst stimulation (TBS) and electroencephalography in late bilinguals. After a sham-controlled baseline, participants received either excitatory or inhibitory TBS over the left DLPFC before conducting picture naming tasks in pure language blocks and a language switching block, as well as a nonverbal switching task. On the behavioral level, we found no effect of TBS. However, the ERP-analysis revealed an effect of Stimulation for the picture naming tasks, characterized by alterations in the left DLPFC at 20-72 ms, and in networks associated with conflict resolution and self-monitoring at 533-600 ms. As we did not find an interaction between Stimulation and Block (switching vs non-switching), prefrontal stimulation did not specifically modulate interlanguage control. The left DLPFC might rather be involved in enhancingmaintenance of task demands and self-monitoring during language production in both mono- and bilingual contexts., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background : Unilateral spatial neglectis an attention disorder frequently occurring after a right-hemispheric stroke. Neglect results in a reduction in qualityof life and performance in activities of daily living. With current technical improvements in virtual reality (VR) technology, trainingwith 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 paper-pencil 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 healthy controls and for stroke patients. Findings for task performance show that the ability of the VR cancellation to detect neglect in stroke patients is similar to paper-pencil cancellation tasks., (Copyright © 2020 Knobel, Kaufmann, Gerber, Cazzoli, Müri, Nyffeler and Nef.)