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Shared neuronal variability has been shown to modulate cognitive processing. However, the relationship between shared variability and behavioral performance is heterogeneous and complex in frontal areas such as the orbitofrontal cortex (OFC). Mounting evidence shows that single-units in OFC encode a detailed cognitive map of task-space events, but the existence of a robust neuronal ensemble coding for the predictability of choice outcome is less established. Here, we hypothesize that the coding of foreseeable outcomes is potentially unclear from the analysis of units activity and their pairwise correlations. However, this code might be established more conclusively when higher-order neuronal interactions are mapped to the choice outcome. As a case study, we investigated the trial-to-trial shared variability of neuronal ensemble activity during a two-choice interval-discrimination task in rodent OFC, specifically designed such that a lose-switch strategy is optimal by repeating the rewarded stimulus in the upcoming trial. Results show that correlations among triplets are higher during correct choices with respect to incorrect ones, and that this is sustained during the entire trial. This effect is not observed for pairwise nor for higher than third-order correlations. This scenario is compatible with constellations of up to three interacting units assembled during trials in which the task is performed correctly. More interestingly, a state-space spanned by such constellations shows that only correct outcome states that can be successfully predicted are robust over 100 trials of the task, and thus they can be accurately decoded. However, both incorrect and unpredictable outcome representations were unstable and thus non-decodeable, due to spurious negative correlations. Our results suggest that predictability of successful outcomes, and hence the optimal behavioral strategy, can be mapped out in OFC ensemble states reliable over trials of the task, and revealed by sufficiency complex neuronal interactions.

Abstract The brain is a complex non-equilibrium system capable of expressing many different dynamics as well as the transitions between them. We hypothesized that the level of non-equilibrium can serve as a signature of a given brain state, which was quantified using the arrow of time (the level of irreversibility). Using this thermodynamic framework, the irreversibility of emergent cortical activity was quantified from local field potential recordings in male Lister-hooded rats at different anesthesia levels and during the sleep-wake cycle. This measure was carried out on five distinct brain states: slow-wave sleep, awake, deep anesthesia–slow waves, light anesthesia–slow waves, and microarousals. Low levels of irreversibility were associated with synchronous activity found both in deep anesthesia and slow-wave sleep states, suggesting that slow waves were the state closest to the thermodynamic equilibrium (maximum symmetry), thus requiring minimum energy. Higher levels of irreversibility were found when brain dynamics became more asynchronous, for example, in wakefulness. These changes were also reflected in the hierarchy of cortical dynamics across different cortical areas. The neural dynamics associated with different brain states were characterized by different degrees of irreversibility and hierarchy, also acting as markers of brain state transitions. This could open new routes to monitoring, controlling, and even changing brain states in health and disease.

Abstract By connecting old and recent notions, different spatial scales, and research domains, we introduce a novel framework on the consequences of brain injury focusing on a key role of slow waves. We argue that the long-standing finding of EEG slow waves after brain injury reflects the intrusion of sleep-like cortical dynamics during wakefulness; we illustrate how these dynamics are generated and how they can lead to functional network disruption and behavioral impairment. Finally, we outline a scenario whereby post-injury slow waves can be modulated to reawaken parts of the brain that have fallen asleep to optimize rehabilitation strategies and promote recovery.

Music is a potent mood regulator that can induce relaxation and reduce anxiety in different situations. While several studies demonstrate that certain types of music have a subjective anxiolytic effect, the reported results from physiological responses are less conclusive. Virtual reality allows us to study diverse scenarios of real life under strict experimental control while preserving high ecological validity. We aimed to study the modulating effect of music on the anxiety responses triggered by an immersive virtual reality scenario designed to induce fear of heights. Subjects experienced a virtual scenario depicting an exterior elevator platform ascending and descending the total height of its 350 meters tall supporting structure. Participants were allocated to either a group that experienced the elevator ride with background music or without, in a between-groups design. Furthermore, each group included participants with different degrees of fear of heights, ranging from low to high fear. Recordings of heart rate, galvanic skin response, body balance, and head movements were obtained during the experiments. Subjective anxiety was measured by means of three questionnaires. The scenario produced significant changes in subjective and physiological measures, confirming its efficacy as a stressor. A significant increase in state anxiety was found between pre and post-assessment in the silence group, but not in the music group indicating that post-stress recovery was faster in the musical group. Results suggest that music can ameliorate the subjective anxiety produced by fear of heights.

Prefrontal Cortex (PFC) in mammals is well known for playing a key role in executive function [1-3]. Orbitofrontal Cortex (OFC), as a part of the PFC, is thought to be mainly involved in reward processing, a fundamental function in goal-directed behavior. In particular it has been proposed that OFC is encoding the expected value of an outcome [4]. Previous studies in rats have shown that neurons in OFC have information about expected reward or punishment [5-7], and guide the relationship between stimulus and reward in a reversal associative learning task [8-9]. It has also been proposed to be involved in spatial representation as well as a proxy for confidence in perceptual decision making tasks [10-11]. In our experiment three rats performed an auditory categorization task while populations of neurons were recorded in OFC. The task was designed such that rats could use both sensory information and task history information in order to maximize reward income. We found that neurons in rats' OFC conveyed a wide variety of task related variables each one with a different time dynamics. Before stimulus onset OFC neurons showed significant amount of information regarding previous choice, previous reward and previous stimulus. After stimulus presentation neurons showed information about trial difficulty, as a proxy for trial's expected value, stimulus, and reaction time, a well known proxy for metacognitive processes as confidence. Information about decision was predominant at stimulus presentation and rat's response. Our results demonstrate that OFC in rats might not only be involved in reward processing but it also conveys a wide variety of task relevant variables. Our hypothesis is that OFC acts as a hub for complex decision-making tasks where all possible information is processed and conveyed to other brain regions responsible for decision execution.

The recurrent circuitry of the cerebral cortex generates an emergent pattern of activity that is organized into rhythmic periods of firing and silence referred to as slow oscillations (ca 1 Hz). Slow oscillations not only are dominant during slow wave sleep and deep anaesthesia, but also can be generated by the isolated cortical network in vitro, being a sort of default activity of the cortical network. The cortex is densely and reciprocally connected with subcortical structures and, as a result, the slow oscillations in situ are the result of an interplay between cortex and thalamus. Due to this reciprocal connectivity and interplay, the mechanism responsible for the initiation of waves in the corticothalamocortical loop during slow oscillations is still a matter of debate. The prevalent view is that infragranular layers of the cortex, where the highest firing rates are found, are leading the periods of activity or Up states, from where activity rapidly spreads to all cortical layers and subcortical structures such as the thalamus. However, other authors support that the slow wave activity is an emergent property of corticothalamocortical networks defining the origin of this activity as a balance between cortical and thalamic contributions. To determine the directionality of the information flow between different layers of the cortex and the connected thalamus during spontaneous activity we obtained multilayer local field potentials from the rat visual cortex and from its connected thalamus, the lateral geniculate nucleus, during deep anaesthesia. We analyzed directionality of information flow between thalamus, cortical infragranular layers (5 and 6) and supragranular layers (2/3) by means of three information theoretical indicators: transfer entropy, symbolic transfer entropy and transcript mutual information. These three indicators coincided in finding that infragranular layers lead the information flow during slow oscillations both towards supragranular layers and towards the thalamus.

We present a closed-loop system able to set the frequency of slow oscillations dynamics observed in acute preparation of ferret cortical slices. The biological activity is recorded through a single electrode, is analyzed on-line and steered through the injection of a DC current of variable intensity. The system guarantees artifacts removal, minimal gaps in the data acquisition and proved to be robust to slice heterogeneities. To achieve such a control we designed a custom programmable stimulator ensuring low-noise and accurate tuning over low current levels. For data recording and analysis we rely on commercial acquisition and software tools. The result is a flexible and reliable system that ensures control over in vitro slow oscillation frequency. Our tool opens new possibilities for the investigation of slow-wave dynamics which have been associated with memory consolidation and whose alteration are observed in different pathologies such as neurodegenerative diseases.

Neuronal spontaneous activity can provide valuable information on the functional structure of the underlying neuronal network. We focused on the spontaneous slow-wave activity that is generated and propagated in cortical slices, aiming at relating their spatio-temporal organization with the laminar structure of the tissue. We extracted multi-unit activities from simultaneous recordings obtained by means of an array of 16 electrodes covering the slice. Although each site displayed alternation between high-firing (Up) and almost quiescent (Down) states, slow oscillations (SO) were not spatially homogeneous, showing layer-dependent state durations and maximum firing rates. A distribution of time lags between electrodes in the onset and offset of Up states reflected a propagating activity wave. We found different propagation modes in terms of velocity, direction, wavefront shape (see Figure 1A), spatial extension and site of origin. Despite such variability, at the level of single waves, we consistently found that the head of the wavefront had a spatial distribution forming a strip almost parallel to the cortical surface (see Figure 1B black line), at a depth compatible with layer 4 and 5 (L4 and L5). Moreover, this strip widely overlapped with the region where Up states had the maximum duration and magnitude (see Figure 1B respectively green and blue line), a region possibly corresponding to the most excitable part of the network. To test such hypothesis, we tried to reproduce the properties of this strip using a large scale simulation of a slice model, with oscillating cortical modules of spiking neurons arranged in a 2D lattice with nearest neighbor connectivity. In this homogeneous medium we implemented a non-monotonic gradient in the connectivity level (see Figure 1C), aiming to embody the physiological differences in layer excitability, and setting an overexcited strip (dark circles). We found that the connectivity level increase was not trivially related to an increase of the speed of wave propagation, rather this parameter has to be chosen in an optimal range (see Figure 1C-D) in order to reproduce propagating patterns compatible with the experiments. Optimal networks were those having a metastable Down state in which finite-size fluctuations were capable to prime Down-to-Up transitions. In addition to this, we further predicted that SO features like maximum firing rate and longest Up state durations should be found at the same excitable strip. Conclusions As the model predicted, we found that strips of early wave propagation reliably overlapped with the regions where maximum Up state duration and firing activity occurred, strengthening the duality between spontaneous activity and network structure. Finally, we matched the excitable strips with the slice cortical layers as identified by histology, finding a reliable overlap between such strips and L4 and L5 (see Figure 1E). Figure 1. A. Wavefronts for 2 modes of propagation. B. Average strips where wavefronts propagate earlier (black), and where Up states have maximum duration (green) and magnitude (blue). C. Modulation of the connectivity parameter in the model. D. Nullclines under mean-field approximation varying levels of connectivity.  and C are average firing rate and fatigue level, respectively. Circles, fixed points. Dark to light gray, different excitability levels as in C, respectively. E. Example match between strip of early wave propagation and slice’s layers.

We have explored the feasibility of improving the quality of multiple recordings from spontaneously oscillating cortical slices. With that purpose we have taken advantage of the advances performed in the development of flexible neuproprobes, either fabricated on polyimide, SU-8, PDMS or parylene (Hassler et al. 2011). With these materials the contact between the electrodes and the tissue is enhanced with respect to the neuroprobes fabricated on rigid substrates, such as silicon or pyrex. However, we had to find a compromise between the necessity to achieve a good contact between the electrode and the slice and the need to allow the flow of oxygenated solution to the slice to maintain its healthy state when using flexible neuroprobes. To overcome this limitation, we have designed, fabricated and characterized a 16-electrode flexible neuroprobe that allocates an array of holes in its sensing area. This neuroprobe has been developed using SU-8 negative photoresist as a substrate material in the clean room facilities of the IMB-CNM. In particular, the neuroprobes have been fabricated following the process described in a previous article from the authors (Guimerà et al. 2013); using silicon wafers with an aluminum sacrificial layer as a support for the fabrication process. Then, the neuroprobes were released from the wafer by an anodic dissolution of the aluminum layer (Metz et al. 2005). In order to validate the usability of the fabricated device, the neuroprobes were used to record spontaneous slow oscillations to study the wave propagation along the cortical networks while manipulating them by means of pharmacological drugs or electric fields. We conclude that the perforated devices provide substantial improvement in the adherence of the electrodes to the tissue, on the mechanical stability of the recordings, and in the healthiness of the slices.

The ability to detect unexpected stimuli in the acoustic environment and determine their behavioral relevance to plan an appropriate reaction is critical for survival. This perspective article brings together several viewpoints and discusses current advances in understanding the mechanisms the auditory system implements to extract relevant information from incoming inputs and to identify unexpected events. This extraordinary sensitivity relies on the capacity to codify acoustic regularities, and is based on encoding properties that are present as early as the auditory midbrain. We review state-of-the-art studies on the processing of stimulus changes using non-invasive methods to record the summed electrical potentials in humans, and those that examine single-neuron responses in animal models. Human data will be based on mismatch negativity (MMN) and enhanced middle latency responses (MLR). Animal data will be based on the activity of single neurons at the cortical and subcortical levels, relating selective responses to novel stimuli to the MMN and to stimulus-specific neural adaptation (SSA). Theoretical models of the neural mechanisms that could create SSA and novelty responses will also be discussed.

Focal brain injuries, such as stroke, cause local structural damage as well as alteration of neuronal activity in distant brain regions. Experimental evidence suggests that one of these changes is the appearance of sleep-like slow waves in the otherwise awake individual. This pattern is prominent in areas surrounding the damaged region and can extend to connected brain regions in a way consistent with the individual's specific long-range connectivity patterns. In this paper we present a generative whole-brain model based on (f)MRI data that, in combination with the disconnection mask associated with a given patient, explains the effects of the sleep-like slow waves originated in the vicinity of the lesion area on the distant brain activity. Our model reveals new aspects of their interaction, being able to reproduce functional connectivity patterns of stroke patients and offering a detailed, causal understanding of how stroke-related effects, in particular slow waves, spread throughout the brain. The presented findings demonstrate that the model effectively captures the links between stroke occurrences, sleep-like slow waves, and their subsequent spread across the human brain.

The input/output relationship in primary visual cortex neurons is influenced by the history of the preceding activity. To understand the impact that membrane potential trajectory and firing pattern has on the activation of slow conductances in cortical neurons we compared the afterpotentials that followed responses to different stimuli evoking similar numbers of action potentials. In particular, we compared afterpotentials following the intracellular injection of either square or sinusoidal currents lasting 20 seconds. Both stimuli were intracellular surrogates of different neuronal responses to prolonged visual stimulation. Recordings from 99 neurons in slices of visual cortex revealed that for stimuli evoking an equivalent number of spikes, sinusoidal current injection activated a slow afterhyperpolarization of significantly larger amplitude (8.5 ± 3.3 mV) and duration (33 ± 17 s) than that evoked by a square pulse (6.4 ± 3.7 mV, 28 ± 17 s; p

Reading music and playing a musical instrument is a complex activity that comprises motor and multisensory (auditory, visual, and somatosensory) integration in a unique way. Music has also a well-known impact on the emotional state, while it can be a motivating activity. For those reasons, musical training has become a useful framework to study brain plasticity. Our aim was to study the specific effects of musical training versus the effects of other leisure activities in elderly people. With that purpose we evaluated the impact of piano training on cognitive function, mood and quality of life in older adults. A group of participants that received piano lessons and did daily training for four-month (n=13) was compared to an age-matched control group (n=16) that participated in other types of leisure activities (physical exercise, computer lessons, painting lessons, among other). An exhaustive assessment that included neuropsychological tests as well as mood and quality of life questionnaires was carried out before starting the piano program and immediately after finishing (4 months later) in the two groups. We found a significant improvement on the piano training group on the Stroop test that measures executive function, inhibitory control and divided attention. Furthermore, a trend indicating an enhancement of visual scanning and motor ability was also found (Trial Making Test part A). Finally, in our study piano lessons decreased depression, induced positive mood states, and improved the psychological and physical quality of life of the elderly. Our results suggest that playing piano and learning to read music can be a useful intervention in older adults to promote cognitive reserve and improve subjective well-being.

It has been demonstrated that visual inputs can modulate pain. However, the influence of skin colour on pain perception is unknown. Red skin is associated to inflamed, hot and more sensitive skin while blue is associated to cold. We aimed to test whether the colour of the skin would alter the heat pain threshold. To this end, we used an immersive virtual environment where we induced embodiment of a virtual arm that was co-located with the real one and seen from a first person perspective. Virtual reality allowed us to dynamically modify the colour of the skin of the virtual arm. In order to test pain threshold, increasing ramps of heat stimulation applied on the participants’ arm were delivered concomitantly with the gradual intensification of different colours on the embodied avatar’s arm. We found that a reddened arm significantly decreased the pain threshold compared with normal and bluish coloured skin. This effect was specific when red was seen in the arm, while seeing red in a spot outside the arm did not decrease pain threshold. These results demonstrate an influence of skin colour on pain perception. This top-down modulation of pain through visual input suggests a potential use of embodied virtual bodies for pain therapy.

Immersive virtual reality (IVR) typically generates the illusion in participants that they are in the displayed virtual scene where they can experience and interact in events as if they were really happening. Teleoperator (TO) systems place people at a remote physical destination embodied as a robotic device, and where typically participants have the sensation of being at the destination, with the ability to interact with entities there. In this paper, we show how to combine IVR and TO to allow a new class of application. The participant in the IVR is represented in the destination by a physical robot (TO) and simultaneously the remote place and entities within it are represented to the participant in the IVR. Hence, the IVR participant has a normal virtual reality experience, but where his or her actions and behaviour control the remote robot and can therefore have physical consequences. Here, we show how such a system can be deployed to allow a human and a rat to operate together, but the human interacting with the rat on a human scale, and the rat interacting with the human on the rat scale. The human is represented in a rat arena by a small robot that is slaved to the human's movements, whereas the tracked rat is represented to the human in the virtual reality by a humanoid avatar. We describe the system and also a study that was designed to test whether humans can successfully play a game with the rat. The results show that the system functioned well and that the humans were able to interact with the rat to fulfil the tasks of the game. This system opens up the possibility of new applications in the life sciences involving participant observation of and interaction with animals but at human scale.

Recent studies have shown that a fake body part can be incorporated into human body representation through synchronous multisensory stimulation on the fake and corresponding real body part - the most famous example being the Rubber Hand Illusion. However, the extent to which gross asymmetries in the fake body can be assimilated remains unknown. Participants experienced, through a head-tracked stereo head-mounted display a virtual body coincident with their real body. There were 5 conditions in a between-groups experiment, with 10 participants per condition. In all conditions there was visuo-motor congruence between the real and virtual dominant arm. In an Incongruent condition (I), where the virtual arm length was equal to the real length, there was visuo-tactile incongruence. In four Congruent conditions there was visuo-tactile congruence, but the virtual arm lengths were either equal to (C1), double (C2), triple (C3) or quadruple (C4) the real ones. Questionnaire scores and defensive withdrawal movements in response to a threat showed that the overall level of ownership was high in both C1 and I, and there was no significant difference between these conditions. Additionally, participants experienced ownership over the virtual arm up to three times the length of the real one, and less strongly at four times the length. The illusion did decline, however, with the length of the virtual arm. In the C2-C4 conditions although a measure of proprioceptive drift positively correlated with virtual arm length, there was no correlation between the drift and ownership of the virtual arm, suggesting different underlying mechanisms between ownership and drift. Overall, these findings extend and enrich previous results that multisensory and sensorimotor information can reconstruct our perception of the body shape, size and symmetry even when this is not consistent with normal body proportions.

In this study, we recorded the single unit activity from rat auditory cortex while the animals performed an interval-discrimination task. The animals had to decide whether two auditory stimuli were separated by either 150 or 300 ms, and go to the left or right nose-poke accordingly. Spontaneous firing in between auditory responses was compared in the attentive versus non-attentive brain states. We describe the firing rate modulation detected during intervals while there was no auditory stimulation. Nearly 18% of neurons (n=14) showed a prominent neuronal discharge during the interstimulus interval, in the form of a upward or downward ramp towards the second auditory stimulus. These patterns of spontaneous activity were often modulated in the attentive versus passive trials. Modulation of the spontaneous firing rate during the task was observed not only between auditory stimuli, but also in the interval preceding the stimulus. This slow modulatory components could be locally generated or the result of a top-down influence originated in higher associative association areas. Such a neuronal discharge may be related to the computation of the interval time and contribute to the perception of the auditory stimulus.

Brain-computer interfaces (BCI) are using the EEG (Electroencephalogram), the ECoG (Electrocorticogram) and trains of action potentials as inputs to analyze brain activity for communication purposes and/or the control of external devices. Thus far it is not known whether a BCI system can be developed that utilizes the states of brain structures that are situated well below the cortical surface, such as the hippocampus. In order to address this question we used the activity of hippocampal place cells to predict the position of an rodent in real-time. First, spike activity was recorded from the hippocampus during foraging and analyzed off-line to optimize the spike sorting and position reconstruction algorithm of rats. Then the spike activity was recorded and analyzed in real-time. The rat was running in a box of 80x80 cm and its locomotor movement was captured with a video tracking system. Data were acquired to calculate the rat’s trajectories and to identify place fields. Then a Bayesian classifier was trained to predict the position of the rat given its neural activity. This information was used in subsequent trials to predict the rat’s position in real-time.The real-time experiments were successfully performed and yielded an error between 12.2 and 17.4 % using 5-6 neurons. It must be noted here that the encoding step was done with data recorded before the real-time experiment and comparable accuracies between off-line (mean error of 15.9 % for 3 rats) and real-time experiments (mean error of 14.7%) were achieved. The experiment shows proof of principle that position reconstruction can be done in real-time, that place cells were stable and spike sorting was robust enough to generalize from the training run to the real-time reconstruction phase of the experiment. Real-time reconstruction may be used for a variety of purposes, including creating behavioral-neuronal feedback loops or for implementing neuroprosthetic control.

Altering the normal association between touch and its visual correlate can result in the illusory perception of a fake limb as part of our own body. Thus, when touch is seen to be applied to a rubber hand while felt synchronously on the corresponding hidden real hand, an illusion of ownership of the rubber hand usually occurs. The illusion has also been demonstrated using visuomotor correlation between the movements of the hidden real hand and the seen fake hand. This type of paradigm has been used with respect to the whole body generating out-of-the-body and body substitution illusions. However, such studies have only ever manipulated a single factor and although they used a form of virtual reality have not exploited the power of immersive virtual reality (IVR) to produce radical transformations in body ownership.Here we show that a first person perspective of a life-sized virtual human female body that appears to substitute the male subjects' own bodies was sufficient to generate a body transfer illusion. This was demonstrated subjectively by questionnaire and physiologically through heart-rate deceleration in response to a threat to the virtual body. This finding is in contrast to earlier experimental studies that assume visuotactile synchrony to be the critical contributory factor in ownership illusions. Our finding was possible because IVR allowed us to use a novel experimental design for this type of problem with three independent binary factors: (i) perspective position (first or third), (ii) synchronous or asynchronous mirror reflections and (iii) synchrony or asynchrony between felt and seen touch.The results support the notion that bottom-up perceptual mechanisms can temporarily override top down knowledge resulting in a radical illusion of transfer of body ownership. The research also illustrates immersive virtual reality as a powerful tool in the study of body representation and experience, since it supports experimental manipulations that would otherwise be infeasible, with the technology being mature enough to represent human bodies and their motion.

BackgroundOur body schema gives the subjective impression of being highly stable. However, a number of easily-evoked illusions illustrate its remarkable malleability. In the rubber-hand illusion, illusory ownership of a rubber-hand is evoked by synchronous visual and tactile stimulation on a visible rubber arm and on the hidden real arm. Ownership is concurrent with a proprioceptive illusion of displacement of the arm position towards the fake arm. We have previously shown that this illusion of ownership plus the proprioceptive displacement also occurs towards a virtual 3D projection of an arm when the appropriate synchronous visuotactile stimulation is provided. Our objective here was to explore whether these illusions (ownership and proprioceptive displacement) can be induced by only synchronous visuomotor stimulation, in the absence of tactile stimulation.Methodology/principal findingsTo achieve this we used a data-glove that uses sensors transmitting the positions of fingers to a virtually projected hand in the synchronous but not in the asynchronous condition. The illusion of ownership was measured by means of questionnaires. Questions related to ownership gave significantly larger values for the synchronous than for the asynchronous condition. Proprioceptive displacement provided an objective measure of the illusion and had a median value of 3.5 cm difference between the synchronous and asynchronous conditions. In addition, the correlation between the feeling of ownership of the virtual arm and the size of the drift was significant.Conclusions/significanceWe conclude that synchrony between visual and proprioceptive information along with motor activity is able to induce an illusion of ownership over a virtual arm. This has implications regarding the brain mechanisms underlying body ownership as well as the use of virtual bodies in therapies and rehabilitation.

We discuss three experiments that investigate how virtual limbs and bodies can come to feel like real limbs and bodies. The first experiment shows that an illusion of ownership of a virtual arm appearing to project out of a person’s shoulder can be produced by tactile stimulation on a person’s hidden real hand and synchronous stimulation on the seen virtual hand. The second shows that the illusion can be produced by synchronous movement of the person’s hidden real hand and a virtual hand. The third shows that a weaker form of the illusion can be produced when a brain-computer interface is employed to move the virtual hand by means of motor imagery without any tactile stimulation. We discuss related studies that indicate that the ownership illusion may be generated for an entire body. This has important implications for the scientific understanding of body ownership and several practical applications.

BackgroundThe neuronal cortical network generates slow (Methodology/principal findingsIntracellular recordings from different areas of the cerebral cortex were obtained from both in vitro and in vivo preparations during slow oscillations. A method that separates up and down states recorded intracellularly is defined and analyzed here. The method exploits the crossover of moving averages, such that transitions between up and down membrane regimes can be anticipated based on recent and past voltage dynamics. We demonstrate experimentally the utility and performance of this method both offline and online, the online use allowing to trigger stimulation or other events in the desired period of the rhythm. This technique is compared with a histogram-based approach that separates the states by establishing one or two discriminating membrane potential levels. The robustness of the method presented here is tested on data that departs from highly regular alternating up and down states.Conclusions/significanceWe define a simple method to detect cortical states that can be applied in real time for offline processing of large amounts of recorded data on conventional computers. Also, the online detection of up and down states will facilitate the study of cortical dynamics. An open-source MATLAB toolbox, and Spike 2-compatible version are made freely available.

BackgroundThe cerebral cortex is permanently active during both awake and sleep states. This ongoing cortical activity has an impact on synaptic transmission and short-term plasticity. An activity pattern generated by the cortical network is a slow rhythmic activity that alternates up (active) and down (silent) states, a pattern occurring during slow wave sleep, anesthesia and even in vitro. Here we have studied 1) how network activity affects short term synaptic plasticity and, 2) how synaptic transmission varies in up versus down states.Methodology/principal findingsIntracellular recordings obtained from cortex in vitro and in vivo were used to record synaptic potentials, while presynaptic activation was achieved either with electrical or natural stimulation. Repetitive activation of layer 4 to layer 2/3 synaptic connections from ferret visual cortex slices displayed synaptic augmentation that was larger and longer lasting in active than in silent slices. Paired-pulse facilitation was also significantly larger in an active network and it persisted for longer intervals (up to 200 ms) than in silent slices. Intracortical synaptic potentials occurring during up states in vitro increased their amplitude while paired-pulse facilitation disappeared. Both intracortical and thalamocortical synaptic potentials were also significantly larger in up than in down states in the cat visual cortex in vivo. These enhanced synaptic potentials did not further facilitate when pairs of stimuli were given, thus paired-pulse facilitation during up states in vivo was virtually absent. Visually induced synaptic responses displayed larger amplitudes when occurring during up versus down states. This was further tested in rat barrel cortex, where a sensory activated synaptic potential was also larger in up states.Conclusions/significanceThese results imply that synaptic transmission in an active cortical network is more secure and efficient due to larger amplitude of synaptic potentials and lesser short term plasticity.

Local neocortical circuits are characterized by stereotypical physiological and structural features that subserve generic computational operations. These basic computations of the cortical microcircuit emerge through the interplay of neuronal connectivity, cellular intrinsic properties, and synaptic plasticity dynamics. How these interacting mechanisms generate specific computational operations in the cortical circuit remains largely unknown. Here, we identify the neurophysiological basis of both the rate of change and anticipation computations on synaptic inputs in a cortical circuit. Through biophysically realistic computer simulations and neuronal recordings, we show that the rate-of-change computation is operated robustly in cortical networks through the combination of two ubiquitous brain mechanisms: short-term synaptic depression and spike-frequency adaptation. We then show how this rate-of-change circuit can be embedded in a convergently connected network to anticipate temporally incoming synaptic inputs, in quantitative agreement with experimental findings on anticipatory responses to moving stimuli in the primary visual cortex. Given the robustness of the mechanism and the widespread nature of the physiological machinery involved, we suggest that rate-of-change computation and temporal anticipation are principal, hard-wired functions of neural information processing in the cortical microcircuit.

Patient focus groups can be invaluable for facilitating user-centered design of medical devices and new technologies, effectively capturing the richness and depth of patient experiences to help thoroughly assess feasibility, tolerance, and usability. While the metaverse holds promise for healthcare applications, its use in patient focus groups remains unexplored. In this Perspective we discuss the potential of the metaverse for conducting focus groups with patients. The theme of the focus group was the design and development of a therapeutic virtual reality application for patients with chronic low back pain. We carried out a pilot study comparing a focus group in a shared virtual space versus a physical location. This experience was positively received by patients, researchers, and clinicians, suggesting the metaverse is a viable medium for conducting these meetings and has potential advantages for remotely located participants, opening the doors for future expansion beyond focus groups to encompass all kinds of patient support and information groups. This approach fosters patient-centered healthcare by helping to facilitate patient voices directly into the design process, which may help lead to improved healthcare delivery, patient satisfaction, and treatment outcomes.

Stanley Milgram's 1960s experimental findings that people would administer apparently lethal electric shocks to a stranger at the behest of an authority figure remain critical for understanding obedience. Yet, due to the ethical controversy that his experiments ignited, it is nowadays impossible to carry out direct experimental studies in this area. In the study reported in this paper, we have used a similar paradigm to the one used by Milgram within an immersive virtual environment. Our objective has not been the study of obedience in itself, but of the extent to which participants would respond to such an extreme social situation as if it were real in spite of their knowledge that no real events were taking place.Following the style of the original experiments, the participants were invited to administer a series of word association memory tests to the (female) virtual human representing the stranger. When she gave an incorrect answer, the participants were instructed to administer an 'electric shock' to her, increasing the voltage each time. She responded with increasing discomfort and protests, eventually demanding termination of the experiment. Of the 34 participants, 23 saw and heard the virtual human, and 11 communicated with her only through a text interface.Our results show that in spite of the fact that all participants knew for sure that neither the stranger nor the shocks were real, the participants who saw and heard her tended to respond to the situation at the subjective, behavioural and physiological levels as if it were real. This result reopens the door to direct empirical studies of obedience and related extreme social situations, an area of research that is otherwise not open to experimental study for ethical reasons, through the employment of virtual environments.

Abstract Background Recent evidence supports the use of immersive virtual reality (VR) as a means of delivering bodily illusions that may have therapeutic potential for the treatment of musculoskeletal conditions. We wanted to investigate whether a single session of an embodiment-based immersive VR training program influences pain-free range of motion in patients with shoulder pain. Methods We designed a rehabilitation program based on developing ownership over a virtual body and then “exercising” the upper limb in immersive VR, while the real arm remains static. We then carried out a single-arm pre-post experiment in which 21 patients with movement-related musculoskeletal shoulder pain were exposed to the 15-min VR program and measured their active pain-free range of motion immediately before and afterwards. Results We found that shoulder abduction and hand-behind-back movements, but not shoulder flexion, were significantly and clinically improved post-intervention and that the level of improvement correlated with the level of embodiment. Following this one session, at 1-week follow-up the improvements were not maintained. Conclusions Virtual embodiment may be a useful therapeutic tool to help improve range of motion in patients with movement-related shoulder pain in the short term, which in turn could expedite rehabilitation and recovery in these conditions.

Abstract Chronic pain alters the experience of owning a body and leads to disturbances in bodily perception. We tested whether women with fibromyalgia (FM) are receptive to bodily illusions of owning a visible and progressively invisible body in immersive virtual reality (VR), and what modulates this experience. Twenty patients participated in two experimental sessions; each session included two conditions in a counterbalanced order. We found that patients with FM could indeed experience virtual embodiment. Sentiment analysis revealed significantly more positive reactions to the progressively invisible body, yet twice as many patients declared they preferred the illusion of a visible virtual body. A linear mixed model revealed that the strength of embodiment was positively associated with body perception disturbances and negatively associated with FM symptoms intensity. No effect of pain during the VR experience nor interoception awareness on embodiment was found. The results indicated that patients with FM are receptive to virtual bodily illusions and that the impact of the embodiment depends on affective reactions, the level of cognitive body distortions, and the intensity of symptoms. Importantly, there is a large variation among patients which should be considered in future VR-based interventions.

Abstract Recent evidence supports the use of immersive virtual reality (immersive VR) as a means of applying visual feedback techniques in neurorehabilitation. In this study, we investigated the benefits of an embodiment-based immersive VR training program for orthopedic upper limb rehabilitation, with the aim of improving the motor functional ability of the arm and accelerating the rehabilitation process in patients with a conservatively managed distal radius fracture. We designed a rehabilitation program based on developing ownership over a virtual arm and then exercising it in immersive VR. We carried out a between 3-group controlled trial with 54 patients (mean age = 61.80 ± 14.18): 20 patients were assigned to the experimental training group (immersive VR), 20 to the conventional digit mobilization (CDM) training control group, and 14 to a non-immersive (non-immersive VR) training control group. We found that functional recovery of the arm in the immersive VR group was correlated with the ownership and agency scores over the virtual arm. We also found larger range of joint movements and lower disability of the fractured arm compared with patients in the Non-immersive VR and CDM groups. Feeling embodied in a virtual body can be used as a rehabilitation tool to speed up and improve motor functional recovery of a fractured arm after the immobilization period.

Rehabilitation and prevention strategies to reduce intimate partner violence (IPV) have limited effectiveness in terms of improving key risk factors and reducing occurrence. Accumulated experimental evidence demonstrates that virtual embodiment, which results in the illusion of owning a virtual body, has a large impact on people’s emotional, cognitive, and behavioral responses. This narrative review discusses work that has investigated how embodied perspective - taking in virtual reality has been used as a tool to reduce bias, to enhance recognition of the emotional state of another, and to reduce violent behaviors, in particular in the realm of IPV. Some of the potential neurological mechanisms behind these affective and behavioral changes are also discussed. The process of rehabilitation and prevention is complex and not always effective, but the integration of neuroscience-inspired and validated state-of-the-art technology into the rehabilitation process can make a positive contribution.

Chronic neuropathic pain is highly disabling and difficult to treat and manage. Patients with such conditions often report altered bodily perceptions that are thought to be associated with maladaptive structural and functional alterations in the somatosensory cortex. Manipulating these altered perceptions using body illusions in virtual reality is being investigated and may have positive clinical implications for the treatment of these conditions. Here, we have conducted a narrative review of the evidence for the types of bodily distortions associated with a variety of peripheral and central neuropathic pain conditions. In addition, we summarize the experimental and clinical studies that have explored embodiment and body transformation illusions in immersive virtual reality for neuropathic pain relief, which are thought to target these maladaptive changes, as well as suggesting directions for future research.

Virtual reality (VR) allows the user to be immersed in environments in which they can experience situations and social interactions from different perspectives by means of virtual embodiment. In the context of rehabilitation of violent behaviors, a participant could experience a virtual violent confrontation from different perspectives, including that of the victim and bystanders. This approach and other virtual scenes can be used as a useful tool for the rehabilitation of intimate partner violence (IPV) perpetrators, through improvement of their empathic skills or for training in non-violent responses. In this perspective, we revise and discuss the use of this tool in a prison environment for the rehabilitation of IPV perpetrators with a particular focus on practical aspects based on our experience.

Summary: In the arousal process, the brain restores its integrative activity from the synchronized state of slow wave activity (SWA). The mechanisms underpinning this state transition remain, however, to be elucidated. Here we simultaneously probed neuronal assemblies throughout the whole cortex with micro-electrocorticographic recordings in mice. We investigated the progressive shaping of propagating SWA at different levels of isoflurane. We found a form of memory of the wavefront shapes at deep anesthesia, tightly alternating posterior-anterior-posterior patterns. At low isoflurane, metastable patterns propagated in more directions, reflecting an increased complexity. The wandering across these mesostates progressively increased its randomness, as predicted by simulations of a network of spiking neurons, and confirmed in our experimental data. The complexity increase is explained by the elevated excitability of local assemblies with no modifications of the network connectivity. These results shed new light on the functional reorganization of the cortical network as anesthesia fades out.

The prevailing scientific paradigm is that matter is primary and everything, including consciousness can be derived from the laws governing matter. Although the scientific explanation of consciousness on these lines has not been realized, in this view it is only a matter of time before consciousness will be explained through neurobiological activity in the brain, and nothing else. There is an alternative view that holds that it is fundamentally impossible to explain how subjectivity can arise solely out of material processes—“the hard problem of consciousness”—and instead consciousness should be regarded in itself as a primary force in nature. This view attempts to derive, for example, the laws of physics from models of consciousness, instead of the other way around. While as scientists we can understand and have an intuition for the first paradigm, it is very difficult to understand what “consciousness is primary” might mean since it has no intuitive scientific grounding. Here we show that worlds experienced through virtual reality (VR) are such that consciousness is a first order phenomenon. We discuss the Interface Theory of Perception which claims that in physical reality perceptions are not veridical and that we do not see the “truth” but that perception is based on evolutionary payoffs. We show that this theory may provide an accurate description of perception and consciousness within VR, and we put forward an experimental study that could throw light on this. We conclude that VR does offer an experimental frame that provides intuition with respect to the idea that “consciousness is first” and what this might mean regarding the perceived world. However, we do not draw any conclusions about the veracity of this notion with respect to physical reality or question the emergence of consciousness from brain function.

Abstract The ability to control neural activity is essential for research not only in basic neuroscience, as spatiotemporal control of activity is a fundamental experimental tool, but also in clinical neurology for therapeutic brain interventions. Transcranial‐magnetic, ultrasound, and alternating/direct current (AC/DC) stimulation are some available means of spatiotemporal controlled neuromodulation. There is also light‐mediated control, such as optogenetics, which has revolutionized neuroscience research, yet its clinical translation is hampered by the need for gene manipulation. As a drug‐based light‐mediated control, the effect of a photoswitchable muscarinic agonist (Phthalimide‐Azo‐Iper (PAI)) on a brain network is evaluated in this study. First, the conditions to manipulate M2 muscarinic receptors with light in the experimental setup are determined. Next, physiological synchronous emergent cortical activity consisting of slow oscillations—as in slow wave sleep—is transformed into a higher frequency pattern in the cerebral cortex, both in vitro and in vivo, as a consequence of PAI activation with light. These results open the way to study cholinergic neuromodulation and to control spatiotemporal patterns of activity in different brain states, their transitions, and their links to cognition and behavior. The approach can be applied to different organisms and does not require genetic manipulation, which would make it translational to humans.

Slow oscillations are a pattern of synchronized network activity generated by the cerebral cortex. They consist of Up and Down states, which are periods of activity interspersed with periods of silence, respectively. However, even when this is a unique dynamic regime of transitions between Up and Down states, this pattern is not constant: there is a range of oscillatory frequencies (0.1–4 Hz), and the duration of Up vs. Down states during the cycles is variable. This opens many questions. Is there a constant relationship between the duration of Up and Down states? How much do they vary across conditions and oscillatory frequencies? Are there different sub regimes within the slow oscillations? To answer these questions, we aimed to explore a concrete aspect of slow oscillations, Up and Down state durations, across three conditions: deep anesthesia, light anesthesia, and slow-wave sleep (SWS), in the same chronically implanted rats. We found that light anesthesia and SWS have rather similar properties, occupying a small area of the Up and Down state duration space. Deeper levels of anesthesia occupy a larger region of this space, revealing that a large variety of Up and Down state durations can emerge within the slow oscillatory regime. In a network model, we investigated the network parameters that can explain the different points within our bifurcation diagram in which slow oscillations are expressed.

Immersive virtual reality is widely used for research and clinical purposes. Here we explored the impact of an immersive virtual scene of intimate partner violence experienced from the victim’s perspective (first person), as opposed to witnessing it as an observer (third person). We are ultimately interested in the potential of this approach to rehabilitate batterers and in understanding the mechanisms underlying this process. For this, non-offender men experienced the scene either from the perspective of the victim’s virtual body (a female avatar), which moved synchronously with the participants’ real movements, or from the perspective of an observer, while we recorded their behavior and physiological responses. We also evaluated through questionnaires, interviews and implicit association tests their subjective impressions and potential pre/post changes in implicit gender bias following the experience. We found that in all participants, regardless of perspective, the magnitude of the physiological reactions to virtual threatening stimuli was related to how vulnerable they felt for being a woman, the sensation that they could be assaulted, how useful the scene could be for batterer rehabilitation, and how different it would have been to experience the scenario on TV. Furthermore, we found that their level of identification with the female avatar correlated with the decrease in prejudice against women. Although the first-person perspective (1PP) facilitated taking the scene personally, generated a sensation of fear, helplessness, and vulnerability, and tended to induce greater behavioral and physiological reactions, we show that the potential for batterer rehabilitation originates from presence and identification with the victim, which in turn is more easily, but not exclusively, achieved through 1PP. This study is relevant for the development of advanced virtual reality tools for clinical purposes.

Abstract Background We present a closed-loop system able to control the frequency of slow oscillations (SO) spontaneously generated by the cortical network in vitro. The frequency of SO can be controlled by direct current (DC) electric fields within a certain range. Here we set out to design a system that would be able to autonomously bring the emergent oscillatory activity to a target frequency determined by the experimenter. Methods The cortical activity was recorded through an electrode and was analyzed online. Once a target frequency was set, the frequency of the slow oscillation was steered through the injection of DC of variable intensity that generated electric fields of proportional amplitudes in the brain slice. To achieve such closed-loop control, we designed a custom programmable stimulator ensuring low noise and accurate tuning over low current levels. For data recording and analysis, we relied on commercial acquisition and software tools. Results The result is a flexible and reliable system that ensures control over SO frequency in vitro. The system guarantees artifact removal, minimal gaps in data acquisition and robustness in spite of slice heterogeneity. Conclusions Our tool opens new possibilities for the investigation of dynamics of cortical slow oscillations—an activity pattern that is associated with cognitive processes such as memory consolidation, and that is altered in several neurological conditions—and also for potential applications of this technology.

Abstract The development and maturation of cortical circuits relies on the coordinated actions of long and short range axonal guidance cues. In this regard, the class 3 semaphorins and their receptors have been seen to be involved in the development and maturation of the hippocampal connections. However, although the role of most of their family members have been described, very few data about the participation of Semaphorin 3E (Sema3E) and its receptor PlexinD1 during the development and maturation of the entorhino-hippocampal (EH) connection are available. In the present study, we focused on determining their roles both during development and in adulthood. We determined a relevant role for Sema3E/PlexinD1 in the layer-specific development of the EH connection. Indeed, mice lacking Sema3E/PlexinD1 signalling showed aberrant layering of entorhinal axons in the hippocampus during embryonic and perinatal stages. In addition, absence of Sema3E/PlexinD1 signalling results in further changes in postnatal and adult hippocampal formation, such as numerous misrouted ectopic mossy fibers. More relevantly, we describe how subgranular cells express PlexinD1 and how the absence of Sema3E induces a dysregulation of the proliferation of dentate gyrus progenitors leading to the presence of ectopic cells in the molecular layer. Lastly, Sema3E mutant mice displayed increased network excitability both in the dentate gyrus and the hippocampus proper.

The orbitofrontal cortex encodes outcomes, expected rewards and values, but it is unclear how this region uses this information to inform action selection. Here, the authors show that lateral orbitofrontal cortex anticipates upcoming choices and combines recent prior information with current sensory information.