Spontaneous Responses Research Articles

Association of brain-autonomic activities and task accuracy under cognitive load: a pilot study using electroencephalogram, autonomic activity measurements, and arousal level estimated by machine learning.

The total amount of mental activity applied to working memory at a given point in time is called cognitive load, which is an important factor in various activities in daily life. We have proposed new feature quantities that reflect the time-series changes in the power of typical frequency bands in electroencephalogram (EEG) for use in examining the relationship between brain activity and behavior under cognitive load. We also measured heart rate variability (HRV) and spontaneous skin conductance responses (SCR) to examine functional associations among brain activity, autonomic activity, and behavior under cognitive load. Additionally, we applied our machine learning model previously developed using EEG to the estimation of arousal level to interpret the brain-autonomic-behavior functional association under cognitive load. Experimental data from 12 healthy undergraduate students showed that participants with higher levels of infra-slow fluctuations of alpha power have more cognitive resources and thus can process information under cognitive load more efficiently. In addition, HRV reflecting parasympathetic activity correlated with task accuracy. The arousal level estimated using our machine learning model showed its robust relationship with EEG. Despite the limitation of the sample size, the results of this pilot study suggest that the information processing efficiency of the brain under cognitive load is reflected by time-series fluctuations in EEG, which are associated with an individual's task performance. These findings can contribute to the evaluation of the internal state of humans associated with cognitive load and the prediction of human behaviors in various situations under cognitive load.

Two Dimensions of a Bodhisattva

This paper presents two dimensions of a bodhisattva, the ideal of Maha- ya- na Buddhism. One dimension involves contemplative practices that disclose a pure nature that is always already present; this reality is unveiled after the obscurations that cloud it are removed. I refer to this as a “top-down” approach because it is based on qualities of awakening that are already there, yet lie beyond an ordinary being’s comprehension. The second dimension, which I refer to as a “bottom-up” approach, involves directed training and discipline. Unlike the top-down approach, this is not about “going with the flow” or simply letting the innate qualities of mind express themselves. In contrast, the bottom-up approach is better described as “breaking the cycle” of suffering. That is to say, this orientation toward a bodhisattva’s practice involves restraint and discipline to train the mind by turning it away from habitual, destructive patterns to shape it into spontaneous and skillful responses and expressions. This paper will discuss both of these orientations and will show how they are complementary aspects of a bodhisattva’s practice.

Incidental Gliosis in the Central Nervous System of Control Nonhuman Primates and Rats.

Gliosis, including microgliosis and astrocytosis, can be challenging to interpret in nonclinical studies. Incidences of glial foci in brains and spinal cords of control rats and nonhuman primates (NHPs) were reviewed in the historical control databases from two contract research organizations, including one specializing in neuropathology. In the brain, minimal to mild (grades 1-2) microgliosis was the most common diagnosis, especially in NHPs, although occasional moderate or marked microgliosis (grades 3 and 4) was encountered in both species. Microgliosis was more common in the cerebral cortex, cerebellum, and medulla oblongata in both species and was frequent in the white matter (brain), thalamus, and basal nuclei of NHPs. Gliosis ("not otherwise specified") of minimal severity was diagnosed in similar brain sub-sites for both species and was more common in NHPs compared with rats. Astrocytosis was most prominent in the cerebellum (molecular layer) of NHPs but was otherwise uncommon. In the spinal cord, microgliosis was most common in the lateral white matter tracts in rats and NHPs, and in the dorsal white matter tracts in NHPs. These data indicate that low-grade spontaneous glial responses occur with some frequency in control animals of two common nonclinical species.

Plasmacytoid dendritic cell‐derived secretome ameliorates neuropathic corneal pain

Aims/Purpose: Prior work from our group has demonstrated a role for plasmacytoid dendritic cells (pDCs) in corneal nerve homeostasis. Herein, we sought to determine if pDC‐derived secretome could be used for the treatment of neuropathic corneal pain.Methods: The BDCA2‐DTR transgenic mice, in which pDCs can be selectively depleted result in subsequent nerve degeneration, were utilized for ex vivo electrophysiology studies. Animals were treated with pDC secretome drops, beginning 1 day after initial depletion. Electrophysiologic recordings were taken at day 3 post‐depletion analysed. A ciliary nerve ligation model of neuropathic corneal pain (NCP), was used to assess the therapeutic potential of pDC secretome. Spontaneous and evoked pain responses were assessed by palpebral opening measurements and hyperosmolar saline, respectively.Results: There was a significant reduction in cooling threshold following pDC depletion, which was rescued by pDC secretome treatment (26.85 ± 0.65°C vs. 29.52 ± 0.42°C; p < 0.05), restoring the cooling threshold to control levels (29.21 ± 0.51). Furthermore, nerve terminal exhaustion was reduced following pDC depletion and rescued by pDC secretome treatment (0.55 ± 0.08 vs. 1.11 ± 0.10; p < 0.01). Spontaneous pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (0.67 ± 0.03 vs. 0.85 ± 0.02; p < 0.001). Similarly, evoked pain responses were worse in the vehicle‐treated compared to pDC secretome‐treated group (30.25 ± 1.50 wipes/30 sec vs. 15.38 ± 1.29; p < 0.0001).Conclusions: Herein, we demonstrate that pDC secretome restores normal functioning of corneal cold receptors. Importantly, in a translational model of NCP, pDC secretome treatment improved both spontaneous and evoked pain responses. Thus, pDC secretome is a viable therapeutic modality for further development and may hold promise in treatment of NCP and other corneal nerve related diseases.Reference1. Jamali A, Kenyon B, Ortiz G, Abou‐Slaybi A, Sendra VG, Harris DL, Hamrah P. Plasmacytoid Dendritic Cells in the Eye. Prog Retin Eye Res 2021; 80: 100877.2. Jamali A, Hu K, Sendra VG, Blanco T, Qazi Y, Zheng L, Turhan A, Hamrah P. Characterization of Resident Corneal Plasmacytoid Dendritic Cells and Their Pivotal Role in Herpes Simplex Keratitis. Cell Rep 2020; 32: 108099.

Multicultural Learning Strategies to Improve Social Care Character at an Elementary School: A Case Study at Muhammadiyah 6 Elementary School North Samarinda

This study aims to analyze teacher strategies in shaping social care character and constraints experienced in shaping social care character of third grade students at Muhammadiyah 6 Elementary School North Samarinda 2022/2023 Academic Year. This study uses qualitative methods with data collection techniques namely interviews, observations, and documentation. The study conducted at SD Muhammadiyah 6 Samarinda Utara revealed creative strategies adopted by teachers to cultivate social care character among third grade students. By implementing routine activities such as ‘Sharing Friday’, weekly infaq, and spontaneous responses in the form of reprimands and advice, teachers inculcate caring values. They also demonstrate exemplary behavior and transform the classroom environment to facilitate better social interactions. The use of magic words in daily interactions and the integration of social care values in Civics Education lessons emphasize the importance of empathy and solidarity. The researcher recommends that the school develop learning materials that reflect the cultural, religious and ethnic diversity in Indonesia and provide professional training for teachers on how to integrate multicultural education into their teaching and how to identify and respond to bias in the classroom.

The hidden cues of social class: What do people rely on when determining someone else's social class?

AbstractWe aimed to understand the cues individuals use to assess social class, and their relation to social theories. Participant (N = 235) open‐ended survey responses were coded in response to the following: “If you can at least sometimes tell if someone is (#1) working‐class/poor OR (#2) middle‐/upper‐class, how can you tell? What are all of the characteristics, behaviors, and/or other indicators that communicate their social class to you?” Based on participant comments, we created six themes: embodied cultural capital, material/economic capital, taste, status/position, institutional cultural capital, and social capital. First, we found spontaneous participant responses reflected several classic social class theories. Second, while the content often differed in terms of how participants discussed the working‐class/poor compared to the middle‐/upper‐class, there was only one significant difference in frequency of response. Specifically, participants were more likely to express the embodied cultural capital theme when asked about the working‐class/poor. Finally, participants with some more privileged identities (e.g., racially white, those with higher education, straight/heterosexual participants) were more likely to focus on symbolic or non‐material aspects of class compared to participants with some less privileged identities (e.g., participants with lower incomes in their families of origin), who focused more on material and economic cues in determining a person's class.

Comparison of two reaction-time-based and one foraging-based behavioral approach-avoidance tasks in relation to interindividual differences and their reliability

Approaching rewards and avoiding punishments is a fundamental aspect of behavior, yet individuals differ in the extent of these behavioral tendencies. One popular method to assess differences in approach-avoidance tendencies and even modify them, is using behavioral tasks in which spontaneous responses to differently valenced stimuli are assessed (e.g., the visual joystick and the manikin task). Understanding whether these reaction-time-based tasks map onto the same underlying constructs, how they predict interindividual differences in theoretically related constructs and how reliable they are, seems vital to make informed judgements about current findings and future studies. In this preregistered study, 168 participants (81 self-identified men, 87 women) completed emotional face versions of these tasks as well as an alternative, foraging-based paradigm, the approach-avoidance-conflict task, and answered self-report questionnaires regarding anxiety, aggression, depressive symptoms, behavioral inhibition and activation. Importantly, approach-avoidance outcome measures of the two reaction-time-based tasks were unrelated with each other, showed little relation to self-reported interindividual differences and had subpar internal consistencies. In contrast, the approach-avoidance-conflict task was related to behavioral inhibition and aggression, and had good internal consistencies. Our study highlights the need for more research into optimizing behavioral approach-avoidance measures when using task-based approach-avoidance measures to assess interindividual differences.

An Exploratory Study to Investigate the Implementation of Feynman Learning Method in a Physics Classroom Setting

In order to explore alternative methods to learn physics effectively, this research was inspired by a fundamental question: how did famous physicists use to learn and/or teach physics? Are there any recipies suggested by these physicists which are still relevant and can be imitated and applied to physics learning in a today classroom? This research aims at exploring the impact of the implementation of Feynman learning method on students’ physics concepts understanding and describing their spontaneous responses about the implementation of this learning method afterwards. This research was an exploratory research conducted at one grade X science class of St. Gabriel Catholic Senior High School in Maumere city, Flores. Data regarding students’ understanding were collected through pre and post test questionnairres and their spontaneous responses were obtained through unstructured interview. The results of N-gain pretest and post test score was 0.49. Apart from few non-positive responses, students’ responses indicated that the method can encourage them to actively participate in the learning process, improve their communication skill, and train their abilities to explain things in simple ways. The results suggest that there was an improvement in students’ physics concepts understanding with a medium N-gain score and that this learning method is positively appreciated by the participants.

EGFR Tyrosine Kinase Inhibitor Lazertinib Activates a Subset of Mouse Sensory Neurons Via TRPA1

Lazertinib (JNJ-73841937, YH25448) is a mutant-selective irreversible epidermal growth factor receptor tyrosine kinase inhibitor targeting both the T790M and activating mutation while sparing wild-type epidermal growth factor receptor. Paresthesia is one of the most common adverse events seen with lazertinib treatment, suggesting that lazertinib could affect the sensory nervous system. However, the mechanism of action for this paresthesia remains unclear. In this study, we investigated whether and how lazertinib affects peripheral sensory neurons. Through Fura-2-based calcium imaging and whole-cell patch clamp recording in primary-cultured dorsal root ganglion (DRG) neurons from adult mice, we found that application of lazertinib elicits spontaneous calcium responses in a subset of small-to-medium-sized neurons. Moreover, lazertinib induced spontaneous firings and hyperexcitability in a subset of transient receptor potential vanilloid 1-lineage DRG neurons and sensitized transient receptor potential ankyrin 1 (TRPA1) response, while sparing transient receptor potential vanilloid 1 response. Lazertinib-responsive neurons were also responsive to capsaicin, further supporting that lazertinib selectively activates nociceptive neurons. Lazertinib-induced calcium responses were pharmacologically blocked with HC-030031 (TRPA1 antagonist) and MDL-12330A (adenylyl cyclase inhibitor), suggesting that lazertinib activates sensory neurons through indirect activation of TRPA1. However, unlike vincristine which produces peripheral neuropathy by axonal degeneration, lazertinib did not cause neurite fragmentation in cultured DRG neurons. Finally, intraplantar injection of lazertinib induced TRPA1-dependent pain-like behaviors in vivo. Collectively, our data suggest a direct effect of lazertinib on nociceptive sensory neurons via TRPA1 selective mechanisms, which could be a putative mechanism of lazertinib-induced sensory abnormalities in clinical patients. PerspectiveThis article presents a TRPA1-dependent, lazertinib-induced activation of mouse sensory neurons in vitro and lazertinib-induced pain-like behaviors in vivo. The same mechanisms may underlie the clinical condition, suggesting that TRPA1 could be a potential therapeutic target to manage lazertinib-induced paresthesia.

Two-photon live imaging of direct glia-to-neuron conversion in the mouse cortex.

JOURNAL/nrgr/04.03/01300535-202408000-00032/figure1/v/2023-12-16T180322Z/r/image-tiff Over the past decade, a growing number of studies have reported transcription factor-based in situ reprogramming that can directly convert endogenous glial cells into functional neurons as an alternative approach for neuroregeneration in the adult mammalian central nervous system. However, many questions remain regarding how a terminally differentiated glial cell can transform into a delicate neuron that forms part of the intricate brain circuitry. In addition, concerns have recently been raised around the absence of astrocyte-to-neuron conversion in astrocytic lineage-tracing mice. In this study, we employed repetitive two-photon imaging to continuously capture the in situ astrocyte-to-neuron conversion process following ectopic expression of the neural transcription factor NeuroD1 in both proliferating reactive astrocytes and lineage-traced astrocytes in the mouse cortex. Time-lapse imaging over several weeks revealed the step-by-step transition from a typical astrocyte with numerous short, tapered branches to a typical neuron with a few long neurites and dynamic growth cones that actively explored the local environment. In addition, these lineage-converting cells were able to migrate radially or tangentially to relocate to suitable positions. Furthermore, two-photon Ca2+ imaging and patch-clamp recordings confirmed that the newly generated neurons exhibited synchronous calcium signals, repetitive action potentials, and spontaneous synaptic responses, suggesting that they had made functional synaptic connections within local neural circuits. In conclusion, we directly visualized the step-by-step lineage conversion process from astrocytes to functional neurons in vivo and unambiguously demonstrated that adult mammalian brains are highly plastic with respect to their potential for neuroregeneration and neural circuit reconstruction.

Proprioceptive Modulation of Pallidal Physiology in Cervical Dystonia.

There is a growing body of evidence suggesting that botulinum toxin can alter proprioceptive feedback and modulate the muscle-spindle output for the treatment of dystonia. However, the mechanism for this modulation remains unclear. We conducted a study involving 17 patients with cervical dystonia (CD), seven of whom had prominent CD and 10 with generalized dystonia (GD) along with CD. We investigated the effects of neck vibration, a form of proprioceptive modulation, on spontaneous single-neuron responses and local field potentials (LFPs) recorded from the globus pallidum externus (GPe) and internus (GPi). Our findings demonstrated that neck vibration notably increased the regularity of neck-sensitive GPi neurons in focal CD patients. Additionally, in patients with GD and CD, the vibration enhanced the firing regularity of non-neck-sensitive neurons. These effects on single-unit activity were also mirrored in ensemble responses measured through LFPs. Notably, the LFP modulation was particularly pronounced in areas populated with burst neurons compared to pause or tonic cells. The results from our study emphasize the significance of burst neurons in the pathogenesis of dystonia and in the efficacy of proprioceptive modulation for its treatment. Moreover, we observed that the effects of vibration on focal CD were prominent in the α band LFP, indicating modulation of pallido-cerebellar connectivity. Moreover, the pallidal effects of vibration in GD with CD involved modulation of cerebro-pallidal θ band connectivity. Our analysis provides insight into how vibration-induced changes in pallidal activity are integrated into the downstream motor circuit. © 2023 International Parkinson and Movement Disorder Society.

Spontaneous and Visual Stimulation Evoked Firing Sequences Are Distinct Under Desflurane Anesthesia.

Recurring spike sequences are thought to underlie cortical computations and may be essential for information processing in the conscious state. How anesthesia at graded levels may influence spontaneous and stimulus-related spike sequences in visual cortex has not been fully elucidated. We recorded extracellular single-unit activity in the rat primary visual cortex in vivo during wakefulness and three levels of anesthesia produced by desflurane. The latencies of spike sequences within 0-200ms from the onset of spontaneous UP states and visual flash-evoked responses were compared. During wakefulness, spike latency patterns linked to the local field potential theta cycle were similar to stimulus-evoked patterns. Under desflurane anesthesia, spontaneous UP state sequences differed from flash-evoked sequences due to the recruitment of low-firing excitatory neurons to the UP state. Flash-evoked spike sequences showed higher reliability and longer latency when stimuli were applied during DOWN states compared to UP states. At deeper levels, desflurane altered both UP state and flash-evoked spike sequences by selectively suppressing inhibitory neuron firing. The results reveal desflurane-induced complex changes in cortical firing sequences that may influence visual information processing.

Kinetic, Equilibrium and Thermodynamic Study for Adsorptive Detoxification of Pb+2 by Thiocarbamoyl Chitosan

The environmental effect of industrial effluents, including chromium (Cr), lead (Pb), mercury (Hg), copper (Cu), and nickel (Ni) can have harmful impacts, which includes soil, water, and air pollution, bioaccumulation in food chains, degradation of ecosystems, loss of biodiversity, and contaminated drinking water. Biopolymers such as chitosan have been widely used in wastewater treatment. The ability of thiocarbamoyl chitosan to remove lead ions was assessed by combining thio urea and glutaraldehyde (GLA). During the first two hours of interaction with sorbent, 86% of the metal ions were shown to have been eliminated. According to the adsorption investigation, the prepared sorbent had an outstanding removal rate of metal ions, with a Langmuir maximum absorption capacity of 38 mg/gm at 25 degrees Celsius and a pH of 6. With a linear coefficient of 0.9996, the data on adsorption kinetics were predicted using a pseudo-second order kinetic model. The Langmuir isotherm, which suggests favourable adsorption by homogenous monolayer adsorption, might represent the adsorption process effectively. The adsorption procedure was also demonstrated to be exothermic at all temperatures, with spontaneous responses being energetically endorsed as indicated by negative free energy values.

PDE4D mediates impaired β-adrenergic receptor signalling in the sinoatrial node in mice with hypertensive heart disease.

The sympathetic nervous system increases HR by activating β-adrenergic receptors (β-ARs) and increasing cAMP in sinoatrial node (SAN) myocytes while phosphodiesterases (PDEs) degrade cAMP. Chronotropic incompetence, the inability to regulate heart rate (HR) in response to sympathetic nervous system activation, is common in hypertensive heart disease; however, the basis for this is poorly understood. The objective of this study was to determine the mechanisms leading to chronotropic incompetence in mice with angiotensin II (AngII)-induced hypertensive heart disease. C57BL/6 mice were infused with saline or AngII (2.5 mg/kg/day for 3 weeks) to induce hypertensive heart disease. HR and SAN function in response to the β-AR agonist isoproterenol (ISO) were studied in vivo using telemetry and electrocardiography, in isolated atrial preparations using optical mapping, in isolated SAN myocytes using patch-clamping, and using molecular biology. AngII-infused mice had smaller increases in HR in response to physical activity and during acute ISO injection. Optical mapping of the SAN in AngII-infused mice demonstrated impaired increases in conduction velocity and altered conduction patterns in response to ISO. Spontaneous AP firing responses to ISO in isolated SAN myocytes from AngII-infused mice were impaired due to smaller increases in diastolic depolarization (DD) slope, hyperpolarization-activated current (If), and L-type Ca2+ current (ICa,L). These changes were due to increased localization of PDE4D surrounding β1- and β2-ARs in the SAN, increased SAN PDE4 activity, and reduced cAMP generation in response to ISO. Knockdown of PDE4D using a virus-delivered shRNA or inhibition of PDE4 with rolipram normalized SAN sensitivity to β-AR stimulation in AngII-infused mice. AngII-induced hypertensive heart disease results in impaired HR responses to β-AR stimulation due to up-regulation of PDE4D and reduced effects of cAMP on spontaneous AP firing in SAN myocytes.

Piercing the Veil: Metatheatrical Utterances in the Stratford Festival’s 2022 Hamlet

This article uses the Stratford Festival’s 2022 production of Hamlet, directed by Peter Pasyk and starring Amaka Umeh, to examine the performance conditions which shaped the play’s metatheatrical speech acts and subsequent audience responses. Building on J.L. Austin’s theory of speech acts and recent work by Stephen Purcell on Shakespearean metatheatricality, this article demonstrates spontaneous audience responses within the Stratford Hamlet as essential to the co-creation of the performance. This performance analysis also proposes new theoretical language for how metatheatrical speech acts provoke responses in a thrust-stage performance space such as Stratford’s Festival Theatre.

The parabrachial to central amygdala pathway is critical to injury-induced pain sensitization in mice

The spino-ponto-amygdaloid pathway is a major ascending circuit relaying nociceptive information from the spinal cord to the brain. Potentiation of excitatory synaptic transmission in the parabrachial nucleus (PBN) to central amygdala (CeA) pathway has been reported in rodent models of persistent pain. However, the functional significance of this pathway in the modulation of the somatosensory component of pain was recently challenged by studies showing that spinal nociceptive neurons do not target CeA-projecting PBN cells and that manipulations of this pathway have no effect on reflexive-defensive somatosensory responses to peripheral noxious stimulation. Here, we showed that activation of CeA-projecting PBN neurons is critical to increase both stimulus-evoked and spontaneous nociceptive responses following an injury in male and female mice. Using optogenetic-assisted circuit mapping, we confirmed a functional excitatory projection from PBN→CeA that is independent of the genetic or firing identity of CeA cells. We then showed that peripheral noxious stimulation increased the expression of the neuronal activity marker Fos in CeA-projecting PBN neurons and that chemogenetic inactivation of these cells decreased behavioral hypersensitivity in models of neuropathic and inflammatory pain without affecting baseline nociception. Lastly, we showed that chemogenetic activation of CeA-projecting PBN neurons is sufficient to induced bilateral hypersensitivity without injury. Together, our results indicate that the PBN→CeA pathway is a key modulator of pain-related behaviors that can increase reflexive-defensive and affective-motivational responses to somatosensory stimulation in injured states without affecting nociception under normal physiological conditions.

Error-related Potentials in a Virtual Pick-and-Place Experiment: Toward Real-world Shared-control.

In Human-Robot Collaboration setting a robot may be controlled by a user directly or through a Brain-Computer Interface that detects user intention, and it may act as an autonomous agent. As such interaction increases in complexity, conflicts become inevitable. Goal conflicts can arise from different sources, for instance, interface mistakes - related to misinterpretation of human's intention - or errors of the autonomous system to address task and human's expectations. Such conflicts evoke different spontaneous responses in the human's brain, which could be used to regulate intrinsic task parameters and to improve system response to errors - leading to improved transparency, performance, and safety. To study the possibility of detecting interface and agent errors, we designed a virtual pick and place task with sequential human and robot responsibility and recorded the electroencephalography (EEG) activity of six participants. In the virtual environment, the robot received a command from the participants through a computer keyboard or it moved as autonomous agent. In both cases, artificial errors were defined to occur in 20% - 25% of the trials. We found differences in the responses to interface and agent errors. From the EEG data, correct trials, interface errors, and agent errors were truly predicted for 51.62% ± 9.99% (chance level 38.21%) of the pick movements and 46.84%±6.62% (chance level 36.99%) for the place movements in a pseudo-asynchronous fashion. Our study suggests that in a human-robot collaboration setting one may improve the future performance of a system with intention detection and autonomous modes. Specific examples could be Neural Interfaces that replace and restore motor functions.

Representations of dating apps for Brazilian users

The objective of this study was to investigate representations of dating apps for Brazilian users, and whether there were differences regarding sex, sexual orientation and age. It had quantitative and qualitative approaches. Instrument used for data collection was an online questionnaire. Spontaneous responses brought up representations linked to unspecified relationships, feelings of discomfort or suffering, and practicality. Most prevalent closed-question representations were practicality, getting initial information before meeting people and searching for a stable love relationship. Establishing a long-term relationship was more prevalent in women and heterosexuals in general; aiming for sex was more prevalent in men and homosexuals, and living veiled experiences that cannot be openly experienced in face-to-face life was more prevalent in homosexuals. There were little statistically significant differences related to age. Despite changes in contemporary love relationships, traditional social representations are still in place: linked to the search for an ideal partner (women) and for sex and a transgressive jouissance (men). Apps reflect search for practicality and utilitarianism of postmodern capitalism in large cities, but also fun and pastime.

Adaptation shapes local cortical reactivity: from bifurcation diagram and simulations to human physiological and pathological responses.

Human studies employing intracerebral and transcranial perturbations suggest that the input-output properties of cortical circuits are dramatically affected during sleep in healthy subjects as well as in awake patients with multifocal and focal brain injury. In all these conditions, cortical circuits react to direct stimulation with an initial activation followed by suppression of activity (Off-period) that disrupts the build-up of sustained causal interactions typically observed in healthy wakefulness. The transition to this stereotypical response has important clinical implications, being associated with loss of consciousness or loss of function. Here, we provide a mechanistic explanation of these findings by means of simulations of a cortical-like module endowed with activity-dependent adaptation and mean-field theory. First, we show that fundamental aspects of the local responses elicited in humans by direct cortical stimulation can be replicated by systematically varying the relationships between adaptation strength and excitation level in the network. Then, we reveal a region in the adaptation-excitation parameter space of crucial relevance for both physiological and pathological conditions, where spontaneous activity and responses to perturbation diverge in their ability to reveal Off-periods. Finally, we substantiate through simulations of connected cortical-like modules the role of adaptation mechanisms in preventing cortical neurons from engaging in reciprocal causal interactions, as suggested by empirical studies. These modeling results provide a general theoretical framework and a mechanistic interpretation for a body of neurophysiological measurements that bears critical relevance for physiological states as well as for the assessment and rehabilitation of brain-injured patients.Significance StatementSuppression of cortical activity following an initial activation is a defining feature of deep sleep in healthy subjects and wakefulness in patients affected by focal and multifocal brain injuries. Experimental findings suggest that these bimodal responses disrupt the emergence of complex interactions among cortical regions, leading to loss of consciousness or functional impairments. Given their practical implications, studying the mechanisms involved within a general theoretical framework is essential. Using a neuronal network model, we provide evidence for the key role of activity-dependent adaptation mechanisms in shaping the responses to perturbation and affecting the build-up of complex cortical interactions. Overall, this work provides a mechanistic interpretation relevant to the stratification, follow-up, and rehabilitation of brain-injured patients.

Descending Facilitation of Nociceptive Transmission From the Rostral Ventromedial Medulla Contributes to Hyperalgesia in Mice with Sickle Cell Disease

Sickle cell disease (SCD) is an inherited blood disorder that is associated with acute episodic and chronic pain. Mice with SCD have robust hyperalgesia mediated, in part, by sensitization of spinal dorsal horn neurons. However, underlying mechanisms are not fully understood. Since the rostral ventromedial medulla (RVM) is a major component of descending circuitry that modulates nociceptive transmission in the spinal cord, we examined if the RVM contributes to hyperalgesia in mice with SCD. Injection of lidocaine, but not vehicle, into the RVM eliminated mechanical and heat hyperalgesia in sickle (HbSS-BERK) mice without altering mechanical and heat sensitivity in naïve C57B mice. These data indicate that the RVM contributes to the maintenance of hyperalgesia in mice with SCD. In electrophysiological studies, we determined the changes in response properties of RVM neurons that might contribute to hyperalgesia in sickle mice. Recordings were made from single ON, OFF, and Neutral cells in the RVM of sickle and control (HbAA-BERK) mice. Spontaneous activity and responses of ON, OFF and Neutral cells evoked by heat (50 °C) and mechanical (26 g) stimuli applied to the hind paw were compared between sickle and control mice. Although there were no differences in the proportions of functionally-identified neurons or spontaneous activity between sickle and control mice, evoked responses of ON cells to heat and mechanical stimuli were increased approximately 3-fold in sickle mice as compared to control mice. Thus, the RVM contributes to hyperalgesia in sickle mice via a specific ON cell-dependent descending facilitation of nociceptive transmission.