Epigenetics: An opportunity to shape innate and adaptive immune responses.

Epigenetics connects genetic and environmental factors: it includes DNA methylation, histone post-translational modifications and the regulation of chromatin accessibility by non-coding RNAs, all of which control constitutive or inducible gene transcription. This plays a key role in harnessing the transcriptional programs of both innate and adaptive immune cells due to its plasticity and environmental-driven nature, piloting myeloid and lymphoid cell fate decisions with no change in their genomic sequence. In particular, epigenetic marks at the site of lineage-specific transcription factors and maintenance of cell type-specific epigenetic modifications, referred to as 'epigenetic memory', dictate cell differentiation, cytokine production and functional capacity following repeated antigenic exposure in memory T cells. Moreover, metabolic and epigenetic reprogramming occurring during a primary innate immune response leads to enhanced responses to secondary challenges, a phenomenon known as 'trained immunity'. Here, we discuss how stable and dynamic epigenetic states control immune cell identity and plasticity in physiological and pathological conditions. Dissecting the regulatory circuits of cell fate determination and maintenance is of paramount importance for understanding the delicate balance between immune cell activation and tolerance, in healthy conditions and in autoimmune diseases.

Changes in motoneuron excitability during voluntary muscle activity in humans with spinal cord injury.

The excitability of resting motoneurons increases following spinal cord injury (SCI). The extent to which motoneuron excitability changes during voluntary muscle activity in humans with SCI, however, remains poorly understood. To address this question, we measured F waves by using supramaximal electrical stimulation of the ulnar nerve at the wrist and cervicomedullary motor-evoked potentials (CMEPs) by using high-current electrical stimulation over the cervicomedullary junction in the first dorsal interosseous muscle at rest and during 5 and 30% of maximal voluntary contraction into index finger abduction in individuals with chronic cervical incomplete SCI and aged-matched control participants. We found higher persistence (number of F waves present in each set) and amplitude of F waves at rest in SCI compared with control participants. With increasing levels of voluntary contraction, the amplitude, but not the persistence, of F waves increased in both groups but to a lesser extent in SCI compared with control participants. Similarly, the CMEP amplitude increased in both groups but to a lesser extent in SCI compared with controls. These results were also found at matched absolutely levels of electromyographic activity, suggesting that these changes were not related to decreases in voluntary motor output after SCI. F-wave and CMEP amplitudes were positively correlated across conditions in both groups. These results support the hypothesis that the responsiveness of the motoneuron pool during voluntary activity decreases following SCI, which could alter the generation and strength of voluntary muscle contractions.NEW & NOTEWORTHY How the excitability of motoneurons changes during voluntary muscle activity in humans with spinal cord injury (SCI) remains poorly understood. We found that F-wave and cervicomedullary motor-evoked potential amplitude, outcomes reflecting motoneuronal excitability, increased during voluntary activity compared with rest in SCI participants but to a lesser extent that in controls. These results suggest that the responsiveness of motoneurons during voluntary activity decreases following SCI, which might affect functionally relevant plasticity after the injury.

The impact of eye contact on the sense of agency.

Recent research suggests that eye contact can lead to enhanced self-awareness. A related phenomenon, the sense of agency deals with the notion of the self as the origin of our actions. Possible links between eye contact and agency have been so far neglected. Here, we investigated whether an implicit sense of agency could be modulated by eye gaze. We asked participants to respond (button press) to a face stimulus: looking or not at the participant (experiment 1); or displaying distinct eye gaze before or after a mask (experiment 2). After each trial, participants estimated the time between their key press and the ensuing effects. We found enhanced intentional binding for conditions that involved direct compared to averted gaze. This study supports the idea that eye contact is an important cue that affects complex cognitive processes and suggests that modulating self-processing can impact the sense of agency.

Temporal binding effect in the action observation domain: Evidence from an action-based somatosensory paradigm.

Temporal binding is understood as an effect in which a temporal interval between a voluntary action and its consequent effect is perceived as compressed. It denotes an implicit measure of a sense of agency. When people observe someone else performing an action that generates an effect, temporal binding also takes place. We aimed to test whether the interaction between observed actions and tactile sensation influences temporal binding. Participants observed finger tapping movements (of a human or wooden hand), in parallel to receiving tactile stimulations on their fingertip. These stimulations were either congruent or incongruent with the tactile consequences of the observed movement. The finger tapping movement was followed by a tone. Participants estimated the intervals between the observed action and the tone. We found that temporal binding for observed actions depends on the congruency between the perceived touch and tactile consequences of observed actions restricted to intentional actors.

The action congruency effect on the feelings of agency.

Previous studies suggest that the sense of agency (SoA), the feeling of control about one's own actions and ensuing effects is also generated during action selection processes. We investigate whether the conflict at the action selection stage induced by a supraliminal stimulus, modulates an implicit measure of SoA, namely intentional binding. Furthermore, we were interested to investigate the influence of different types of stimulus-response compatibility on SoA. To this aim we compared the influence of an automatic imitation task and a stroop-like task on intentional binding. In both tasks participants performed congruent and incongruent fingers movements (key release) in response to an external stimulus. Their movements caused an effect and participants estimated the time between their action and the ensuing effect. We found a reduced intentional binding effect in incongruent compared to congruent conditions in both tasks. The results are discussed within the theoretical framework of the fluency of action.

Tactile perception during action observation.

It has been suggested that tactile perception becomes less acute during movement to optimize motor control and to prevent an overload of afferent information generated during action. This empirical phenomenon, known as "tactile gating effect," has been associated with mechanisms of sensory feedback prediction. However, less attention has been given to the tactile attenuation effect during the observation of an action. The aim of this study was to investigate whether and how the observation of a goal-directed action influences tactile perception as during overt action. In a first experiment, we recorded vocal reaction times (RTs) of participants to tactile stimulations during the observation of a reach-to-grasp action. The stimulations were delivered on different body parts that could be either congruent or incongruent with the observed effector (the right hand and the right leg, respectively). The tactile stimulation was contrasted with a no body-related stimulation (an auditory beep). We found increased RTs for tactile congruent stimuli compared to both tactile incongruent and auditory stimuli. This effect was reported only during the observation of the reaching phase, whereas RTs were not modulated during the grasping phase. A tactile two-alternative forced-choice (2AFC) discrimination task was then conducted in order to quantify the changes in tactile sensitivity during the observation of the same goal-directed actions. In agreement with the first experiment, the tactile perceived intensity was reduced only during the reaching phase. These results suggest that tactile processing during action observation relies on a process similar to that occurring during action execution.

Embodied and disembodied allocentric simulation in high schizotypal subjects.

It is known that non-clinical subjects with high levels of schizotypal personality traits (High-S), as well as schizophrenic patients, have difficulties to judge how a scene would appear (so-called Appearance questions) from a point of view other than their own after having performed a disembodied perspective taking (D-PT, a mental self-rotation cued by an object like a chair). This inability has been defined allocentric simulation deficit. However, it is still unclear whether this inability might also regard an embodied transformation (E-PT), which is a self-rotation cued by another individual in the scene, and whether the observed deficit regards the pure mental transformation phase. In the present study, we took advantage of a virtual reality environment to explore both embodied and disembodied allocentric simulation in healthy volunteers with low and high levels of schizotypal personality traits, as assessed by the Schizotypal Personality Questionnaire. All subjects performed a pure self-rotation cued by a chair (D-PT) or by an avatar (E-PT), or a control array rotation. Each rotation was followed by classical Appearance and Item questions. Results revealed no between-groups differences in the mental transformation phase, while High-S subjects were significantly slower than Low-S subjects in the Appearance task after D-PT, but not after E-PT. Accordingly, higher schizotypy levels (cognitive-perceptual subscale) were positively correlated with slower reaction times in the Appearance task after D-PT. These data suggest the existence of a disembodied allocentric simulation deficit in non-clinical High-S, paving the way to future studies on clinical populations.

Perspectives of people with spinal cord injury on a pain education resource.

Introduction: Spinal cord injury (SCI) often leads to neuropathic pain that negatively affects quality of life. Several qualitative research studies in individuals with SCI who experience neuropathic pain indicate the lack of adequate information about pain. We previously developed an educational resource, the SeePain, based on scientific literature and a series of qualitative interviews of people with SCI, their significant others/family members, and SCI healthcare providers. Methods: However, to quantitatively evaluate the utility of this educational resource in a larger sample, we examined the agreement and usefulness ratings of statements regarding clarity/comprehensibility, content, and format of the SeePain, derived from the thematic analysis of our previous qualitative interviews. Participants completed a survey that provided a digital version of the SeePain and then rated their agreement/usefulness with the statements using numerical rating scales. Results: There were overall high perceived agreement and usefulness ratings regarding the SeePain's clarity, content, and format. A factor analysis reduced the agreement and usefulness ratings into 4 components (content, clarity, format, and delivery medium). Group comparisons showed that individuals with higher education were more likely to endorse electronic and website formats, and the usefulness of a shorter version of the SeePain; females and younger individuals showed greater endorsement for clarity. Finally, higher pain intensity ratings were associated with greater agreement and usefulness of the content of the SeePain. Discussion: Overall, these results support the utility of the SeePain as a source of information regarding pain that may facilitate communication about pain and its management following SCI.

Event-related potentials during mental rotation of body-related stimuli in spinal cord injury population.

Mental rotations of body-related stimuli are known to engage the motor system and activate body schema. Sensorimotor deficits following spinal cord injury (SCI) alter the representation of the body with a negative impact on the performance during motor-related tasks, such as mental rotation of body parts. Here we investigated the relationship between event-related potentials in SCI participants and the difficulty in mentally rotating a body-part. Participants with SCI and healthy control subjects performed a laterality judgment task, in which left or right images of hands, feet or animals (as a control stimulus) were presented in two different orientation angles (75° and 150°), and participants reported the laterality of the stimulus. We found that reaction times of participants with SCI were slower for the rotation of body-related stimuli compared to non-body-related stimuli and healthy controls. At the brain level, we found that relative to healthy controls SCI participants show: 1) reduced amplitudes of the posterior P100 and anterior N100 and larger amplitudes of the anterior P200 for overall stimuli; 2) an absence of the modulation of the rotation related negativity by stimulus type and rotation angles. Our results show that body representation changes after SCI affecting both components of early stimulus processing and late components that process high-order cognitive aspects of body-representation and task complexity.

Neuropsychological Function in Traumatic Brain Injury and the Influence of Chronic Pain.

Cognitive dysfunction, pain, and psychological morbidity all present unique challenges to those living with traumatic brain injury (TBI). In this study we examined (a) the impact of pain across domains of attention, memory, and executive function, and (b) the relationships between pain and depression, anxiety, and post-traumatic stress disorder (PTSD) in persons with chronic TBI. Our sample included 86 participants with a TBI and chronic pain (n = 26), patients with TBI and no chronic pain (n = 23), and a pain-free control group without TBI (n = 37). Participants visited the laboratory and completed a comprehensive battery of neuropsychological tests as part of a structured interview. Multivariate analysis of covariance using education as a covariate, failed to detect a significant group difference for neuropsychological composite scores of attention, memory, and executive function (p = .165). A follow-up analysis using multiple one-way analysis of variance (ANOVA) was conducted for individual measures of executive function. Post-hoc testing indicated that those in both TBI groups preformed significantly worse on measures of semantic fluency when compared to controls (p < 0.001, ηρ2 = .16). Additionally, multiple ANOVAs indicated that those with TBI and pain scored significantly worse across all psychological assessments (p < .001). We also found significant associations between measures of pain and most psychological symptoms. A follow-up stepwise linear regression among those in the TBI pain group indicated that post concussive complaints, pain severity, and neuropathic pain symptoms differentially contributed to symptoms of depression, anxiety, and PTSD. These findings suggest deficits in verbal fluency among those living with chronic TBI, with results also reinforcing the multidimensional nature of pain and its psychological significance in this population.

Maladaptive reorganization following SCI: The role of body representation and multisensory integration.

In this review we focus on maladaptive brain reorganization after spinal cord injury (SCI), including the development of neuropathic pain, and its relationship with impairments in body representation and multisensory integration. We will discuss the implications of altered sensorimotor interactions after SCI with and without neuropathic pain and possible deficits in multisensory integration and body representation. Within this framework we will examine published research findings focused on the use of bodily illusions to manipulate multisensory body representation to induce analgesic effects in heterogeneous chronic pain populations and in SCI-related neuropathic pain. We propose that the development and intensification of neuropathic pain after SCI is partly dependent on brain reorganization associated with dysfunctional multisensory integration processes and distorted body representation. We conclude this review by suggesting future research avenues that may lead to a better understanding of the complex mechanisms underlying the sense of the body after SCI, with a focus on cortical changes.

Multisensory integration in humans with spinal cord injury.

Although multisensory integration (MSI) has been extensively studied, the underlying mechanisms remain a topic of ongoing debate. Here we investigate these mechanisms by comparing MSI in healthy controls to a clinical population with spinal cord injury (SCI). Deafferentation following SCI induces sensorimotor impairment, which may alter the ability to synthesize cross-modal information. We applied mathematical and computational modeling to reaction time data recorded in response to temporally congruent cross-modal stimuli. We found that MSI in both SCI and healthy controls is best explained by cross-modal perceptual competition, highlighting a common competition mechanism. Relative to controls, MSI impairments in SCI participants were better explained by reduced stimulus salience leading to increased cross-modal competition. By combining traditional analyses with model-based approaches, we examine how MSI is realized during normal function, and how it is compromised in a clinical population. Our findings support future investigations identifying and rehabilitating MSI deficits in clinical disorders.

Multidimensional pain phenotypes after Traumatic Brain Injury.

More than 50% of individuals develop chronic pain following traumatic brain injury (TBI). Research suggests that a significant portion of post-TBI chronic pain conditions is neuropathic in nature, yet the relationship between neuropathic pain, psychological distress, and somatosensory function following TBI is not fully understood. This study evaluated neuropathic pain symptoms, psychological and somatosensory function, and psychosocial factors in individuals with TBI (TBI, N = 38). A two-step cluster analysis was used to identify phenotypes based on the Neuropathic Pain Symptom Inventory and Beck's Anxiety Inventory scores. Phenotypes were then compared on pain characteristics, psychological and somatosensory function, and psychosocial factors. Our analyses resulted in two different neuropathic pain phenotypes: (1) Moderate neuropathic pain severity and anxiety scores (MNP-AS, N = 11); and (2) mild or no neuropathic pain symptoms and anxiety scores (LNP-AS, N = 27). Furthermore, the MNP-AS group exhibited greater depression, PTSD, pain severity, and affective distress scores than the LNP-AS group. In addition, thermal somatosensory function (difference between thermal pain and perception thresholds) was significantly lower in the MNP-AS compared to the LNP-AS group. Our findings suggest that neuropathic pain symptoms are relatively common after TBI and are not only associated with greater psychosocial distress but also with abnormal function of central pain processing pathways.

Humoral efficacy of the third SARS-CoV-2 vaccine dose in Multiple Sclerosis subjects undergoing different disease-modifying therapies.

BACKGROUND: It remains unclear how vaccine doses and combinations of vaccination and infection affect the magnitude and quality of immune responses, particularly against novel SARS-CoV-2 variants in subjects with immune-related disorders, such as people with multiple sclerosis (pwMS). Several studies have evaluated the duration of anti-SARS-CoV-2 immune protection in healthy individuals; however clinical data suggest an attenuated short-term humoral response to SARS-CoV-2 vaccines in pwMS receiving disease-modifying therapies (DMTs). METHODS: In this prospective study, we evaluated the humoral response to the third (3rd) BNT162b2 vaccine (booster) dose in a monocentric cohort of pwMS undergoing eight different DMTs, all without previous SARS-CoV-2 infection. Quantitative determination of SARS-CoV-2 IgG Spike titre was carried out by anti-SARS-CoV-2 S assay in 65 pwMS and 9 healthy controls, all without previous SARS-CoV-2 infection. Moreover, these measurements were also compared to their relative levels at 21 days (T1) and ∼6 months (T2) after the second (2nd) vaccination. RESULTS: We observed that the humoral response to the booster dose in Interferon ß-1a-, Dimethyl fumarate- and Teriflunomide-treated pwMS is comparable to healthy controls, while increased in Cladribine-treated pwMS. Additionally, the 3rd dose elicits a seroconversion in the 100% of pwMS under Fingolimod and in the 65% of those under Ocrelizumab. Moreover, multivariate regression analysis showed that treatment with Interferon ß-1a, Dimethyl fumarate and Cladribine positively associates with an increased humoral response. CONCLUSIONS: Taken together this evidence strongly indicates the importance of the booster dose to enhance SARS-CoV-2-specific immunity especially in immunocompromised subjects, such as pwMS under DMTs.

Action selection conflict and intentional binding: An ERP study.

The fluency with which we plan and execute actions has been demonstrated to increase our sense of agency (SoA). However, the exact mechanisms how fluency influences SoA are still poorly understood. It is an open question whether this effect is primarily driven by fluency of stimulus processing, response preparation or by processes following response execution. In the current study we aim at addressing this question by measuring event-related potentials reflecting pre- and post-response mechanisms and relate them to intentional binding, a measure of implicit SoA. To manipulate the fluency of action we asked participants to perform actions that were congruent or incongruent with a visual target (a finger movement). Participants' actions triggered an auditory outcome. To measure the intentional binding effect we asked participants to estimate the time between the executed actions and the ensuing auditory effects. We found that congruent actions generated a larger intentional binding effect (i.e., stronger time compression between actions and effects) and this positively correlated with a late P300 evoked during the processing of congruent stimuli. At the action selection level, we found a larger central pre-response positivity for incongruent condition as relates to interference effects. Finally, post response mechanisms elicited a larger central negativity for incongruent responses presumably related to uncertainty. We provide new evidence on the determinants of intentional binding driven by the fluency of action, by showing that both pre and post-response mechanisms are crucial in the generation of the feelings of agency. Importantly, stimulus processing and response preparation ERPs seem to be more selectively modulated by congruency-effects given specific brain-behavioral correlations.

Observation of Point-Light-Walker Locomotion Induces Motor Resonance When Explicitly Represented; An EEG Source Analysis Study.

Understanding human motion, to infer the goal of others' actions, is thought to involve the observer's motor repertoire. One prominent class of actions, the human locomotion, has been object of several studies, all focused on manipulating the shape of degraded human figures like point-light walker (PLW) stimuli, represented as walking on the spot. Nevertheless, since the main goal of the locomotor function is to displace the whole body from one position to the other, these stimuli might not fully represent a goal-directed action and thus might not be able to induce the same motor resonance mechanism expected when observing a natural locomotion. To explore this hypothesis, we recorded the event-related potentials (ERP) of canonical/scrambled and translating/centered PLWs decoding. We individuated a novel ERP component (N2c) over central electrodes, around 435 ms after stimulus onset, for translating compared to centered PLW, only when the canonical shape was preserved. Consistently with our hypothesis, sources analysis associated this component to the activation of trunk and lower legs primary sensory-motor and supplementary motor areas. These results confirm the role of own motor repertoire in processing human action and suggest that ERP can detect the associated motor resonance only when the human figure is explicitly involved in performing a meaningful action.

Functional Relations Modulate the Responsiveness to Affordances Despite the Impact of Conflicting Stimulus-Response Mappings.

The study investigated how conflicting stimulus-response mappings influenced affordance processing given a manipulation of the functional relations. Participants performed a task involving consistent-inconsistent stimulus-response mappings: Implicit Relational Assessment Procedure (IRAP). They were instructed to confirm or to deny a relation between words and tool-objects (consistent blocks) or to provide non-conventional responses (inconsistent blocks). The relations between stimuli could functionally match (e.g., Kitchen - Spatula) or not (e.g., Kitchen - Hammer), as well as the spatial relations (e.g., a match or a mismatch between participants' hand response and the tool-object orientation). The results showed faster reaction times (RTs) when functional relations between stimuli matched both in consistent and inconsistent blocks. Differences in RTs and accuracy between consistent and inconsistent blocks were only found when the functional relation between stimuli matched. No modulation of the performance was observed for mismatching functional relations and spatial relations between blocks. These results support the hypothesis that the responsiveness to affordances is strongly modulated by matching functional relations, despite the impact of conflicting stimulus-response mappings.

The heaviness of invisible objects: Predictive weight judgments from observed real and pantomimed grasps.

Observation of others' actions has been proposed to provide a shared experience of the properties of objects acted upon. We report results that suggest a similar form of shared experience may be gleaned from the observation of pantomimed grasps, i.e., grasps aimed at pretended objects. In a weight judgment task, participants were asked to observe a hand reaching towards and grasping either a real or imagined glass, and to predictively judge its weight. Results indicate that participants were able to discriminate whether the to-be-grasped glass was empty, and thus light, or full, and thus heavy. Worthy of further investigation, this finding suggests that by observing others' movements we can make predictions, and form expectations about the characteristics of objects that exist only in others' minds.

Emotion-inducing approaching sounds shape the boundaries of multisensory peripersonal space.

In order to survive in a complex environment, inhabited by potentially threatening and noxious objects or living beings, we need to constantly monitor our surrounding space, especially in the vicinity of our body. Such a space has been commonly referred to as one's 'peripersonal space' (PPS). In this study we investigated whether emotion-inducing approaching sound sources impact the boundaries of PPS. Previous studies have indeed showed that the boundaries of PPS are not fixed but modulate according to properties of stimuli in the surrounding environment. In Experiment 1, participants performed a simple tactile detection task of targets presented to their right hand. Concurrently, they were presented with intensity-changing task-irrelevant artificial sound sources perceived as approaching toward their body. The physical properties of the sound elicited emotional responses of either neutral or negative valence. Results showed larger PPS when the approaching stimulus had negative as compared to neutral emotional valence. In Experiment 2, we used ecological sounds which content (i.e., psychological associations to the sound producing source), rather than physical properties, elicited emotional responses of negative, positive or neutral valence. In agreement with results from experiment 1, we found larger PPS when the approaching stimuli had negative emotional valence as compared to both neutral and positive ones. Results are discussed within the theoretical framework that conceives PPS as a safety zone around one's body.