Anteromedial thalamus gates the selection and stabilization of long-term memories.

Memories initially formed in hippocampus gradually stabilize to cortex over weeks-to-months for long-term storage. The mechanistic details of this brain re-organization remain poorly understood. We recorded bulk neural activity in circuits that link hippocampus and cortex as mice performed a memory-guided virtual-reality task over weeks. We identified a prominent and sustained neural correlate of memory in anterior thalamus, whose inhibition substantially disrupted memory consolidation. More strikingly, gain amplification enhanced consolidation of otherwise unconsolidated memories. To gain mechanistic insights, we developed a technology for simultaneous cellular-resolution imaging of hippocampus, thalamus, and cortex throughout consolidation. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus preferentially encodes salient memories, and gradually increases correlations with cortex to facilitate tuning and synchronization of cortical ensembles. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer-term cortical storage.

A tridimensional atlas of the developing human head.

The evolution and development of the head have long captivated researchers due to the crucial role of the head as the gateway for sensory stimuli and the intricate structural complexity of the head. Although significant progress has been made in understanding head development in various vertebrate species, our knowledge of early human head ontogeny remains limited. Here, we used advanced whole-mount immunostaining and 3D imaging techniques to generate a comprehensive 3D cellular atlas of human head embryogenesis. We present detailed developmental series of diverse head tissues and cell types, including muscles, vasculature, cartilage, peripheral nerves, and exocrine glands. These datasets, accessible through a dedicated web interface, provide insights into human embryogenesis. We offer perspectives on the branching morphogenesis of human exocrine glands and unknown features of the development of neurovascular and skeletomuscular structures. These insights into human embryology have important implications for understanding craniofacial defects and neurological disorders and advancing diagnostic and therapeutic strategies.

Targeted Activation of Hippocampal Place Cells Drives Memory-Guided Spatial Behavior.

The hippocampus is crucial for spatial navigation and episodic memory formation. Hippocampal place cells exhibit spatially selective activity within an environment and have been proposed to form the neural basis of a cognitive map of space that supports these mnemonic functions. However, the direct influence of place cell activity on spatial navigation behavior has not yet been demonstrated. Using an 'all-optical' combination of simultaneous two-photon calcium imaging and two-photon optogenetics, we identified and selectively activated place cells that encoded behaviorally relevant locations in a virtual reality environment. Targeted stimulation of a small number of place cells was sufficient to bias the behavior of animals during a spatial memory task, providing causal evidence that hippocampal place cells actively support spatial navigation and memory.

A Map-like Micro-Organization of Grid Cells in the Medial Entorhinal Cortex.

How the topography of neural circuits relates to their function remains unclear. Although topographic maps exist for sensory and motor variables, they are rarely observed for cognitive variables. Using calcium imaging during virtual navigation, we investigated the relationship between the anatomical organization and functional properties of grid cells, which represent a cognitive code for location during navigation. We found a substantial degree of grid cell micro-organization in mouse medial entorhinal cortex: grid cells and modules all clustered anatomically. Within a module, the layout of grid cells was a noisy two-dimensional lattice in which the anatomical distribution of grid cells largely matched their spatial tuning phases. This micro-arrangement of phases demonstrates the existence of a topographical map encoding a cognitive variable in rodents. It contributes to a foundation for evaluating circuit models of the grid cell network and is consistent with continuous attractor models as the mechanism of grid formation.

Dynamic Reorganization of Neuronal Activity Patterns in Parietal Cortex.

Neuronal representations change as associations are learned between sensory stimuli and behavioral actions. However, it is poorly understood whether representations for learned associations stabilize in cortical association areas or continue to change following learning. We tracked the activity of posterior parietal cortex neurons for a month as mice stably performed a virtual-navigation task. The relationship between cells' activity and task features was mostly stable on single days but underwent major reorganization over weeks. The neurons informative about task features (trial type and maze locations) changed across days. Despite changes in individual cells, the population activity had statistically similar properties each day and stable information for over a week. As mice learned additional associations, new activity patterns emerged in the neurons used for existing representations without greatly affecting the rate of change of these representations. We propose that dynamic neuronal activity patterns could balance plasticity for learning and stability for memory.

Observing heroic behavior and its influencing factors in immersive virtual environments.

Studying heroism in controlled settings presents challenges and ethical controversies due to its association with physical risk. Leveraging virtual reality (VR) technology, we conducted a three-study series with 397 participants from China to investigate heroic actions. Participants unexpectedly witnessed a criminal event in a simulated scenario, allowing observation of their tendency to physically intercept a thief. We examined situational factors (voluntariness, authority, and risk) and personal variables [gender, impulsivity, empathy, and social value orientation (SVO)] that may influence heroism. Also, the potential association between heroism and social conformity was explored. In terms of situational variables, voluntariness modulated participants' tendency to intercept the escaping thief, while perceived risk demonstrated its impact by interacting with gender. That is, in study 3 where the perceived risk was expected to be higher (as supported by an online study 5), males exhibited a greater inclination toward heroic behavior compared to females. Regarding other personal variables, the tendency to engage in heroic behavior decreased as empathy levels rose among males, whereas the opposite trend was observed for females. SVO influenced heroic behavior but without a gender interaction. Finally, an inverse relationship between heroism and social conformity was observed. The robustness of these findings was partly supported by the Chinese sample (but not the international sample) of an online study 4 that provided written descriptions of VR scenarios, indicating cultural variations. These results advance insights into motivational factors influencing heroism in the context of restoring order and highlight the power of VR technology in examining social psychological hypotheses beyond ethical constraints.

Changes in spatial self-consciousness elicit grid cell-like representation in the entorhinal cortex.

Grid cells in the entorhinal cortex (EC) encode an individual's location in space, integrating both environmental and multisensory bodily cues. Notably, body-derived signals are also primary signals for the sense of self. While studies have demonstrated that continuous application of visuo-tactile bodily stimuli can induce perceptual shifts in self-location, it remains unexplored whether these illusory changes suffice to trigger grid cell-like representation (GCLR) within the EC, and how this compares to GCLR during conventional virtual navigation. To address this, we systematically induced illusory drifts in self-location toward controlled directions using visuo-tactile bodily stimulation, while maintaining the subjects' visual viewpoint fixed (absent conventional virtual navigation). Subsequently, we evaluated the corresponding GCLR in the EC through functional MRI analysis. Our results reveal that illusory changes in perceived self-location (independent of changes in environmental navigation cues) can indeed evoke entorhinal GCLR, correlating in strength with the magnitude of perceived self-location, and characterized by similar grid orientation as during conventional virtual navigation in the same virtual room. These data demonstrate that the same grid-like representation is recruited when navigating based on environmental, mainly visual cues, or when experiencing illusory forward drifts in self-location, driven by perceptual multisensory bodily cues.

Skin-integrated systems for power efficient, programmable thermal sensations across large body areas.

Thermal sensations contribute to our ability to perceive and explore the physical world. Reproducing these sensations in a spatiotemporally programmable manner through wireless computer control could enhance virtual experiences beyond those supported by video, audio and, increasingly, haptic inputs. Flexible, lightweight and thin devices that deliver patterns of thermal stimulation across large areas of the skin at any location of the body are of great interest in this context. Applications range from those in gaming and remote socioemotional communications, to medical therapies and physical rehabilitation. Here, we present a set of ideas that form the foundations of a skin-integrated technology for power-efficient generation of thermal sensations across the skin, with real-time, closed-loop control. The systems exploit passive cooling mechanisms, actively switchable thermal barrier interfaces, thin resistive heaters and flexible electronics configured in a pixelated layout with wireless interfaces to portable devices, the internet and cloud data infrastructure. Systematic experimental studies and simulation results explore the essential mechanisms and guide the selection of optimized choices in design. Demonstration examples with human subjects feature active thermoregulation, virtual social interactions, and sensory expansion.

Architectural experience influences the processing of others' body expressions.

The interplay between space and cognition is a crucial issue in Neuroscience leading to the development of multiple research fields. However, the relationship between architectural space and the movement of the inhabitants and their interactions has been too often neglected, failing to provide a unifying view of architecture's capacity to modulate social cognition broadly. We bridge this gap by requesting participants to judge avatars' emotional expression (high vs. low arousal) at the end of their promenade inside high- or low-arousing architectures. Stimuli were presented in virtual reality to ensure a dynamic, naturalistic experience. High-density electroencephalography (EEG) was recorded to assess the neural responses to the avatar's presentation. Observing highly aroused avatars increased Late Positive Potentials (LPP), in line with previous evidence. Strikingly, 250 ms before the occurrence of the LPP, P200 amplitude increased due to the experience of low-arousing architectures, reflecting an early greater attention during the processing of body expressions. In addition, participants stared longer at the avatar's head and judged the observed posture as more arousing. Source localization highlighted a contribution of the dorsal premotor cortex to both P200 and LPP. In conclusion, the immersive and dynamic architectural experience modulates human social cognition. In addition, the motor system plays a role in processing architecture and body expressions suggesting that the space and social cognition interplay is rooted in overlapping neural substrates. This study demonstrates that the manipulation of mere architectural space is sufficient to influence human social cognition.

Neural correlates of an illusionary sense of agency caused by virtual reality.

Sense of agency (SoA) is the sensation that self-actions lead to ensuing perceptual consequences. The prospective mechanism emphasizes that SoA arises from motor prediction and its comparison with actual action outcomes, while the reconstructive mechanism stresses that SoA emerges from retrospective causal processing about the action outcomes. Consistent with the prospective mechanism, motor planning regions were identified by neuroimaging studies using the temporal binding (TB) effect, a behavioral measure often linked to implicit SoA. Yet, TB also occurs during passive observation of another's action, lending support to the reconstructive mechanism, but its neural correlates remain unexplored. Here, we employed virtual reality (VR) to modulate such observation-based SoA and examined it with functional magnetic resonance imaging (fMRI). After manipulating an avatar hand in VR, participants passively observed an avatar's "action" and showed a significant increase in TB. The binding effect was associated with the right angular gyrus and inferior parietal lobule, which are critical nodes for inferential and agency processing. These results suggest that the experience of controlling an avatar may potentiate inferential processing within the right inferior parietal cortex and give rise to the illusionary SoA without voluntary action.

Real-time visualization of mRNA synthesis during memory formation in live mice.

Memories are thought to be encoded in populations of neurons called memory trace or engram cells. However, little is known about the dynamics of these cells because of the difficulty in real-time monitoring of them over long periods of time in vivo. To overcome this limitation, we present a genetically encoded RNA indicator (GERI) mouse for intravital chronic imaging of endogenous Arc messenger RNA (mRNA)-a popular marker for memory trace cells. We used our GERI to identify Arc-positive neurons in real time without the delay associated with reporter protein expression in conventional approaches. We found that the Arc-positive neuronal populations rapidly turned over within 2 d in the hippocampal CA1 region, whereas ∼4% of neurons in the retrosplenial cortex consistently expressed Arc following contextual fear conditioning and repeated memory retrievals. Dual imaging of GERI and a calcium indicator in CA1 of mice navigating a virtual reality environment revealed that only the population of neurons expressing Arc during both encoding and retrieval exhibited relatively high calcium activity in a context-specific manner. This in vivo RNA-imaging approach opens the possibility of unraveling the dynamics of the neuronal population underlying various learning and memory processes.

Scene Perception and Visuospatial Memory Converge at the Anterior Edge of Visually Responsive Cortex.

To fluidly engage with the world, our brains must simultaneously represent both the scene in front of us and our memory of the immediate surrounding environment (i.e., local visuospatial context). How does the brain's functional architecture enable sensory and mnemonic representations to closely interface while also avoiding sensory-mnemonic interference? Here, we asked this question using first-person, head-mounted virtual reality and fMRI. Using virtual reality, human participants of both sexes learned a set of immersive, real-world visuospatial environments in which we systematically manipulated the extent of visuospatial context associated with a scene image in memory across three learning conditions, spanning from a single FOV to a city street. We used individualized, within-subject fMRI to determine which brain areas support memory of the visuospatial context associated with a scene during recall (Experiment 1) and recognition (Experiment 2). Across the whole brain, activity in three patches of cortex was modulated by the amount of known visuospatial context, each located immediately anterior to one of the three scene perception areas of high-level visual cortex. Individual subject analyses revealed that these anterior patches corresponded to three functionally defined place memory areas, which selectively respond when visually recalling personally familiar places. In addition to showing activity levels that were modulated by the amount of visuospatial context, multivariate analyses showed that these anterior areas represented the identity of the specific environment being recalled. Together, these results suggest a convergence zone for scene perception and memory of the local visuospatial context at the anterior edge of high-level visual cortex.SIGNIFICANCE STATEMENT As we move through the world, the visual scene around us is integrated with our memory of the wider visuospatial context. Here, we sought to understand how the functional architecture of the brain enables coexisting representations of the current visual scene and memory of the surrounding environment. Using a combination of immersive virtual reality and fMRI, we show that memory of visuospatial context outside the current FOV is represented in a distinct set of brain areas immediately anterior and adjacent to the perceptually oriented scene-selective areas of high-level visual cortex. This functional architecture would allow efficient interaction between immediately adjacent mnemonic and perceptual areas while also minimizing interference between mnemonic and perceptual representations.

Re-Imagining Hospital Patient Room Design for People After stroke: A Randomized Controlled Study Using Virtual Reality.

BACKGROUND: The hospital's physical environment can impact health and well-being. Patients spend most of their time in their hospital rooms. However, little experimental evidence supports specific physical design variables in these rooms, particularly for people poststroke. The study aimed to explore the influence of patient room design variables modeled in virtual reality using a controlled experimental design. METHODS: Adults within 3 years of stroke who had spent >2 nights in hospital for stroke and were able to consent were included (Melbourne, Australia). Using a factorial design, we immersed participants in 16 different virtual hospital patient rooms in both daytime and nighttime conditions, systematically varying design attributes: patient room occupancy, social connectivity, room size (spaciousness), noise (nighttime), greenery outlook (daytime). While immersed, participants rated their affect (Pick-A-Mood Scale) and preference. Mixed-effect regression analyses were used to explore participant responses to design variables in both daytime and nighttime conditions. Feasibility and safety were monitored throughout. Australian New Zealand Clinical Trials Registry, Trial ID: ACTRN12620000375954. RESULTS: Forty-four adults (median age, 67 [interquartile range, 57.3-73.8] years, 61.4% male, and a third with stroke in the prior 3-6 months) completed the study in 2019-2020. We recorded and analyzed 701 observations of affective responses (Pick-A-Mood Scale) in the daytime (686 at night) and 698 observations of preference responses in the daytime (685 nighttime) while continuously immersed in the virtual reality scenarios. Although single rooms were most preferred overall (daytime and nighttime), the relationship between affective responses differed in response to different combinations of nighttime noise, social connectivity, and greenery outlook (daytime). The virtual reality scenario intervention was feasible and safe for stroke participants. CONCLUSIONS: Immediate affective responses can be influenced by exposure to physical design variables other than room occupancy alone. Virtual reality testing of how the physical environment influences patient responses and, ultimately, outcomes could inform how we design new interventions for people recovering after stroke. REGISTRATION: URL: https://anzctr.org.au; Unique identifier: ACTRN12620000375954.

Enhancing learning outcomes through multisensory integration: A fMRI study of audio-visual training in virtual reality.

The integration of information from different sensory modalities is a fundamental process that enhances perception and performance in real and virtual environments (VR). Understanding these mechanisms, especially during learning tasks that exploit novel multisensory cue combinations provides opportunities for the development of new rehabilitative interventions. This study aimed to investigate how functional brain changes support behavioural performance improvements during an audio-visual (AV) learning task. Twenty healthy participants underwent a 30 min daily VR training for four weeks. The task was an AV adaptation of a 'scanning training' paradigm that is commonly used in hemianopia rehabilitation. Functional magnetic resonance imaging (fMRI) and performance data were collected at baseline, after two and four weeks of training, and four weeks post-training. We show that behavioural performance, operationalised as mean reaction time reduction in VR, significantly improves. In separate tests in a controlled laboratory environment, we showed that the behavioural performance gains in the VR training environment transferred to a significant mean RT reduction for the trained AV voluntary task on a computer screen. Enhancements were observed in both the visual-only and AV conditions, with the latter demonstrating a faster response time supported by the presence of audio cues. The behavioural learning effect also transfers to two additional tasks that were tested: a visual search task and an involuntary visual task. Our fMRI results reveal an increase in functional activation (BOLD signal) in multisensory brain regions involved in early-stage AV processing: the thalamus, the caudal inferior parietal lobe and cerebellum. These functional changes were only observed for the trained, multisensory, task and not for unimodal visual stimulation. Functional activation changes in the thalamus were significantly correlated to behavioural performance improvements. This study demonstrates that incorporating spatial auditory cues to voluntary visual training in VR leads to augmented brain activation changes in multisensory integration, resulting in measurable performance gains across tasks. The findings highlight the potential of VR-based multisensory training as an effective method for enhancing cognitive function and as a potentially valuable tool in rehabilitative programmes.

Virtual reality for pain management in hospitalized patients with cancer: A randomized controlled trial.

BACKGROUND: Hospitalized patients with cancer often experience acute and/or chronic pain. Although virtual reality (VR) has been extensively studied across a wide range of clinical settings, no studies have yet evaluated potential impact on pain management in this patient population. METHODS: Prospective randomized controlled trial at an urban academic hospital comparing VR against an active control to mitigate moderate-severe cancer disease and treatment-related pain. RESULTS: A total of 128 adult hospitalized patients with cancer (any tumor type) were randomized to 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy delivered by handheld tablet. Participants in the two arms were similar in age, sex, race, presence of metastatic disease, concurrent pain specialist consultation, and baseline opioid use. Although both groups experienced improved self-reported pain scores (primary outcome), those randomized to VR experienced significantly greater reduction in pain immediately after intervention compared with active control (p = .03). This difference was sustained for 24 hours as well (p = .004). Within-group analysis showed significant improvement in VR arm of pain bothersomeness (p = .05) and general distress (p = .03) as well. CONCLUSION: Among hospitalized adult patients with moderate-severe pain related to cancer and cancer therapies, VR provided more nonpharmacologic pain relief than active control and this benefit sustained long after conclusion of the intervention. PLAIN LANGUAGE SUMMARY: Virtual reality (VR), a developing technology that immerses the user in new environments, has been shown to improve pain in different patient populations. To test the role of VR in improving pain in hospitalized patients with cancer who report moderate-severe pain, we compared the impact of a 10-minute immersive VR intervention to that of a 10-minute two-dimensional guided imagery experience to improve self-reported pain scores. We found that, although both interventions improved pain, VR did so significantly more. Moreover, participants assigned to VR had sustained improvement in pain 24 hours later.

Neural sensitivity to translational self- and object-motion velocities.

The ability to detect and assess world-relative object-motion is a critical computation performed by the visual system. This computation, however, is greatly complicated by the observer's movements, which generate a global pattern of motion on the observer's retina. How the visual system implements this computation is poorly understood. Since we are potentially able to detect a moving object if its motion differs in velocity (or direction) from the expected optic flow generated by our own motion, here we manipulated the relative motion velocity between the observer and the object within a stationary scene as a strategy to test how the brain accomplishes object-motion detection. Specifically, we tested the neural sensitivity of brain regions that are known to respond to egomotion-compatible visual motion (i.e., egomotion areas: cingulate sulcus visual area, posterior cingulate sulcus area, posterior insular cortex [PIC], V6+, V3A, IPSmot/VIP, and MT+) to a combination of different velocities of visually induced translational self- and object-motion within a virtual scene while participants were instructed to detect object-motion. To this aim, we combined individual surface-based brain mapping, task-evoked activity by functional magnetic resonance imaging, and parametric and representational similarity analyses. We found that all the egomotion regions (except area PIC) responded to all the possible combinations of self- and object-motion and were modulated by the self-motion velocity. Interestingly, we found that, among all the egomotion areas, only MT+, V6+, and V3A were further modulated by object-motion velocities, hence reflecting their possible role in discriminating between distinct velocities of self- and object-motion. We suggest that these egomotion regions may be involved in the complex computation required for detecting scene-relative object-motion during self-motion.

Virtual reality as an engaging and enjoyable method for delivering emergency clinical simulation training: a prospective, interventional study of medical undergraduates.

BACKGROUND: It is a requirement that medical students are educated in emergencies and feel well prepared for practice as a doctor, yet national surveys show that many students feel underprepared. Virtual reality (VR), combined with 360-degree filming, provides an immersive, realistic, and interactive simulation experience. Unlike conventional in-person simulation, it is scalable with reduced workforce demands. We sought to compare students' engagement and enjoyment of VR simulation to desktop computer-based simulation. METHODS: We conducted a prospective, interventional, evaluation study. The study was carried out on final year medical students undertaking their Pre-Foundation Assistantship (n = 116) at Imperial College School of Medicine (ICSM) in London. We compared objective engagement, subjective engagement, and subjective enjoyment of VR simulation to desktop computer-based simulation using cardiac arrest and life-threatening asthma scenarios. Engagement was measured objectively using students' physiological parameters, including heart rate and eye tracking, and facilitator observations using the validated 'Behavioural Engagement Related to Instruction' (BERI) protocol. Students' subjective engagement and enjoyment levels were measured using a post-session survey. RESULTS: Students' maximum heart rates were significantly higher during VR simulation with a mean difference of 4.2 beats per minute (3.2 to 5.2, p < 0.001), and eye tracking showed they spent a significantly greater mean percentage of time of 6.4% (5.1 to 7.7, p < 0.001) focusing on the scenarios in VR compared to standard desktop. Qualitative data showed students enjoyed and felt engaged with the sessions, which provided a safe space for learning. CONCLUSIONS: Our study shows that students found VR simulations enjoyable and were more engaged compared to standard desktop simulation. This suggests that 360-degree VR simulation experiences provide students with immersive, realistic training, which is scalable, giving them the unique opportunity to manage emergencies and work within emergency teams, which would not typically occur during traditional training.

Efficacy of virtual reality for pain relief in medical procedures: a systematic review and meta-analysis.

BACKGROUND: Effective pain control is crucial to optimise the success of medical procedures. Immersive virtual reality (VR) technology could offer an effective non-invasive, non-pharmacological option to distract patients and reduce their experience of pain. We aimed to evaluate the efficacy of Immersive virtual reality (VR) technology in reducing patient's pain perception during various medical procedures by conducting a systematic review and meta-analysis. METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, and SIGLE until December 2022 for all randomised clinical trials (RCT) evaluating any type of VR in patients undergoing any medical procedure. We conducted a random effect meta-analysis summarising standardised mean differences (SMD) with 95% confidence intervals (CI). We evaluated heterogeneity using I 2 and explored it using subgroup and meta-regression analyses. RESULTS: In total, we included 92 RCTs (n = 7133 participants). There was a significant reduction in pain scores with VR across all medical procedures (n = 83, SMD - 0.78, 95% CI - 1.00 to - 0.57, I 2 = 93%, p = < 0.01). Subgroup analysis showed varied reduction in pain scores across trial designs [crossover (n = 13, SMD - 0.86, 95% CI - 1.23 to - 0.49, I 2 = 72%, p = < 0.01) vs parallel RCTs (n = 70, SMD - 0.77, 95% CI - 1.01 to - 0.52, I 2 = 90%, p = < 0.01)]; participant age groups [paediatric (n = 43, SMD - 0.91, 95% CI - 1.26 to - 0.56, I 2 = 87%, p = < 0.01) vs adults (n = 40, SMD - 0.66, 95% CI - 0.94 to - 0.39, I 2 = 89%, p = < 0.01)] or procedures [venepuncture (n = 32, SMD - 0.99, 95% CI - 1.52 to - 0.46, I 2 = 90%, p = < 0.01) vs childbirth (n = 7, SMD - 0.99, 95% CI - 1.59 to - 0.38, I 2 = 88%, p = < 0.01) vs minimally invasive medical procedures (n = 25, SMD - 0.51, 95% CI - 0.79 to - 0.23, I 2 = 85%, p = < 0.01) vs dressing changes in burn patients (n = 19, SMD - 0.8, 95% CI - 1.16 to - 0.45, I 2 = 87%, p = < 0.01)]. We explored heterogeneity using meta-regression which showed no significant impact of different covariates including crossover trials (p = 0.53), minimally invasive procedures (p = 0.37), and among paediatric participants (p = 0.27). Cumulative meta-analysis showed no change in overall effect estimates with the additional RCTs since 2018. CONCLUSIONS: Immersive VR technology offers effective pain control across various medical procedures, albeit statistical heterogeneity. Further research is needed to inform the safe adoption of this technology across different medical disciplines.

No pain relief by virtual reality during hysterosalpingography (HSG): results from a randomized controlled trial.

STUDY QUESTION: Is virtual reality (VR) an effective non-pharmacological tool to reduce procedural pain during hysterosalpingography (HSG)? SUMMARY ANSWER: An HSG with VR does not reduce procedural pain scores compared to an HSG without VR. WHAT IS KNOWN ALREADY: An HSG is often experienced as painful and uncomfortable. VR has been proven successful to reduce acute procedural pain during a variety of medical procedures and interventions. STUDY DESIGN, SIZE, DURATION: We performed a two-centre open-label randomized controlled trial between January 2021 and October 2022. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women scheduled for HSG as part of their infertility work-up were screened for participation. After informed consent, women were randomized between HSG with or without VR. Due to the nature of the intervention, the study was not blinded. VR was administered by a head-mounted device displaying nature movies and/or relaxation exercises. The primary endpoint was procedural pain measured using VAS (scale 0.0-10.0 cm). Procedural pain was divided into overall pain score and peak pain score during the procedure. It was measured immediately after HSG. Secondary endpoints included patient satisfaction, VR preferences, and adverse effects of VR. MAIN RESULTS AND THE ROLE OF CHANCE: We included a total of 134 women, 69 to the intervention group (HSG with VR) and 65 to the control group (HSG without VR). The mean VAS for peak pain was 6.80 cm (SD 2.25) in the intervention group versus 6.60 cm (SD 2.40) in the control group (mean difference 0.28 (95% CI -0.57, 1.12), P = 0.52). The mean VAS for overall pain was 5.00 cm (SD 2.10) in the intervention group versus 4.90 cm (SD 2.13) in the control group (mean difference 0.06 (95% CI -0.71, 0.84), P = 0.88). The expectation that VR would be a good distraction from pain during HSG was correlated with both overall and peak pain scores. When correcting for this expectation, we found that women in the intervention group reported significantly higher scores, both in peak (adjusted MD 0.58 (95% CI -0.81, 1.97), P = 0.021) and overall (adjusted MD 0.43 (95% CI -0.84, 1.71), P = 0.013) pain, compared to the control group. There were no differences in the prevalence of symptoms that were considered as adverse effects of VR. LIMITATIONS, REASONS FOR CAUTION: The study was not blinded. Reasons for declining participation in the study were anxiety or wanting full control during HSG, which might have created selection bias. The distraction score possibly indicates that the level of VR immersiveness was not optimal due to the lack of sound and/or the type of VR applications. Future studies should investigate whether more immersive or interactive VR applications could decrease procedural pain scores during HSG. WIDER IMPLICATIONS OF THE FINDINGS: Since VR does not reduce procedural pain, this additional tool should not be used during HSG. STUDY FUNDING/COMPETING INTEREST(S): There was no external funding for this study. KR and AvH report receiving a travel grant from Merck outside the scope of this study. BM is supported by a National Health and Medical Research Council (NHMRC) investigator grant (GNT1176437) and BM reports consultancy for Merck, Organon, and Norgine and travel and research funding from Merck. BM holds stock for ObsEva. CL reports receiving research grants from Merck, and Ferring. KD and VM report receiving travel and speaker's fees from Guerbet and research grants from Guerbet. VM also reports research grants from Merck and Ferring. The remaining authors have nothing to declare. TRIAL REGISTRATION NUMBER: The trial is registered prospectively in the Netherlands Trial Register (trialregister.nl registration number NL9203, currently accessible on trialsearch.who.int). TRIAL REGISTRATION DATE: 16-01-2021. DATE OF FIRST PATIENT'S ENROLMENT: The first participant was enrolled on 19 January 2021.

Morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic and fetal growth: the Rotterdam Periconception Cohort.

STUDY QUESTION: Is morphologic development of the first-trimester utero-placental vasculature associated with embryonic growth and development, fetal growth, and birth weight percentiles? SUMMARY ANSWER: Using the utero-placental vascular skeleton (uPVS) as a new imaging marker, this study reveals morphologic development of the first-trimester utero-placental vasculature is positively associated with embryonic growth and development, fetal growth, and birth weight percentiles. WHAT IS KNOWN ALREADY: First-trimester development of the utero-placental vasculature is associated with placental function, which subsequently impacts embryonic and fetal ability to reach their full growth potential. The attribution of morphologic variations in the utero-placental vascular development, including the vascular structure and branching density, on prenatal growth remains unknown. STUDY DESIGN, SIZE, DURATION: This study was conducted in the VIRTUAL Placental study, a subcohort of 214 ongoing pregnancies, embedded in the prospective observational Rotterdam Periconception Cohort (Predict study). Women were included before 10 weeks gestational age (GA) at a tertiary referral hospital in The Netherlands between January 2017 and March 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS: We obtained three-dimensional power Doppler volumes of the gestational sac including the embryo and the placenta at 7, 9, and 11 weeks of gestation. Virtual Reality-based segmentation and a recently developed skeletonization algorithm were applied to the power Doppler volumes to generate the uPVS and to measure utero-placental vascular volume (uPVV). Absolute vascular morphology was quantified by assigning a morphologic characteristic to each voxel in the uPVS (i.e. end-, bifurcation-crossing-, or vessel point). Additionally, total vascular length (mm) was calculated. The ratios of the uPVS characteristics to the uPVV were calculated to determine the density of vascular branching. Embryonic growth was estimated by crown-rump length and embryonic volume. Embryonic development was estimated by Carnegie stages. Fetal growth was measured by estimated fetal weight in the second and third trimester and birth weight percentiles. Linear mixed models were used to estimate trajectories of longitudinal measurements. Linear regression analysis with adjustments for confounders was used to evaluate associations between trajectories of the uPVS and prenatal growth. Groups were stratified for conception method (natural/IVF-ICSI conceptions), fetal sex (male/female), and the occurrence of placenta-related complications (yes/no). MAIN RESULTS AND THE ROLE OF CHANCE: Increased absolute vascular morphologic development, estimated by positive random intercepts of the uPVS characteristics, is associated with increased embryonic growth, reflected by crown-rump length (endpoints ß = 0.017, 95% CI [0.009; 0.025], bifurcation points ß = 0.012, 95% CI [0.006; 0.018], crossing points ß = 0.017, 95% CI [0.008; 0.025], vessel points ß = 0.01, 95% CI [0.002; 0.008], and total vascular length ß = 0.007, 95% CI [0.003; 0.010], and similarly with embryonic volume and Carnegie stage, all P-values ≤ 0.01. Density of vascular branching was negatively associated with estimated fetal weight in the third trimester (endpoints: uPVV ß = -94.972, 95% CI [-185.245; -3.698], bifurcation points: uPVV ß = -192.601 95% CI [-360.532; -24.670]) and birth weight percentiles (endpoints: uPVV ß = -20.727, 95% CI [-32.771; -8.683], bifurcation points: uPVV ß -51.097 95% CI [-72.257; -29.937], and crossing points: uPVV ß = -48.604 95% CI [-74.246; -22.961])), all P-values < 0.05. After stratification, the associations were observed in natural conceptions specifically. LIMITATION, REASONS FOR CAUTION: Although the results of this prospective observational study clearly demonstrate associations between first-trimester utero-placental vascular morphologic development and prenatal growth, further research is required before we can draw firm conclusions about a causal relationship. WIDER IMPLICATIONS OF THE FINDINGS: Our findings support the hypothesis that morphologic variations in utero-placental vascular development play a role in the vascular mechanisms involved in embryonic and fetal growth and development. Application of the uPVS could benefit our understanding of the pathophysiology underlying placenta-related complications. Future research should focus on the clinical applicability of the uPVS as an imaging marker for the early detection of fetal growth restriction. STUDY FUNDING/COMPETING INTEREST(S): This research was funded by the Department of Obstetrics and Gynecology of the Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. There are no conflicts of interest. TRIAL REGISTRATION NUMBER: Registered at the Dutch Trial Register (NTR6854).