Chronic full-band recordings with graphene microtransistors as neural interfaces for discrimination of brain states.

Brain states such as sleep, anesthesia, wakefulness, or coma are characterized by specific patterns of cortical activity dynamics, from local circuits to full-brain emergent properties. We previously demonstrated that full-spectrum signals, including the infraslow component (DC, direct current-coupled), can be recorded acutely in multiple sites using flexible arrays of graphene solution-gated field-effect transistors (gSGFETs). Here, we performed chronic implantation of 16-channel gSGFET arrays over the rat cerebral cortex and recorded full-band neuronal activity with two objectives: (1) to test the long-term stability of implanted devices; and (2) to investigate full-band activity during the transition across different levels of anesthesia. First, we demonstrate it is possible to record full-band signals with stability, fidelity, and spatiotemporal resolution for up to 5.5 months using chronic epicortical gSGFET implants. Second, brain states generated by progressive variation of levels of anesthesia could be identified as traditionally using the high-pass filtered (AC, alternating current-coupled) spectrogram: from synchronous slow oscillations in deep anesthesia through to asynchronous activity in the awake state. However, the DC signal introduced a highly significant improvement for brain-state discrimination: the DC band provided an almost linear information prediction of the depth of anesthesia, with about 85% precision, using a trained algorithm. This prediction rose to about 95% precision when the full-band (AC + DC) spectrogram was taken into account. We conclude that recording infraslow activity using gSGFET interfaces is superior for the identification of brain states, and further supports the preclinical and clinical use of graphene neural interfaces for long-term recordings of cortical activity.

Immersive virtual reality in orthopaedics-a narrative review.

PURPOSE: This narrative review explores the applications and benefits of immersive virtual reality (VR) in orthopaedics, with a focus on surgical training, patient functional recovery, and pain management. METHODS: The review examines existing literature and research studies on immersive VR in orthopaedics, analyzing both experimental and clinical studies. RESULTS: Immersive VR provides a realistic simulation environment for orthopaedic surgery training, enhancing surgical skills, reducing errors, and improving overall performance. In post-surgical recovery and rehabilitation, immersive VR environments can facilitate motor learning and functional recovery through virtual embodiment, motor imagery during action observation, and virtual training. Additionally VR-based functional recovery programs can improve patient adherence and outcomes. Moreover, VR has the potential to revolutionize pain management, offering a non-invasive, drug-free alternative. Virtual reality analgesia acts by a variety of means including engagement and diverting patients' attention, anxiety reduction, and specific virtual-body transformations. CONCLUSION: Immersive virtual reality holds significant promise in orthopaedics, demonstrating potential for improved surgical training, patient functional recovery, and pain management but further research is needed to fully exploit the benefits of VR technology in these areas.

Offenders become the victim in virtual reality: impact of changing perspective in domestic violence.

The role of empathy and perspective-taking in preventing aggressive behaviors has been highlighted in several theoretical models. In this study, we used immersive virtual reality to induce a full body ownership illusion that allows offenders to be in the body of a victim of domestic abuse. A group of male domestic violence offenders and a control group without a history of violence experienced a virtual scene of abuse in first-person perspective. During the virtual encounter, the participants' real bodies were replaced with a life-sized virtual female body that moved synchronously with their own real movements. Participants' emotion recognition skills were assessed before and after the virtual experience. Our results revealed that offenders have a significantly lower ability to recognize fear in female faces compared to controls, with a bias towards classifying fearful faces as happy. After being embodied in a female victim, offenders improved their ability to recognize fearful female faces and reduced their bias towards recognizing fearful faces as happy. For the first time, we demonstrate that changing the perspective of an aggressive population through immersive virtual reality can modify socio-perceptual processes such as emotion recognition, thought to underlie this specific form of aggressive behaviors.

Heterogeneous spatial representation by different subpopulations of neurons in the subiculum.

The subiculum is a pivotal structure located in the hippocampal formation that receives inputs from grid and place cells and that mediates the output from the hippocampus to cortical and sub-cortical areas. Previous studies have demonstrated the existence of boundary vector cells (BVC) in the subiculum, as well as exceptional stability during recordings conducted in the dark, suggesting that the subiculum is involved in the coding of allocentric cues and also in path integration. In order to better understand the role of the subiculum in spatial processing and the coding of external cues, we recorded subicular units in freely moving rats while performing two experiments: the "size experiment" in which we modified the arena size, and the "barrier experiment" in which we inserted new barriers in a familiar open field thus dividing the enclosure into four comparable sub-chambers. We hypothesized that if physical boundaries were deterministic of the firing of subicular units a strong spatial replication pattern would be found in most spatially modulated units. In contrast, our results demonstrate heterogeneous space coding by different cell types: place cells, barrier-related units and BVC. We also found units characterized by narrow spike waveforms, most likely belonging to axonal recordings, that showed grid-like patterns. Our data indicate that the subiculum codes space in a flexible manner, and that it is involved in the processing of allocentric information, external cues and path integration, thus broadly supporting spatial navigation.

Infragranular layers lead information flow during slow oscillations according to information directionality indicators.

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 anesthesia, 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. It was our objective to determine the directionality of the information flow between different layers of the cortex and the connected thalamus during spontaneous activity. With that purpose 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.

Modulation of pain threshold by virtual body ownership.

BACKGROUND: Appropriate sensorimotor correlations can result in the illusion of ownership of exogenous body parts. Nevertheless, whether and how the illusion of owning a new body part affects human perception, and in particular pain detection, is still poorly investigated. Recent findings have shown that seeing one's own body is analgesic, but it is not known whether this effect is transferable to newly embodied, but exogenous, body parts. In recent years, results from our laboratory have demonstrated that a virtual body can be felt as one's own, provided realistic multisensory correlations. METHODS: The current work aimed at investigating the impact of virtual body ownership on pain threshold. An immersive virtual environment allowed a first-person perspective of a virtual body that replaced the own. Passive movement of the index finger congruent with the movement of the virtual index finger was used in the 'synchronous' condition to induce ownership of the virtual arm. The pain threshold was tested by thermal stimulation under four conditions: (1) synchronous movements of the real and virtual fingers; (2) asynchronous movements; (3) seeing a virtual object instead of an arm; and (4) not seeing any limb in real world. RESULTS: Our results show that, independently of attentional and stimulus adaptation processes, the ownership of a virtual arm per se can significantly increase the thermal pain threshold. CONCLUSIONS: This finding may be relevant for the development and improvement of digital solutions for rehabilitation and pain treatment.

Slow wave activity as the default mode of the cerebral cortex.

The function of sleep remained one of largest enigmas of neuroscience for most of the 20th century. However in recent years different evidence has accumulated in support of a critical role of sleep on functions such as replay and memory consolidation. In particular slow wave sleep, and its underlying corticothalamocortical activity, slow oscillations, could be critical not only for memory but also for the maintenance of the brain's structural and func- tional connectivity. In this article we ask: why slow oscillations? To answer this question we put forward the idea that slow oscillations are the default activity of the cortical network based on both experimental and theoretical evidence. We go on to discuss why slow oscillations emerge from the cortical circuits and what are the dynamic advantages of this activity pattern, such as the resilience to perturbances and the facilitation of transitions between a disconnected (e.g. deep sleep) brain and a connected, awake brain.

What Color is My Arm? Changes in Skin Color of an Embodied Virtual Arm Modulates Pain Threshold.

It has been demonstrated that visual inputs can modulate pain. However, the influence of skin color on pain perception is unknown. Red skin is associated to inflamed, hot and more sensitive skin, while blue is associated to cyanotic, cold skin. We aimed to test whether the color 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 color 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 colors on the embodied avatar's arm. We found that a reddened arm significantly decreased the pain threshold compared with normal and bluish skin. This effect was specific when red was seen on the arm, while seeing red in a spot outside the arm did not decrease pain threshold. These results demonstrate an influence of skin color on pain perception. This top-down modulation of pain through visual input suggests a potential use of embodied virtual bodies for pain therapy.

Variability and information content in auditory cortex spike trains during an interval-discrimination task.

Processing of temporal information is key in auditory processing. In this study, we recorded single-unit activity from rat auditory cortex while they performed an interval-discrimination task. The animals had to decide whether two auditory stimuli were separated by either 150 or 300 ms and nose-poke to the left or to the right accordingly. The spike firing of single neurons in the auditory cortex was then compared in engaged vs. idle brain states. We found that spike firing variability measured with the Fano factor was markedly reduced, not only during stimulation, but also in between stimuli in engaged trials. We next explored if this decrease in variability was associated with an increased information encoding. Our information theory analysis revealed increased information content in auditory responses during engagement compared with idle states, in particular in the responses to task-relevant stimuli. Altogether, we demonstrate that task-engagement significantly modulates coding properties of auditory cortical neurons during an interval-discrimination task.

The relationship between virtual body ownership and temperature sensitivity.

In the rubber hand illusion, tactile stimulation seen on a rubber hand, that is synchronous with tactile stimulation felt on the hidden real hand, can lead to an illusion of ownership over the rubber hand. This illusion has been shown to produce a temperature decrease in the hidden hand, suggesting that such illusory ownership produces disownership of the real hand. Here, we apply immersive virtual reality (VR) to experimentally investigate this with respect to sensitivity to temperature change. Forty participants experienced immersion in a VR with a virtual body (VB) seen from a first-person perspective. For half the participants, the VB was consistent in posture and movement with their own body, and in the other half, there was inconsistency. Temperature sensitivity on the palm of the hand was measured before and during the virtual experience. The results show that temperature sensitivity decreased in the consistent compared with the inconsistent condition. Moreover, the change in sensitivity was significantly correlated with the subjective illusion of virtual arm ownership but modulated by the illusion of ownership over the full VB. This suggests that a full body ownership illusion results in a unification of the virtual and real bodies into one overall entity-with proprioception and tactile sensations on the real body integrated with the visual presence of the VB. The results are interpreted in the framework of a 'body matrix' recently introduced into the literature.

Mutual information and redundancy in spontaneous communication between cortical neurons.

An important question in neural information processing is how neurons cooperate to transmit information. To study this question, we resort to the concept of redundancy in the information transmitted by a group of neurons and, at the same time, we introduce a novel concept for measuring cooperation between pairs of neurons called relative mutual information (RMI). Specifically, we studied these two parameters for spike trains generated by neighboring neurons from the primary visual cortex in the awake, freely moving rat. The spike trains studied here were spontaneously generated in the cortical network, in the absence of visual stimulation. Under these conditions, our analysis revealed that while the value of RMI oscillated slightly around an average value, the redundancy exhibited a behavior characterized by a higher variability. We conjecture that this combination of approximately constant RMI and greater variable redundancy makes information transmission more resistant to noise disturbances. Furthermore, the redundancy values suggest that neurons can cooperate in a flexible way during information transmission. This mostly occurs via a leading neuron with higher transmission rate or, less frequently, through the information rate of the whole group being higher than the sum of the individual information rates-in other words in a synergetic manner. The proposed method applies not only to the stationary, but also to locally stationary neural signals.

Cortical auditory adaptation in the awake rat and the role of potassium currents.

Responses to sound in the auditory cortex are influenced by the preceding history of firing. We studied the time course of auditory adaptation in primary auditory cortex (A1) from awake, freely moving rats. Two identical stimuli were delivered with different intervals ranging from 50 ms to 8 s. Single neuron recordings in the awake animal revealed that the response to a sound is influenced by sounds delivered even several seconds earlier, the second one usually yielding a weaker response. To understand the role of neuronal intrinsic properties in this phenomenon, we obtained intracellular recordings from rat A1 neurons in vitro and mimicked the same protocols of adaptation carried out in awake animals by means of depolarizing pulses of identical duration and intervals. The intensity of the pulses was adjusted such that the first pulse would evoke a similar number of spikes as its equivalent in vivo. A1 neurons in vitro adapted with a similar time course but less than in awake animals. At least two potassium currents participated in the in vitro adaptation: a Na(+)-dependent K(+) current and an apamin-sensitive K(+) current. Our results suggest that potassium currents underlie at least part of cortical auditory adaptation during the awake state.

Temperature modulation of slow and fast cortical rhythms.

In the local cortical network, spontaneous emergent activity self-organizes in rhythmic patterns. These rhythms include a slow one (<1 Hz), consisting in alternation of up and down states, and also faster rhythms (10-80 Hz) generated during up states. Varying the temperature in the bath between 26 and 41 degrees C resulted in a strong modulation of the emergent network activity. Up states became shorter for warmer temperatures and longer with cooling, whereas down states were shortest at physiological (36-37 degrees C) temperature. The firing rate during up states was robustly modulated by temperature, increasing with higher temperatures. The sparse firing rate during down states hardly varied with temperature, thus resulting in a progressive merging of up and down states for temperatures around 30 degrees C. Below 30 degrees C and down to 26 degrees C the firing lost rhythmicity, becoming progressively continuous. The slope of the down-to-up transitions, which reflects the speed of recruitment of the local network, was progressively steeper for higher temperatures, whereas wave-propagation speed exhibited only a moderate increase. Fast rhythms were particularly sensitive to temperature. Broadband high-frequency fluctuations in the local field potential were maximal for recordings at 36-38 degrees C. Overall, we found that maintaining cortical slices at physiological temperature is critical for the generated activity to be analogous to that in vivo. We also demonstrate that changes in activity with temperature were not secondary to oxygenation changes. Temperature variation sets the in vitro cortical network at different functional regimes, allowing the exploration of network activity generation and control mechanisms.

Crossmodal audio-visual interactions in the primary visual cortex of the visually deprived cat: a physiological and anatomical study.

Blind individuals often demonstrate enhanced non-visual perceptual abilities. Neuroimaging and transcranial magnetic stimulation experiments have suggested that computations carried out in the occipital cortex may underlie these enhanced somatosensory or auditory performances. Thus, cortical areas that are dedicated to the analysis of the visual scene may, in the blind, acquire the capacity to participate in other sensory processing. However, the neural substrate that underlies this transfer of function is not fully characterized. Here we studied the synaptic and anatomical basis of this phenomenon in cats that were visually deprived by dark rearing, either early visually deprived after birth (EVD), or late visually deprived after the end of the critical period (LVD); data were compared with those obtained in normally reared cats (controls). The presence of synaptic and spike responses to auditory stimulation was examined by means of intracellular recordings in area 17 and the border between areas 17 and 18. While none of the cells recorded in control and LVD cats showed responses to sound, 14% of the cells recorded in EVD cats showed both subthreshold synaptic responses and suprathreshold spike responses to auditory stimuli. Synaptic responses were of small amplitude, but well time-locked to the stimuli and had an average latency of 30+/-12ms. In an attempt to identify the origin of the inputs carrying auditory information to the visual cortex, wheat germ agglutinin-horseradish peroxidase (WGA-HRP) was injected in the visual cortex and retrograde labeling examined in the cortex and thalamus. No significant retrograde labeling was found in auditory cortical areas. However, the proportion of neurons projecting from supragranular layers of the posteromedial and posterolateral parts of the lateral suprasylvian region to V1 was higher than that in control cats. Retrograde labeling in the lateral geniculate nucleus showed no difference in the total number of neurons between control and visually deprived cats, but there was a higher proportion of labeling in C-laminae in deprived cats. Labeled cells were not found in the medial geniculate nucleus, a thalamic relay for auditory information, in either control or visually deprived cats. Finally, immunohistochemistry of the visual cortex of deprived cats revealed a striking decrease in pavalbumin- and calretinin-positive neurons, the functional implications of which we discuss.

Slow adaptation in fast-spiking neurons of visual cortex.

Fast-spiking (FS) neurons are a class of inhibitory interneurons classically characterized as having short-duration action potentials (<0.5 ms at half height) and displaying little to no spike-frequency adaptation during short (<500 ms) depolarizing current pulses. As a consequence, the resulting injected current intensity versus firing frequency relationship is typically steep, and they can achieve firing frequencies of < or =1 kHz. Here we have investigated the properties of FS neurons discharges on a longer time scale. Twenty second discharges were induced in electrophysiologically identified FS neurons by means of current injection either with sinusoidal current or with square pulses. We found that virtually all FS neurons recorded in cortical slices do show spike-frequency adaptation but with a slow time course (tau = 2-19 s). This slow time course has precluded the observation of this property in previous studies that used shorter pulses. Contrary to the classical view of FS neurons functional properties, long-duration discharges were followed by a slow afterhyperpolarization lasting < or =23 s. During this postadaptation period, the excitability of the neurons was decreased on average for 16.7 +/- 6.8 s, therefore rendering the cell less responsive to subsequent afferent inputs. Slow adaptation is also reported here for FS neurons recorded in vivo. This longer time scale of adaptation in FS neurons may be critical for balancing excitation and inhibition as well as for the understanding of cortical network computations.

Application of Lempel-Ziv complexity to the analysis of neural discharges.

Pattern matching is a simple method for studying the properties of information sources based on individual sequences (Wyner et al 1998 IEEE Trans. Inf. Theory 44 2045-56). In particular, the normalized Lempel-Ziv complexity (Lempel and Ziv 1976 IEEE Trans. Inf. Theory 22 75-88), which measures the rate of generation of new patterns along a sequence, is closely related to such important source properties as entropy and information compression ratio. We make use of this concept to characterize the responses of neurons of the primary visual cortex to different kinds of stimulus, including visual stimulation (sinusoidal drifting gratings) and intracellular current injections (sinusoidal and random currents), under two conditions (in vivo and in vitro preparations). Specifically, we digitize the neuronal discharges with several encoding techniques and employ the complexity curves of the resulting discrete signals as fingerprints of the stimuli ensembles. Our results show, for example, that if the neural discharges are encoded with a particular one-parameter method ('interspike time coding'), the normalized complexity remains constant within some classes of stimuli for a wide range of the parameter. Such constant values of the normalized complexity allow then the differentiation of the stimuli classes. With other encodings (e.g. 'bin coding'), the whole complexity curve is needed to achieve this goal. In any case, it turns out that the normalized complexity of the neural discharges in vivo are higher (and hence carry more information in the sense of Shannon) than in vitro for the same kind of stimulus.

On the number of states of the neuronal sources.

In a previous paper (Proceedings of the World Congress on Neuroinformatics (2001)) the authors applied the so-called Lempel-Ziv complexity to study neural discharges (spike trains) from an information-theoretical point of view. Along with other results, it is shown there that this concept of complexity allows to characterize the responses of primary visual cortical neurons to both random and periodic stimuli. To this aim we modeled the neurons as information sources and the spike trains as messages generated by them. In this paper, we study further consequences of this mathematical approach, this time concerning the number of states of such neuronal information sources. In this context, the state of an information source means an internal degree of freedom (or parameter) which allows outputs with more general stochastic properties, since symbol generation probabilities at every time step may additionally depend on the value of the current state of the neuron. Furthermore, if the source is ergodic and Markovian, the number of states is directly related to the stochastic dependence lag of the source and provides a measure of the autocorrelation of its messages. Here, we find that the number of states of the neurons depends on the kind of stimulus and the type of preparation ( in vivo versus in vitro recordings), thus providing another way of differentiating neuronal responses. In particular, we observed that (for the encoding methods considered) in vitro sources have a higher lag than in vivo sources for periodic stimuli. This supports the conclusion put forward in the paper mentioned above that, for the same kind of stimulus, in vivo responses are more random (hence, more difficult to compress) than in vitro responses and, consequently, the former transmit more information than the latter.

Cellular and network mechanisms of rhythmic recurrent activity in neocortex.

The neocortex generates periods of recurrent activity, such as the slow (0.1-0.5 Hz) oscillation during slow-wave sleep. Here we demonstrate that slices of ferret neocortex maintained in vitro generate this slow (< 1 Hz) rhythm when placed in a bathing medium that mimics the extracellular ionic composition in situ. This slow oscillation seems to be initiated in layer 5 as an excitatory interaction between pyramidal neurons and propagates through the neocortex. Our results demonstrate that the cerebral cortex generates an 'up' or depolarized state through recurrent excitation that is regulated by inhibitory networks, thereby allowing local cortical circuits to enter into temporarily activated and self-maintained excitatory states. The spontaneous generation and failure of this self-excited state may account for the generation of a subset of cortical rhythms during sleep.

Membrane mechanisms underlying contrast adaptation in cat area 17 in vivo.

Contrast adaptation is a psychophysical phenomenon, the neuronal bases of which reside largely in the primary visual cortex. The cellular mechanisms of contrast adaptation were investigated in the cat primary visual cortex in vivo through intracellular recording and current injections. Visual cortex cells, and to a much less extent, dorsal lateral geniculate nucleus (dLGN) neurons, exhibited a reduction in firing rate during prolonged presentations of a high-contrast visual stimulus, a process we termed high-contrast adaptation. In a majority of cortical and dLGN cells, the period of adaptation to high contrast was followed by a prolonged (5-80 sec) period of reduced responsiveness to a low-contrast stimulus (postadaptation suppression), an effect that was associated, and positively correlated, with a hyperpolarization of the membrane potential and an increase in apparent membrane conductance. In simple cells, the period of postadaptation suppression was not consistently associated with a decrease in the grating modulated component of the evoked synaptic barrages (the F1 component). The generation of the hyperpolarization appears to be at least partially intrinsic to the recorded cells, because the induction of neuronal activity with the intracellular injection of current resulted in both a hyperpolarization of the membrane potential and a decrease in the spike response to either current injections or visual stimuli. Conversely, high-contrast visual stimulation could suppress the response to low-intensity sinusoidal current injection. We conclude that control of the membrane potential by intrinsic neuronal mechanisms contributes importantly to the adaptation of neuronal responsiveness to varying levels of contrast. This feedback mechanism, internal to cortical neurons, provides them with the ability to continually adjust their responsiveness as a function of their history of synaptic and action potential activity.