Novel rat model of gaming disorder: assessment of social reward and sex differences in behavior and c-Fos brain activity.

RATIONALE: In 2018, the International Classification of Diseases (ICD-11) classified Gaming Disorder (GD) as a mental disorder. GD mainly occurs among adolescents, who, after developing addiction, show psychopathological traits, such as social anxiety, depression, social isolation, and attention deficit. However, the different studies conducted in humans so far show several limitations, such as the lack of demographic heterogeneity and equal representation of age, differences in the type of game and in the follow-up period. Furthermore, at present, no animal models specific to GD are available. OBJECTIVES: To address the lack of an experimental model for GD, in the present work, we proposed a new GD rat model to investigate some peculiar tracts of the disorder. METHODS: Two-month-old Wistar Kyoto rats, both males and females, were subject to a five-week training with a new innovative touch-screen platform. After five weeks of training, rats were assessed for: (a) their attachment to the play under several conditions, (b) their hyperactivity during gaming, and (c) the maintenance of these conditions after a period of game pause and reward interruption. After sacrifice, using immunohistochemistry techniques, the immunoreactivity of c-Fos (a marker of neuronal activity) was analyzed to study different neural areas. RESULTS: After the training, the rats subjected to GD protocol developed GD-related traits (e.g., hyperactivity, loss control), and the behavioral phenotype was maintained consistently over time. These aspects were completely absent in the control groups. Lastly, the analysis of c-Fos immunoreactivity in prelimbic cortex (PrL), orbitofrontal cortex (OFC), nucleus Accumbens, amygdala and bed nucleus of stria terminalis (BNST) highlighted significant alterations in the GD groups compared to controls, suggesting modifications in neural activity related to the development of the GD phenotype. CONCLUSIONS: The proposal of a new GD rat model could represent an innovative tool to investigate, in both sexes, the behavioral and neurobiological features of this disorder, the possible role of external factors in the predisposition and susceptibility and the development of new pharmacological therapies.

Perinatal exposure to bisphenol A or S: Effects on anxiety-related behaviors and serotonergic system.

Bisphenols, synthetic organic compounds used in the production of plastics, are an extremely abundant class of Endocrine Disrupting Chemicals, i.e., exogenous chemicals or mixtures of chemicals that can interfere with any aspect of hormone action. Exposure to BPs can lead to a wide range of effects, and it is especially dangerous if it occurs during specific critical periods of life. Focusing on the perinatal exposure to BPA or its largely used substitute BPS, we investigated the effects on anxiety-related behaviors and the serotonergic system, which is highly involved in controlling these behaviors, in adult mice. We treated C57BL/6J dams orally with a dose of 4 µg/kg body weight/day (i.e., EFSA TDI) of BPA or BPS dissolved in corn oil or with vehicle alone, at the onset of mating and continued treatment until the offspring were weaned. Adult offspring of both sexes performed the elevated plus maze and the open field tests. Then, we analyzed the serotonergic system in dorsal (DR) and median (MnR) raphe nuclei by immunohistochemical techniques. Behavioral tests highlighted alterations in BPA- and BPS-treated mice, suggesting different effects of the bisphenols exposure on anxiety-related behavior in males (anxiolytic) and females (anxiogenic). The analysis of the serotonergic system highlighted a sex dimorphism in the DR only, with control females showing higher values of serotonin immunoreactivity (5-HT-ir) than control males. BPA-treated males displayed a significant increase of 5-HT-ir in all analyzed nuclei, whereas BPS-treated males showed an increase in ventral DR only. In females, both bisphenols-treated groups showed a significant increase of 5-HT-ir in dorsal DR compared to the controls, and BPA-treated females also showed a significant increase in MnR.These results provide evidence that exposure during the early phases of life to BPA or BPS alters anxiety and the raphe serotonergic neurons in a sex-dependent manner.

Head-Mounted Displays for Upper Limb Stroke Rehabilitation: A Scoping Review.

Upper extremity (UE) paresis is one of the most frequent and disabling clinical consequences after stroke. Head-Mounted Displays (HMDs) are wearable virtual reality devices that seem effective in promoting the recovery of functional abilities by increasing adherence levels in this population. This scoping review is aimed at collecting available evidence on the use of HMD-based immersive virtual reality systems for UE rehabilitation treatment in stroke survivors. Four electronic bibliographic databases were consulted from inception until 18 January 2023. A total of 19 clinical trials in which HMDs were used as a clinical tool for increasing UE functioning, as a single intervention or in adjunct to other rehab treatments, were included; no restrictions were applied for UE paresis severity or stroke onset. The large majority of the clinical trials involved chronic stroke patients (15 out of 19), with a wide range of UE impairments. Overall, HMD use seemed to be well-tolerated and promising for increasing UE motor function in adult chronic stroke survivors, with benefits in subjects' arm use and independence. The possibility of executing highly realistic and task-oriented movements appears to be promising in enhancing gesture relevance, thus promoting new motor strategies in a "virtual ecological way". Across studies, we found a high heterogeneity in protocol design and a lack of reporting that prevents us drawing conclusions regarding potential subgroups of patients that could benefit more from HMD-based interventions or suggested treatment modalities.

Modeling Multiple Sclerosis in the Two Sexes: MOG35-55-Induced Experimental Autoimmune Encephalomyelitis.

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease affecting the central nervous system (CNS). It is characterized by different prevalence in the sexes, affecting more women than men, and different outcomes, showing more aggressive forms in men than in women. Furthermore, MS is highly heterogeneous in terms of clinical aspects, radiological, and pathological features. Thus, it is necessary to take advantage of experimental animal models that allow the investigation of as many aspects of the pathology as possible. Experimental autoimmune encephalomyelitis (EAE) represents one of the most used models of MS in mice, modeling different disease features, from the activation of the immune system to CNS damage. Here we describe a protocol for the induction of EAE in both male and female C57BL/6J mice using myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) immunization, which leads to the development of a chronic form of the disease. We also report the evaluation of the daily clinical score and motor performance of these mice for 28 days post immunization (28 dpi). Lastly, we illustrate some basic histological analysis at the CNS level, focusing on the spinal cord as the primary site of disease-induced damage.

Quantitative Comparison of Hand Kinematics Measured with a Markerless Commercial Head-Mounted Display and a Marker-Based Motion Capture System in Stroke Survivors.

Upper-limb paresis is common after stroke. An important tool to assess motor recovery is to use marker-based motion capture systems to measure the kinematic characteristics of patients' movements in ecological scenarios. These systems are, however, very expensive and not readily available for many rehabilitation units. Here, we explored whether the markerless hand motion capabilities of the cost-effective Oculus Quest head-mounted display could be used to provide clinically meaningful measures. A total of 14 stroke patients executed ecologically relevant upper-limb tasks in an immersive virtual environment. During task execution, we recorded their hand movements simultaneously by means of the Oculus Quest's and a marker-based motion capture system. Our results showed that the markerless estimates of the hand position and peak velocity provided by the Oculus Quest were in very close agreement with those provided by a marker-based commercial system with their regression line having a slope close to 1 (maximum distance: mean slope = 0.94 ± 0.1; peak velocity: mean slope = 1.06 ± 0.12). Furthermore, the Oculus Quest had virtually the same sensitivity as that of a commercial system in distinguishing healthy from pathological kinematic measures. The Oculus Quest was as accurate as a commercial marker-based system in measuring clinically meaningful upper-limb kinematic parameters in stroke patients.

Representational momentum of biological motion in full-body, point-light and single-dot displays.

Observing the actions of others triggers, in our brain, an internal and automatic simulation of its unfolding in time. Here, we investigated whether the instantaneous internal representation of an observed action is modulated by the point of view under which an action is observed and the stimulus type. To this end, we motion captured the elliptical arm movement of a human actor and used these trajectories to animate a photorealistic avatar, a point-light stimulus or a single dot rendered either from an egocentric or an allocentric point of view. Crucially, the underlying physical characteristics of the movement were the same in all conditions. In a representational momentum paradigm, we then asked subjects to report the perceived last position of an observed movement at the moment in which the stimulus was randomly stopped. In all conditions, subjects tended to misremember the last configuration of the observed stimulus as being further forward than the veridical last showed position. This misrepresentation was however significantly smaller for full-body stimuli compared to point-light and single dot displays and it was not modulated by the point of view. It was also smaller when first-person full body stimuli were compared with a stimulus consisting of a solid shape moving with the same physical motion. We interpret these findings as evidence that full-body stimuli elicit a simulation process that is closer to the instantaneous veridical configuration of the observed movements while impoverished displays (both point-light and single-dot) elicit a prediction that is further forward in time. This simulation process seems to be independent from the point of view under which the actions are observed.

Effects of perinatal exposure to bisphenol A or S in EAE model of multiple sclerosis.

Epidemiological studies support the idea that multiple sclerosis (MS) is a multifactorial disease, overlapping genetic, epigenetic, and environmental factors. A better definition of environmental risks is critical to understand both etiology and the sex-related differences of MS. Exposure to endocrine-disrupting compounds (EDCs) fully represents one of these risks. EDCs are natural or synthetic exogenous substances (or mixtures) that alter the functions of the endocrine system. Among synthetic EDCs, exposure to bisphenol A (BPA) has been implicated in the etiology of MS, but to date, controversial data has emerged. Furthermore, nothing is known about bisphenol S (BPS), one of the most widely used substitutes for BPA. As exposure to bisphenols will not disappear soon, it is necessary to clarify their role also in this pathological condition defining their role in disease onset and course in both sexes. In this study, we examined, in both sexes, the effects of perinatal exposure to BPA and BPS in one of the most widely used mouse models of MS, experimental autoimmune encephalomyelitis (EAE). Exposure to bisphenols seemed to be particularly deleterious in males. In fact, both BPA- and BPS-treated males showed anticipation of the disease onset and an increased motoneuron loss in the spinal cord. Overall, BPA-treated males also displayed an exacerbation of EAE course and an increase in inflammation markers in the spinal cord. Analyzing the consequences of bisphenol exposure on EAE will help to better understand the role of both xenoestrogens and endogenous estrogens on the sexually dimorphic characteristics of MS.

Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models.

Alzheimer's disease (AD) is characterized by genetic and multifactorial risk factors. Many studies correlate AD to sleep disorders. In this study, we performed and validated a mouse model of AD and sleep fragmentation, which properly mimics a real condition of intermittent awakening. We noticed that sleep fragmentation induces a general acceleration of AD progression in 5xFAD mice, while in wild type mice it affects cognitive behaviors in particular learning and memory. Both these events may be correlated to aquaporin-4 (AQP4) modulation, a crucial player of the glymphatic system activity. In particular, sleep fragmentation differentially affects aquaporin-4 channel (AQP4) expression according to the stage of the disease, with an up-regulation in younger animals, while such change cannot be detected in older ones. Moreover, in wild type mice sleep fragmentation affects cognitive behaviors, in particular learning and memory, by compromising the glymphatic system through the decrease of AQP4. Nevertheless, an in-depth study is needed to better understand the mechanism by which AQP4 is modulated and whether it could be considered a risk factor for the disease development in wild type mice. If our hypotheses are going to be confirmed, AQP4 modulation may represent the convergence point between AD and sleep disorder pathogenic mechanisms.

I can see my virtual body in a mirror: The role of visual perspective in changing implicit racial attitudes using virtual reality.

Introduction: Recent studies showed that VR is a valid tool to change implicit attitudes toward outgroup members. Here, we extended this work by investigating conditions under which virtual reality (VR) is effective in changing implicit racial attitudes. Methods: To this end, participants were embodied in a Black or White avatar and we manipulated the perspective through which they could see their virtual body. Participants in one condition, could see their virtual body both from a first-person perspective (i.e., by looking down toward themselves) and reflected in a mirror placed in front of them in the VR environment. Participants in another condition could instead see their virtual body only from a first-person perspective (i.e., by looking down toward themselves) as no mirror was placed in the VR environment. Implicit racial attitudes were assessed using the Implicit Association Test (IAT) before and immediately after the VR intervention. Results: Results showed that when White participants were embodied in a Black avatar compared to a White avatar, they showed a decrease in their implicit pro-White attitudes but only when they could see their virtual body both from a first-person perspective and in a mirror. Discussion: These results suggest that, in immersive virtual reality interventions, the possibility for participants to see their body also reflected in a mirror, might be a critical factor in changing their implicit racial attitudes.

A novel immersive virtual reality environment for the motor rehabilitation of stroke patients: A feasibility study.

We designed and implemented an immersive virtual reality (VR) environment for upper limb rehabilitation, which possesses several notable features. First, by exploiting modern computer graphics its can present a variety of scenarios that make the rehabilitation routines challenging yet enjoyable for patients, thus enhancing their adherence to the therapy. Second, immersion in a virtual 3D space allows the patients to execute tasks that are closely related to everyday gestures, thus enhancing the transfer of the acquired motor skills to real-life routines. Third, in addition to the VR environment, we also developed a client app running on a PC that allows to monitor in real-time and remotely the patients' routines thus paving the way for telerehabilitation scenarios. Here, we report the results of a feasibility study in a cohort of 16 stroke patients. All our patients showed a high degree of comfort in our immersive VR system and they reported very high scores of ownership and agency in embodiment and satisfaction questionnaires. Furthermore, and notably, we found that behavioral performances in our VR tasks correlated with the patients' clinical scores (Fugl-Meyer scale) and they could thus be used to assess improvements during the rehabilitation program. While further studies are needed, our results clearly support the feasibility and effectiveness of VR-based motor rehabilitation processes.

Effects of chronic exposure to bisphenol A in adult female mice on social behavior, vasopressin system, and estrogen membrane receptor (GPER1).

Bisphenol A (BPA), an organic synthetic compound found in some plastics and epoxy resins, is classified as an endocrine disrupting chemical. Exposure to BPA is especially dangerous if it occurs during specific "critical periods" of life, when organisms are more sensitive to hormonal changes (i.e., intrauterine, perinatal, juvenile or puberty periods). In this study, we focused on the effects of chronic exposure to BPA in adult female mice starting during pregnancy. Three months old C57BL/6J females were orally exposed to BPA or to vehicle (corn oil). The treatment (4 µg/kg body weight/day) started the day 0 of pregnancy and continued throughout pregnancy, lactation, and lasted for a total of 20 weeks. BPA-treated dams did not show differences in body weight or food intake, but they showed an altered estrous cycle compared to the controls. In order to evidence alterations in social and sociosexual behaviors, we performed the Three-Chamber test for sociability, and analyzed two hypothalamic circuits (well-known targets of endocrine disruption) particularly involved in the control of social behavior: the vasopressin and the oxytocin systems. The test revealed some alterations in the displaying of social behavior: BPA-treated dams have higher locomotor activity compared to the control dams, probably a signal of high level of anxiety. In addition, BPA-treated dams spent more time interacting with no-tester females than with no-tester males. In brain sections, we observed a decrease of vasopressin immunoreactivity (only in the paraventricular and suprachiasmatic nuclei) of BPA-treated females, while we did not find any alteration of the oxytocin system. In parallel, we have also observed, in the same hypothalamic nuclei, a significant reduction of the membrane estrogen receptor GPER1 expression.

Prediction of Speech Onset by Micro-Electrocorticography of the Human Brain.

Recent technological advances show the feasibility of offline decoding speech from neuronal signals, paving the way to the development of chronically implanted speech brain computer interfaces (sBCI). Two key steps that still need to be addressed for the online deployment of sBCI are, on the one hand, the definition of relevant design parameters of the recording arrays, on the other hand, the identification of robust physiological markers of the patient's intention to speak, which can be used to online trigger the decoding process. To address these issues, we acutely recorded speech-related signals from the frontal cortex of two human patients undergoing awake neurosurgery for brain tumors using three different micro-electrocorticographic ([Formula: see text]ECoG) devices. First, we observed that, at the smallest investigated pitch (600[Formula: see text][Formula: see text]m), neighboring channels are highly correlated, suggesting that more closely spaced electrodes would provide some redundant information. Second, we trained a classifier to recognize speech-related motor preparation from high-gamma oscillations (70-150[Formula: see text]Hz), demonstrating that these neuronal signals can be used to reliably predict speech onset. Notably, our model generalized both across subjects and recording devices showing the robustness of its performance. These findings provide crucial information for the design of future online sBCI.

Robust point-process Granger causality analysis in presence of exogenous temporal modulations and trial-by-trial variability in spike trains.

Assessing directional influences between neurons is instrumental to understand how brain circuits process information. To this end, Granger causality, a technique originally developed for time-continuous signals, has been extended to discrete spike trains. A fundamental assumption of this technique is that the temporal evolution of neuronal responses must be due only to endogenous interactions between recorded units, including self-interactions. This assumption is however rarely met in neurophysiological studies, where the response of each neuron is modulated by other exogenous causes such as, for example, other unobserved units or slow adaptation processes. Here, we propose a novel point-process Granger causality technique that is robust with respect to the two most common exogenous modulations observed in real neuronal responses: within-trial temporal variations in spiking rate and between-trial variability in their magnitudes. This novel method works by explicitly including both types of modulations into the generalized linear model of the neuronal conditional intensity function (CIF). We then assess the causal influence of neuron i onto neuron j by measuring the relative reduction of neuron j's point process likelihood obtained considering or removing neuron i. CIF's hyper-parameters are set on a per-neuron basis by minimizing Akaike's information criterion. In synthetic data sets, generated by means of random processes or networks of integrate-and-fire units, the proposed method recovered with high accuracy, sensitivity and robustness the underlying ground-truth connectivity pattern. Application of presently available point-process Granger causality techniques produced instead a significant number of false positive connections. In real spiking responses recorded from neurons in the monkey pre-motor cortex (area F5), our method revealed many causal relationships between neurons as well as the temporal structure of their interactions. Given its robustness our method can be effectively applied to real neuronal data. Furthermore, its explicit estimate of the effects of unobserved causes on the recorded neuronal firing patterns can help decomposing their temporal variations into endogenous and exogenous components.

Contrast sensitivity reveals an oculomotor strategy for temporally encoding space.

The contrast sensitivity function (CSF), how sensitivity varies with the frequency of the stimulus, is a fundamental assessment of visual performance. The CSF is generally assumed to be determined by low-level sensory processes. However, the spatial sensitivities of neurons in the early visual pathways, as measured in experiments with immobilized eyes, diverge from psychophysical CSF measurements in primates. Under natural viewing conditions, as in typical psychophysical measurements, humans continually move their eyes even when looking at a fixed point. Here, we show that the resulting transformation of the spatial scene into temporal modulations on the retina constitutes a processing stage that reconciles human CSF and the response characteristics of retinal ganglion cells under a broad range of conditions. Our findings suggest a fundamental integration between perception and action: eye movements work synergistically with the spatio-temporal sensitivities of retinal neurons to encode spatial information.

SiNAPS: An implantable active pixel sensor CMOS-probe for simultaneous large-scale neural recordings.

Large-scale neural recordings with high spatial and temporal accuracy are instrumental to understand how the brain works. To this end, it is of key importance to develop probes that can be conveniently scaled up to a high number of recording channels. Despite recent achievements in complementary metal-oxide semiconductor (CMOS) multi-electrode arrays probes, in current circuit architectures an increase in the number of simultaneously recording channels would significantly increase the total chip area. A promising approach for overcoming this scaling issue consists in the use of the modular Active Pixel Sensor (APS) concept, in which a small front-end circuit is located beneath each electrode. However, this approach imposes challenging constraints on the area of the in-pixel circuit, power consumption and noise. Here, we present an APS CMOS-probe technology for Simultaneous Neural recording that successfully addresses all these issues for whole-array read-outs at 25 kHz/channel from up to 1024 electrode-pixels. To assess the circuit performances, we realized in a 0.18 µm CMOS technology an implantable single-shaft probe with a regular array of 512 electrode-pixels with a pitch of 28 µm. Extensive bench tests showed an in-pixel gain of 45.4 ± 0.4 dB (low pass, F-3 dB = 4 kHz), an input referred noise of 7.5 ± 0.67 µVRMS (300 Hz to 7.5 kHz) and a power consumption <6 µW/pixel. In vivo acute recordings demonstrate that our SiNAPS CMOS-probe can sample full-band bioelectrical signals from each electrode, with the ability to resolve and discriminate activity from several packed neurons both at the spatial and temporal scale. These results pave the way to new generations of compact and scalable active single/multi-shaft brain recording systems.

Human movements and abstract motion displays activate different processes in the observer's motor system.

Brain imaging studies have shown that observation of both bodily movements and abstract motion displays complying with human kinematics activate the observer's motor cortex. However, it is unknown whether the same processes are active in the two conditions. Here, we addressed this issue using transcranial magnetic stimulation (TMS) to directly compare cortico-spinal excitability during observation of actions and motion stimuli that complied with or violated normal human kinematics. We found that kinematics significantly modulated the motor-evoked potentials (MEPs) produced by TMS during observation of both human and abstract motion stimuli. However, only the temporal unfolding of cortico-spinal excitability during observation of human movements significantly correlated with instantaneous stimulus velocity. This correlation was present for normal movements and also for a subset of the movements having unnatural kinematics. Furthermore, bodily movements for which we found no correlation between MEPs and stimulus velocity produced significantly higher MEPs. Our novel results suggest a dissociation in how human movements and abstract motion displays engage the observer's motor system. Specifically, while both stimulus types significantly activate the observer's motor cortex, only bodily movements produce patterns of cortico-spinal excitability that closely follow the velocity profile of the observed movement. This internal "re-enactment" of observed bodily movements seems to be only partially attuned to normal human kinematics.

Encoding of point of view during action observation in the local field potentials of macaque area F5.

The discovery of mirror neurons compellingly shows that the monkey premotor area F5 is active not only during the execution but also during the observation of goal-directed motor acts. Previous studies have addressed the functioning of the mirror-neuron system at the single-unit level. Here, we tackled this research question at the network level by analysing local field potentials in area F5 while the monkey was presented with goal-directed actions executed by a human or monkey actor and observed either from a first-person or third-person perspective. Our analysis showed that rhythmic responses are not only present in area F5 during action observation, but are also modulated by the point of view. Observing an action from a subjective point of view produced significantly higher power in the low-frequency band (2-10 Hz) than observing the same action from a frontal view. Interestingly, an increase in power in the 2-10 Hz band was also produced by the execution of goal-directed motor acts. Independently of the point of view, action observation also produced a significant decrease in power in the 15-40 Hz band and an increase in the 60-100 Hz band. These results suggest that, depending on the point of view, action observation might activate different processes in area F5. Furthermore, they may provide information about the functional architecture of action perception in primates.

Mirror neurons (and beyond) in the macaque brain: an overview of 20 years of research.

Mirror neurons are a class of neurons in the ventral pre-motor cortex (area F5) and inferior parietal lobule (area PFG) that respond during the execution as well as the observation of goal-directed motor acts. These intriguing response properties stirred an intense debate in the scientific community with respect to the possible cognitive role of mirror neurons. The aim of the present review is to contribute to this debate by providing, in a single paper, an extended summary of 20 years of neurophysiological research on mirror neurons in the macaque. To this end, I provide a comprehensive description of the methodology and the main results of each paper about mirror neurons published since their first report in 1992. Particular care was devoted in reporting the different response characteristics and the percentages of neurons exhibiting them in relation to the total number of studied neurons. Furthermore, I also discuss recent results indicating that mirror neurons might not be confined to areas F5 and PFG and that "mirroring" might not be limited to action observation. Finally, I offer a unifying framework for many of the results discussed here by speculating that a potential functional role of mirror neurons might be, during action observation, to generalize from the particular grasping movement being observed to the "concept" of grasping.