Sleep deprivation is a pervasive issue in medical training known to impair attention and specific motor abilities, yet its impact on integrated cognitive-motor performance and adaptive motor skill learning during real-world hospital shifts remains insufficiently understood. This study investigated potential declines in these domains across a 26-h night shift and following recovery sleep among medical residents utilizing a Virtual Reality version of the Color Trails Test. The protocol involved thirteen residents who underwent assessment two days prior to the shift, at four time points during the shift, and once more after at least 24 h of recovery sleep. By replicating the core cognitive demands of the classic test while incorporating three-dimensional manual movements, the assessment also included an adaptive module with intermittent left-right mirror reversal to evaluate learning under sleep loss conditions. Findings indicated that completion times improved across sessions, predominantly in mirror-reversal segments, whereas performance on regular segments stabilized following pre-shift practice. Conversely, interference cost increased towards the end of the shift and remained elevated post-shift, suggesting greater relative difficulty in the more demanding condition due to fatigue. Movement distance and speed followed the completion time pattern with progressive improvement. Ultimately, despite preserved motor learning, fatigue appeared to selectively impair higher-order cognitive control, specifically task switching and divided attention, suggesting that such reduced cognitive flexibility during extended shifts may compromise clinical performance even after recovery sleep.

BACKGROUND:Cognitive impairment is a common non-motor symptom in Multiple Sclerosis (MS), negatively affecting autonomy and Quality of Life (QoL). Innovative rehabilitation strategies, such as semi-immersive virtual reality (VR) and computerized cognitive training (CCT), may offer advantages over traditional cognitive rehabilitation (TCR), particularly in terms of engagement, specificity, adaptability, and ecological validity. This study aimed to compare the efficacy of semi-immersive VR, CCT using the ERICA platform, and TCR on cognitive outcomes and depressive/anxiety symptoms in individuals with MS. METHODS:Eighty-seven patients with MS and mild to moderate cognitive impairment were randomly assigned to three groups: VR-based training, CCT, or TCR. Each group underwent 24 individual sessions delivered regularly three times per week over 8 weeks. Neuropsychological assessments were conducted at baseline (T0) and post-intervention (T1), evaluating information processing speed (SDMT), memory (SRT, SPART), executive functions (WLG), emotional status (BDI, HRS-A), and QoL (MSQOL-54). RESULTS:All groups showed significant improvements in most cognitive and depressive (BDI)/anxiety symptoms (HRS-A) after the intervention. However, the VR group demonstrated significantly greater gains in executive functions, working memory, and QoL (MSQOL-54 Physical and Mental Composite scores) compared to both the CCT and TCR groups (p < 0.001). While the CCT group showed selective improvements in mood and working memory, its overall efficacy did not significantly differ from that of TCR. CONCLUSIONS:Semi-immersive VR represents an effective and engaging approach to cognitive rehabilitation in MS, likely due to its capacity to deliver multisensory, adaptive, and ecologically valid stimulation. Nonetheless, a tailored hybrid model integrating VR with conventional and computer-based strategies may further optimize outcomes and support functional independence in individuals with MS.

Cognitive impairments in Parkinson's disease (PD) often emerge alongside motor symptoms, yet most clinical assessments examine these domains separately. This mixed-design study explores the utility of a virtual reality-based Color Trails Test (VR-CTT) as an integrated, immersive tool to assess motor-cognitive interaction in PD. Twenty-three individuals with PD (ON medication) and twenty-three age- and education-matched healthy controls completed both the standard pen-and-paper CTT and the VR-CTT, which preserves the same cognitive demands while introducing an upper-limb motor component through full-arm reaching to virtual targets. As expected, individuals with PD were slower and less accurate across both formats. However, we observed only moderate-to-low correlations between completion times in the two CTTs, thus suggesting that the VR-CTT may capture distinct and ecologically valid aspects of motor-cognitive performance. Indeed, kinematic analysis revealed longer head-hand coordination delays and reduced maximal execution velocities in PD, pointing to subtle, yet specific motor difficulties during cognitive tasks. Beyond confirming feasibility, these results highlight the VR-CTT's potential as a novel tool for identifying motor-cognitive dysfunction and informing targeted rehabilitation strategies. Its immersive nature and multi-competency format position it as a promising intervention platform for cognitive-motor training in PD and related disorders.

INTRODUCTION: Alzheimer's disease (AD) pathological processes begin decades before symptom onset. Early intervention in high-risk populations may be crucial for prevention. We investigated the effect of an intervention utilizing virtual reality (VR) cognitive-motor training on cerebral blood flow (CBF) and cognitive functioning in middle-aged adults at high AD risk due to parental history. METHODS: In this randomized controlled trial, participants (n = 79) were randomly assigned to: VR cognitive-motor training while walking on a treadmill (VR+T, n = 24, treatment); VR cognitive training without treadmill (VR-T, n = 21, active control); treadmill walking while watching documentaries (TV+T, n = 20, active control); or no intervention (n = 14, passive control). Training consisted of 45-min sessions, twice weekly, for 12 weeks. CBF was measured at resting state using arterial spin labeling (ASL) at baseline, 3-month, and 6-month follow-up. Cognition was assessed using a comprehensive neuropsychological battery. We applied the intent-to-treat approach. RESULTS: All groups improved in executive functions and memory over time (all p-values < 0.05), with no consistent between-group differences at follow-up. CBF of the VR+T group significantly increased at 3 months in the superior (p = 0.013, middle (p = 0.014), and inferior (p = 0.003) frontal gyri compared to the passive control group, which showed a decline in CBF over the same period. No significant differences in frontal CBF change were observed between VR+T and the TV+T active control group. This increase was sustained for 6 months in the superior (p = 0.035) and middle (p = 0.028) frontal gyri. In contrast, in the middle temporal gyrus, the VR+T group had lower CBF at 3 months, compared to the VR-T (p = 0.033) and to the passive control groups (p = 0.004). DISCUSSION: Cognitive-motor VR training increased CBF in frontal regions susceptible to early AD-related changes in middle-aged adults at high AD risk. This intervention shows promise as a preventive approach and may be suitable for implementation as a home-based program for individuals at high risk.

Increasing prevalence of Alzheimer’s Disease (AD) and limited pharmacological intervention benefits to decelerate early neurodegeneration have prompted exploration of non-pharmacological options. Recent studies indicate that combining cognitive-motor training enhances outcomes. In a single-blind, parallel-group, randomized controlled trial of middle-aged adults with a parental history of AD, the experimental group (N = 22) underwent training with newly developed “real-world” intensive, progressive, virtual reality (VR) tasks, while walking on a treadmill. Tasks included challenges to sustained attention, selective attention, working memory, covert rule deduction, and planning, all in daily living contexts. An active control group without treadmill (N = 17) and another group walking on a treadmill while watching scientific documentaries (N = 16) were included. A passive control group received no training (N = 11). Training sessions were 45 minutes, twice a week, for twelve weeks. The primary neurobiological outcome, cerebral blood flow (CBF), in the superior (SFG), middle (MFG) and inferior (IFG) frontal gyri and middle temporal gyrus (MTG), was assessed using MRI arterial spin labeling at 12 weeks (i.e., post training) and at 6 months (3 months follow up). Linear mixed regression models, adjusting for age, sex, education and baseline cognition, assessed group differences. Participants averaged 56.2 (SD = 5.78), were primarily female (70%) and had undergraduate education (mean = 16.4; SD = 3.12). The groups did not differ in any baseline characteristics. The interaction of group X time on CBF of the MFG was significant (p = 0.04), such that the experimental group had an increase in CBF at 3 months which then plateaued, there were no changes in CBF in the active control groups, and the passive control group had a decline in CBF (see Figure ). Similar trends were found for the SFG and IFG (p for interaction 0.07 and 0.08, respectively). No differences were found between the groups in the MTG. The sustained increase in CBF, a major contributor to cognitive functioning, observed in the frontal cortex of the experimental group over three months, implies that our innovative VR intervention may beneficially affect cerebrovascular function, even in midlife. This trend underscores the potential effectiveness of our intervention in preserving healthy cognition among asymptomatic individuals at high AD risk.

AbstractINTRODUCTIONWe developed a tool for objective quantification of apathy.METHODSParticipants (n = 97; 67 with cognitive impairment, 30 cognitively normal; mean age = 74.3 ± 6.2 years, 56.7% females) were exposed to emotional and cognitive stimuli in a virtual reality environment. Gaze metrics (time to first fixation [TTFF] and total fixation duration [TFD]) and autonomic nervous system (ANS) reactivity were measured. Apathy and depression were clinically assessed using the Lille Apathy Rating Scale short version and the Geriatric Depression Scale 15‐item version, respectively. Cutoffs of ≥ –7 and ≥ 5 were used to define apathy and depression, respectively.RESULTSThe sample comprised 14 participants with apathy only, 9 with depression only, 10 with both, 63 with neither, and 1 with missing data. For all emotional stimuli, participants with apathy only showed longer TTFF (P = 0.039, effect sizes [ES] = 0.798), and shorter TFD (P = 0.023, ES = 0.578) compared to those without apathy or depression. ANS reactivity was not associated with apathy.DISCUSSIONApathy is associated with decreased gaze engagement at emotional stimuli.Highlights Apathy measurement via questionnaires is limited by subjectivity biases. Apathy measurement via questionnaires is limited by simplistic scoring. We present a novel method for objective measurement of apathy. Gaze characteristics reflect the emotional and cognitive components of apathy.

The force of gravity critically impacts locomotion regulation while walking on inclined surfaces. To construct an updated assessment about the gravitational consequences and change gait patterns accordingly, the central nervous system (CNS) integrates multiple sensorial cues, including vestibular and proprioceptive (i.e., body-based cues) and visual. Not much is known about the contribution of the autonomic nervous system (ANS) to locomotion regulation, especially when multiple types of sensorial cues are involved. Here we examine the responsiveness of the ANS, as reflected by cardiac reactivity, for example heart rate (HR) and heart rate variability (HRV), to coherent versus non-coherent sensorimotor signaling. Fourteen healthy young participants completed level, uphill, and downhill self-paced walking trials in a virtual reality (VR) environment in which the incline of the visual scene was either congruent or incongruent with the physical incline of the walking surface. We found that during level walking, incongruent visual cues (i.e., up/downhill scenery) triggered alterations in ANS balance, reflected in HRV decrease and in a residual increase of HR. Taken together with the fact that an ultimate change in gait patterns requires alterations in cardiac resources, we speculate that ANS function and its responsive modes of action are, in fact, facilitating adaptive behavior.

Eye-tracking studies in virtual reality (VR) deliver insights into behavioral function. The gold standard of evaluating gaze behavior is based on manual scoring, which is labor-intensive. Previously proposed automated eye-tracking algorithms for VR head mount display (HMD) were not validated against manual scoring, or tested in dynamic areas of interest (AOIs). Our study validates the accuracy of an automated scoring algorithm, which determines temporal fixation behavior on static and dynamic AOIs in VR, against subjective human annotation. The interclass-correlation coefficient (ICC) was calculated for the time of first fixation (TOFF) and total fixation duration (TFD), in ten participants, each presented with 36 static and dynamic AOIs. High ICC values (≥0.982; p < 0.0001) were obtained when comparing the algorithm-generated TOFF and TFD to the raters’ annotations. In sum, our algorithm is accurate in determining temporal parameters related to gaze behavior when using HMD-based VR. Thus, the significant time required for human scoring among numerous raters can be rendered obsolete with a reliable automated scoring system. The algorithm proposed here was designed to sub-serve a separate study that uses TOFF and TFD to differentiate apathy from depression in those suffering from Alzheimer’s dementia.

OBJECTIVES:To develop an objective method for assessing apathy by identifying behavioral clusters based on gaze behavior during an emotionally salient virtual reality (VR) task, and examine associations with apathy severity, cognition, and physiological reactivity. DESIGN:Cross-sectional observational study. SETTING:Memory clinic at a university-affiliated hospital. PARTICIPANTS:Eighty-five older adults (mean age 74 ± 5.7 years) with varying cognitive and affective profiles. MEASUREMENTS:Participants completed a naturalistic VR task presenting personalized positive images (e.g., grandchildren), aversive scenes, and neutral stimuli. Eye-tracking data were collected and clustered using unsupervised K-means based on time to first fixation, total fixation duration, and fixation variability. Apathy was assessed using the Lille Apathy Rating Scale (LARS), cognition via the Montreal Cognitive Assessment (MoCA), and depression with the Geriatric Depression Scale (GDS). Physiological reactivity (heart rate variability measured as root mean square of successive differences [RMSSD], galvanic skin response [GSR], respiration) was analyzed using linear mixed-effects models. RESULTS:Two gaze-based subgroups were identified: "Engagers" (n = 48) showed faster, more sustained, and less variable gaze behavior; "Nonengagers" (n = 37) exhibited delayed and more variable gaze responses. Nonengagers were older, had lower MoCA scores, and higher apathy levels. RMSSD was lower overall in nonengagers but increased selectively in response to positive stimuli (grandchildren images). No group differences emerged in GSR or respiration. CONCLUSIONS:Unsupervised clustering of gaze behavior revealed ecologically valid apathy subtypes, linked to cognition and selective RMSSD reactivity. VR-based gaze metrics may offer a scalable, objective tool for detecting motivational impairments in aging.

Hand(s)-tapping tasks have been extensively studied in order to characterize the features of sensorimotor synchronization (SMS). These tasks frequently require participants to synchronize their tapping pace to an external, metronome-like sound. The impact of ageing on SMS abilities remains mainly unexplored. Thus, we conducted a series of hand tapping tasks on 15 young adults (YA) and 15 older adults (OA). The tasks included tapping with the dominant hand only (D), with the non-dominant hand only (ND), with both hands simultaneously (SIM), and alternating between the hands (ALT). Participants in each task performed a synchronization-continuation task, in which they had to tap for one minute according to an external sound set at their spontaneous motor tempo (separately identified), and then, after the sound stopped, continue tapping at the same tempo for another minute. Results indicated a set of preserved and degraded tapping behaviors in OA compared to YA. The ALT task produced the most deteriorated tapping performance, followed by the ND task; the other two tasks revealed no difference between the groups. These findings shed more light on how SMS declines across the lifespan and provide some preliminary but important information that may guide rehabilitation and diagnostic procedures.

Importance Apathy is a common and disabling syndrome in aging and neurodegenerative disease. Existing assessment tools rely on subjective reporting, limiting their accuracy in cognitively impaired individuals or in individuals with otherwise impaired insight. Objective To identify behavioral subgroups relevant to apathy using gaze-based metrics in an emotionally salient virtual reality (VR) setting, and to characterize their clinical and physiological profiles. Design, Setting, and Participants Cross-sectional study of 85 older adults (mean age 74 -+ 5.7 years) with varying cognitive abilities, recruited from a memory clinic. Participants completed a naturalistic VR task while gaze and physiological signals were recorded. Exposures Positive, aversive, and neutral images were presented within a 3D VR environment. Gaze features included time to first fixation, total fixation duration, and fixation variability. Physiological signals included heart rate variability (HRV), galvanic skin response, and respiration. Main Outcomes and Measures Unsupervised clustering (K-means) was applied to gaze metrics to derive behavioral engagement profiles. Between-group differences in apathy severity (LARS), cognitive function (MoCA), and physiological reactivity were examined using linear mixed-effects models. Results Two distinct behavioral subgroups emerged: engagers (n = 48) and non-engagers (n = 37). Non-engagers were older, showed higher apathy scores, and had lower MoCA scores. Physiologically, they exhibited lower baseline HRV but showed a selective increase in HRV during exposure to positive stimuli. No group differences were observed in response to aversive stimuli or in other physiological signals. Conclusions and Relevance This study introduces a novel, nonverbal approach for identifying apathy through naturalistic gaze behavior in VR. The findings highlight a physiologically responsive yet behaviorally disengaged subgroup, suggesting that emotional reactivity may persist even when outward engagement is diminished. Gaze-based phenotyping in immersive environments may offer a scalable tool for detecting motivational impairments in aging and can be further tested in individuals with poor insight to inform future personalized assessment strategies ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This study was funded by the Alzheimer's Disease Discovery Foundation (ADDF)- grant number 201906 and by Tel Aviv University Brecher Banner and Ofer Mordechai grants   ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study did not use openly available human data. All data were collected under institutional IRB approval (Sheba Medical Center, IRB #4436-17), and contain identifiable behavioral and physiological information. Due to ethical and privacy restrictions, the data are not publicly available. However, access to de-identified, encrypted datasets may be considered upon reasonable request and subject to approval by the corresponding author and institutional ethics board. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

Unconscious processing has been widely examined using diverse and well-controlled methodologies. However, the extent to which these findings are relevant to real-life instances of information processing without awareness is limited. Here, we present a novel inattentional blindness (IB) paradigm in virtual reality (VR). In three experiments, we managed to repeatedly induce IB while participants foveally viewed salient stimuli for prolonged durations. The effectiveness of this paradigm demonstrates the close relationship between top-down attention and subjective experience. Thus, this method provides an ecologically valid setup to examine processing without awareness.

The Rey Auditory Verbal Learning Test (RAVLT) is a commonly used tool for evaluating verbal learning and memory in neuropsychological assessments. In recent years, we developed a Virtual Reality (VR) adaptation of the RAVLT (VR-RVLT), aiming for increased ecological validity compared to the traditional pen and paper gold standard (GS-RAVLT). Following validation in healthy cohorts, the VR-RAVLT was validated with thirty individuals with Parkinson's Disease (PD) that completed both the GS-RAVLT and the VR- RAVLT. Validity of the VR-RAVLT was evaluated by assessing its construct and discriminant validity, and test-retest reliability, in comparison to the GS-RAVLT. Results of the PD participants were compared to those of 46 previously recruited healthy participants with comparable age and level of education. Main outcome measures derived from the remembered items on the test lists, exhibited significant and comparable correlations between VR-RAVLT and GS-RAVLT, both among healthy participants and PD participants. Likewise, serial position effects were similar for both formats amog the PD participants. Additionally, both formats showed similar discriminatory ability between healthy controls and PD participants, as well as comparable test-retest reliability measures. Taken together, the results suggest that the VR-based RAVLT is equally effective in measuring verbal memory capabilities in individuals with PD as compared to the GS-RAVLT. Certain results indicate that the virtual reality version has the capability to encompass additional factors that might impact memory performance, thereby suggesting an enhanced ecological validity.

Movement deterioration is the hallmark of Parkinson’s disease (PD), characterized by levodopa-induced motor-fluctuations (i.e., symptoms’ variability related to the medication cycle) in advanced stages. However, motor symptoms are typically too sporadically and/or subjectively assessed, ultimately preventing the effective monitoring of their progression, and thus leading to suboptimal treatment/therapeutic choices. Smartwatches (SW) enable a quantitative-oriented approach to motor-symptoms evaluation, namely home-based monitoring (HBM) using an embedded inertial measurement unit. Studies validated such approach against in-clinic evaluations. In this work, we aimed at delineating personalized motor-fluctuations’ profiles, thus capturing individual differences. 21 advanced PD patients with motor fluctuations were monitored for 2 weeks using a SW and a smartphone-dedicated app (Intel Pharma Analytics Platform). The SW continuously collected passive data (tremor, dyskinesia, level of activity using dedicated algorithms) and active data, i.e., time-up-and-go, finger tapping, hand tremor and hand rotation carried out daily, once in OFF and once in ON levodopa periods. We observed overall high compliance with the protocol. Furthermore, we observed striking differences among the individual patterns of symptoms’ levodopa-related variations across the HBM, allowing to divide our participants among four data-driven, motor-fluctuations’ profiles. This highlights the potential of HBM using SW technology for revolutionizing clinical practices.

Bipedal locomotion requires body adaptation to maintain stability after encountering a transition to incline walking. A major part of this adaptation is reflected by adjusting walking speed. When transitioning to uphill walking, people exert more energy to counteract gravitational forces pulling them backward, while when transitioning to downhill walking people break to avoid uncontrolled acceleration. These behaviors are affected by body-based (proprioception and vestibular) cues as well as by visual cues. Since older age adversely affects walking, it is unclear whether older adults rely on vision during locomotion in a similar manner to younger individuals. In this study, we tested whether the influence of visual cues on these walking speed modulations in healthy older adults (60-75 years old, N = 15) were comparable to those found in healthy young adults (20-40 years old, N = 12). Using a fully immersive virtual-reality system embedded with a self-paced treadmill and projected visual scene, we manipulated the inclinations of both the treadmill and the visual scene in an independent manner, and measured participants walking speed. In addition, we also measured individual visual field dependency using the rod and frame test. The older adults presented the expected braking (decelerating) and exertion (accelerating) effects, in response to downhill and uphill visual illusions, respectively, in a similar manner to the young group. Furthermore, we found a significant correlation between the magnitude of walking speed modulation and visual field dependency in each of the groups with significantly higher visual field dependency in older adults. These results suggest that with aging individuals maintain their reliance on the visual system to modulate their gait in accordance with surface inclination in a manner similar to that of younger adults.

Soldiers, athletes, and rescue personnel must often maintain cognitive focus while performing intense, prolonged, and physically demanding activities. The simultaneous activation of cognitive and physical functions can disrupt their performance reciprocally. In the current study, we developed and demonstrated the feasibility of a virtual reality (VR)-based experimental protocol that enables rigorous exploration of the effects of prolonged physical and cognitive efforts. A battery of established neurocognitive tests was used to compare novel cognitive tasks to simulated loaded marches. We simulated a 10-km loaded march in our virtual reality environment, with or without integrated cognitive tasks (VR-COG). During three experimental visits, participants were evaluated pre- and post-activity, including the Color Trail Test (CTT), the Synthetic Work Environment (SYNWIN) battery for assessing multitasking, and physical tests (i.e., time to exhaustion). Results show that Strong or moderate correlations (r ≥ 0.58, p ≤ 0.05) were found between VR-COG scores and scores on the cognitive tests. Both the SYNWIN and CTT showed no condition effects but significant time effects, indicating better performance in the post-activity assessment than in the pre-activity assessment. This novel protocol can contribute to our understanding of physical-cognitive interactions, since virtual environments are ideal for studying high performance professional activity in realistic but controlled settings.

Parkinson's Disease (PD)-typical declines in gait coordination are possibly explained by weakness in bilateral cortical and muscular connectivity. Here, we seek to determine whether this weakness and consequent decline in gait coordination is affected by dopamine levels. To this end, we compare cortico-cortical, cortico-muscular, and intermuscular connectivity and gait outcomes between body sides in people with PD under ON and OFF medication states, and in older adults. In our study, participants walked back and forth along a 12 m corridor. Gait events (heel strikes and toe-offs) and electrical cortical and muscular activities were measured and used to compute cortico-cortical, cortico-muscular, and intermuscular connectivity (i.e., coherences in the alpha, beta, and gamma bands), as well as features characterizing gait performance (e.g., the step-timing coordination, length, and speed). We observe that people with PD, mainly during the OFF medication, walk with reduced step-timing coordination. Additionally, our results suggest that dopamine intake in PD increases the overall cortico-muscular connectivity during the stance and swing phases of gait. We thus conclude that dopamine corrects defective feedback caused by impaired sensory-information processing and sensory-motor integration, thus increasing cortico-muscular coherences in the alpha bands and improving gait. In Parkinson's disease, dopamine intake strengthens cortico-muscular connectivity, enhancing step-timing gait coordination, probably due to sensory-motor integration improvement.

Coordinated movement of four limbs is a hallmark of healthy locomotion. No measures exist to quantify four-limb coordination. This study aimed to investigate temporal four-limb coordination and proposed a new metric for quantifying the inter-limb phase of rhythmic locomotion-related movements. Kinetic data of arm and leg movements generated during walking (self-selected speed) from healthy adults were used to extract the phases (φ) between all possible limb pairings. The φ series were used to calculate each pair’s Phase Coordination Index (PCI). The PCI quantifies the accuracy and consistency of generating anti-phased rhythmic movements (lower PCI values mean better coordination). We also calculated the Quadruple-PCI (Q-PCI) by combining all φ values of all limb pairs. We found a significant correlation between the PCI values of all limb pairings and the Q-PCI (pairs involving arms: Pearson’s R > 0.79, p < 0.001; leg–leg: Pearson’s R = 0.3, p < 0.01). The PCI values that involve arms (median values between 6.5% and 8.3%) were significantly higher than the leg–leg PCI (median values between 3.8% and 4.1%), and the Q-PCI (median values between 8.3% and 9.7%) was significantly higher than all other PCI values. We also found a negative correlation between the arm swing amplitude and the PCI values (Spearman’s Rho of different limb pairings ranging from −0.25 to −0.5, p < 0.05), suggesting that higher arm swing amplitude leads to better coordination. Four-limb coordination analysis is a novel method for comprehensive assessment of gait coordination, which is often compromised among persons with disabilities.

We aimed to develop a tool for objective measurement of apathy and its differentiation from depression in the context of cognitive impairment. We exposed older adults with and without cognitive impairment (CI and CN, respectively) to emotional (i.e., positive), aversive and neutral, and to cognitive (congruent; incongruent) stimuli in a virtual reality environment and measured their physiological reactivity as reflected by autonomic nervous system (ANS) functions [heart rate (HR), heart rate variability (HRV), respiration and galvanic skin response (GSR)], and gaze [time to gaze fixation (TTGF) and total fixation duration (TFD)]. Apathy and depression were measured via the Lille Apathy Rating Scale (LARS)- and the Geriatric Depression Scale (GDS), respectively. Participants' characteristics are presented in Tables 1-2. Compared to CN, CI participants had lower TFD (ANOAVE: F = 7.471, P = 0.006) and GSR reactivity (F = 6.334, P = 0.014) in response to all stimuli. Among participants with CI, those with apathy (LARS score ≥-7) (n = 21) had shorter TFD compared to those without apathy (F = 19.259, P = 0.001), and those with depression (GDS score ≥5) (n = 46) had longer TFD compared to those without depression ((F = 33.118, P = 0.001) to all stimuli. For all participants, presence of apathy was associated with lower TFD (F = 13.807, P = 0.001) higher TTGF (F = 10.819, P = 0.001), lower HRV reactivity (F = 4.089, P = 0.043) and respiration depth reactivity (F = 8.026, P = 0.005) in response to all stimuli. In contrast, depression was associated with higher TFD (F = 8.448, P = 0.004), lower TTGF (F = 5.290, P = 0.022) and higher HRV reactivity (F = 5.171, P = 0.023) to all stimuli. Increasing LARS scores were negatively associated with respiration rate (R = -0.223, P = 0.025) and TFD (R = -0.253, P = 0.021) in response to positive emotional stimuli, and with TFD in response to congruent (R = -0.265, P = 0.016) and incongruent (R = -0.247, P = 0.024) cognitive stimuli. GDS scores were positively associated with HR (R = 0.219, P = 0.049; R = 0.217, P = 0.05 respectively) and respiration depth (R = 0.216, P = 0.048; R = 0.252, P = 0.021 respectively) reactivity to positive and aversive emotional stimuli. ANS and gaze reactivity to emotional and cognitive stimuli presented in a VR environment is sensitive to cognitive status and to apathy, even in subtle forms. Moreover, this tool can potentially differentiate apathy from depression in the context of cognitive impairment.