TMS highlights the functional relevance and malleability of cortico-cortical connections to motion and action perception

In social environments the human brain evolves systems to make sense of others’ actions and behaviours, allowing the development of social interactions and reactions. Influential theories posit that the understanding of others’ actions is realised through the activation of one’s motor system that internally simulates the kinematics of the ongoing action and predicts its sensorial outcome. This process engages an action observation network (AON) that encompasses temporal-occipital visual and parietal-frontal motor regions. The flowing visual information is coupled with motor representations through recursive bidirectional fronto-temporal interactions that are modelled by sensorimotor experience allegedly via Hebbian plastic mechanisms. However, to date there is no direct evidence on the role that connectivity plays in carrying crucial information for the AON functioning. Recent studies demonstrated the efficacy of a TMS protocol, named cortico-cortical paired associative stimulation (ccPAS), able to induce transient Hebbian-like plastic potentiation in motor neural circuits. For a mechanistic understanding of AON connections relevance for simulative processes and action prediction, we used ccPAS with the aim of empowering the synaptic efficacy of the connections between the nodes of the system. ccPAS impact on behaviour and neurophysiological responses was evaluated. On motor behaviour, a ccPAS to empower premotor-motor connectivity led to improved dexterity (Study I) revealing the circuit’s functional malleability. On low-level perception, ccPAS, boosting the re-entrant connectivity of visual cortices revealed changes in motion perception and in specific features of it (Studies II-III). We then demonstrated that premotor-motor circuit conveys crucial information for the motor simulation of observed movements (Study IV), and finally, that empowering feedback connectivity in the AON enhances action prediction accuracy (Study V). We therefore provided evidence on the functional relevance of AON connectivity that supports theoretical models, and we developed an innovative tool able to promote AON functionality by inducing plastic changes in its connections

Anticipatory and Consummatory Responses to Touch and Food Rewards: A Protocol for Human Research

Understanding the neural basis of reward processing is a major concern, as it holds the key to alleviating symptoms of addiction and poor mental health. However, this goal seems difficult to attain as long as research on reward processing cannot easily be compared across species and reward types, due to methodological differences and the presence of confounding factors. We recently developed an experimental paradigm that allows monitoring anticipatory and consummatory responses to matched social (touch) and nonsocial (food) rewards in adult humans. The following protocol describes in detail the materials and the paradigm, which measures reward wanting and liking with a real effort task and subjective ratings. It can also be used in combination with facial electromyography (EMG), brain imaging (e.g., fMRI), and pharmacological interventions. It is our firm belief that the field will profit greatly from more research being conducted on reward processing using this and similarly controlled paradigms, which allow for cross-species comparison

Gradual enhancement of corticomotor excitability during cortico-cortical paired associative stimulation

Cortico-cortical paired associative stimulation (ccPAS) is an effective transcranial magnetic stimulation (TMS) method for inducing associative plasticity between interconnected brain areas in humans. Prior ccPAS studies have focused on protocol’s aftereffects. Here, we investigated physiological changes induced “online” during ccPAS administration. We tested 109 participants receiving ccPAS over left ventral premotor cortex (PMv) and primary motor cortex (M1) using a standard procedure (90 paired-pulses with 8-ms interstimulus interval, repeated at 0.1 Hz frequency). On each paired-pulse, we recorded a motor-evoked potential (MEP) to continuously trace the emergence of corticomotor changes. Participant receiving forward-ccPAS (on each pair, a first TMS pulse was administered over PMv, second over M1, i.e., PMv-to-M1) showed a gradual and linear increase in MEP size that did not reach a plateau at the end of the protocol and was greater in participants with low motor threshold. Participants receiving reverse-ccPAS (i.e., M1-to-PMv) showed a trend toward inhibition. Our study highlights the facilitatory and inhibitory modulations that occur during ccPAS administration and suggest that online MEP monitoring could provide insights into the malleability of the motor system and protocol’s effectiveness. Our findings open interesting prospects about ccPAS potential optimization in experimental and clinical settings

Driving Hebbian plasticity over ventral premotor-motor projections transiently enhances motor resonance

Background: Making sense of others' actions relies on the activation of an action observation network (AON), which maps visual information about observed actions onto the observer's motor system. This motor resonance process manifests in the primary motor cortex (M1) as increased corticospinal excitability finely tuned to the muscles engaged in the observed action. Motor resonance in M1 is facilitated by projections from higher-order AON regions. However, whether manipulating the strength of AON-to-M1 connectivity affects motor resonance remains unclear. Methods: We used transcranial magnetic stimulation (TMS) in 48 healthy humans. Cortico-cortical paired associative stimulation (ccPAS) was administered over M1 and the ventral premotor cortex (PMv), a key AON node, to induce spike-timing-dependent plasticity (STDP) in the pathway connecting them. Single-pulse TMS assessed motor resonance during action observation. Results: Before ccPAS, action observation increased corticospinal excitability in the muscles corresponding to the observed movements, reflecting motor resonance in M1. Notably, ccPAS aimed at strengthening projections from PMv to M1 (PMv→M1) induced short-term enhancement of motor resonance. The enhancement specifically occurred with the ccPAS configuration consistent with forward PMv→M1 projections and dissipated 20 min post-stimulation; ccPAS administered in the reverse order (M1→PMv) and sham stimulation did not affect motor resonance. Conclusions: These findings provide the first evidence that inducing STDP to strengthen PMv input to M1 neurons causally enhances muscle-specific motor resonance in M1. Our study sheds light on the plastic mechanisms that shape AON functionality and demonstrates that exogenous manipulation of AON connectivity can influence basic mirror mechanisms that underlie social perception

Large Gatherings? No, Thank You. Devaluation of Crowded Social Scenes During the COVID-19 Pandemic

In most European countries, the first wave of the COVID-19 pandemic (spring 2020) led to the imposition of physical distancing rules, resulting in a drastic and sudden reduction of real-life social interactions. Even people not directly affected by the virus itself were impacted in their physical and/or mental health, as well as in their financial security, by governmental lockdown measures. We investigated whether the combination of these events had changed people's appraisal of social scenes by testing 241 participants recruited mainly in Italy, Austria, and Germany in an online, preregistered study conducted about 50 days after the beginning of the COVID-19 outbreak in Europe. Images depicting individuals alone, in small groups (up to four people), and in large groups (more than seven people) were rated in terms of valence, arousal, and perceived physical distance. Pre-pandemic normative ratings were obtained from a validated database (OASIS). Several self-report measures were also taken, and condensed into four factors through factor analysis. All images were rated as more arousing compared to the pre-pandemic period, and the greater the decrease in real-life physical interactions reported by participants, the higher the ratings of arousal. As expected, only images depicting large gatherings of people were rated less positively during, compared to before, the pandemic. These ratings of valence were, however, moderated by a factor that included participants' number of days in isolation, relationship closeness, and perceived COVID-19 threat. Higher scores on this factor were associated with more positive ratings of images of individuals alone and in small groups, suggesting an increased appreciation of safer social situations, such as intimate and small-group contacts. The same factor was inversely related to the perceived physical distance between individuals in images of small and large groups, suggesting an impact of lockdown measures and contagion-related worries on the representation of interpersonal space. These findings point to rapid and compelling psychological and social consequences of the lockdown measures imposed during the COVID-19 pandemic on the perception of social groups. Further studies should assess the long-term impact of such events as typical everyday life is restored

A positive cooperativity binding model between Ly49 natural killer cell receptors and the viral immunoevasin m157: kinetic and thermodynamic studies

Natural killer (NK) cells discriminate between healthy and virally infected or transformed cells using diverse surface receptors that are both activating and inhibitory. Among them, the homodimeric Ly49 NK receptors, which can adopt two distinct conformations (backfolded and extended), are of particular importance for detecting cells infected with mouse cytomegalovirus (CMV) via recognition of the viral immunoevasin m157. The interaction of m157 with activating (Ly49H) and inhibitory (Ly49I) receptors governs the spread of mouseCMV.Wecarried out kinetic and thermodynamic experiments to elucidate the Ly49/m157 binding mechanism. Combining surface plasmon resonance, fluorescence anisotropy, and circular dichroism (CD), we determined that the best model to describe both the Ly49H/m157 and Ly49I/m157 interactions is a conformational selection mechanism where only the extended conformation of Ly49 (Ly49*) is able to bind the first m157 ligand followed by binding of the Ly49*/m157 complex to the second m157. The interaction is characterized by strong positive cooperativity such that the second m157 binds the Ly49 homodimer with a 1000-fold higher sequential constant than the first m157 (108 versus 105 M-1). Using far-UV CD, we obtained evidence for a conformational change in Ly49 upon binding m157 that could explain the positive cooperativity. The rate-limiting step of the overall mechanism is a conformational transition in Ly49 from its backfolded to extended form. The global thermodynamic parameters from the initial state (backfolded Ly49 and m157) to the final state (Ly49*/(m157)2) are characterized by an unfavorable enthalpy that is compensated by a favorable entropy, making the interaction spontaneous.Fil: Romasanta, Pablo Nicolas. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Curto, Lucrecia María. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Urtasun, Nicolás. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Sarratea, Maria Belén. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Chiappini, Santiago Andrés. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Miranda, Maria Victoria. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; ArgentinaFil: Delfino, Jose Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Fisicoquímica Biológicas; ArgentinaFil: Mariuzza, Roy A.. University Of Maryland. Biotechnology Institute; Estados UnidosFil: Fernández, Marisa Mariel. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; ArgentinaFil: Malchiodi, Emilio Luis. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Oficina de Coordinacion Administrativa Houssay. Instituto de Estudios de la Inmunidad Humoral "profesor R. A. Margni"; Argentin

Empowering Reentrant Projections from V5 to V1 Boosts Sensitivity to Motion

Evidence from macaques [1] and humans [2, 3] has shown that back projections from extrastriate areas to the primary visual area (V1) determine whether visual awareness will arise. For example, reentrant projections from the visual motion area (V5) to V1 are considered to be critical for awareness of motion [2, 3]. If these projections are also instrumental to functional processing of moving stimuli [4–8], then increasing synaptic efficacy in V5-V1 connections should induce functionally relevant short-term plastic changes, resulting in enhanced perception of visual motion. Using transcranial magnetic stimulation (TMS), we applied a novel cortico-cortical paired associative stimulation (ccPAS) protocol to transiently enhance visual motion sensitivity and demonstrate both the functional relevance of V5-V1 reentrant projections to motion perception and their plasticity. Specifically, we found that ccPAS aimed at strengthening reentrant connectivity from V5 to V1 (but not in the opposite direction) enhanced the human ability to perceive coherent visual motion. This perceptual enhancement followed the temporal profile of Hebbian plasticity [9–18] and was observed only when an optimal timing of 20 ms between TMS pulses [2, 3, 5, 6] was used, not when TMS pulses were delivered synchronously. Thus, plastic change is critically dependent on both the direction and timing of connectivity; if either of these requirements was not met, perceptual enhancement did not take place. We therefore provide novel causal evidence that V5-V1 back projections, instrumental to motion perception, are functionally malleable. These findings have implications for theoretical models of visual awareness and for the rehabilitation of visual deficits

How culturally unique are pandemic effects? Evaluating cultural similarities and differences in effects of age, biological sex, and political beliefs on COVID impacts

Despite being bio-epidemiological phenomena, the causes and effects of pandemics are culturally influenced in ways that go beyond national boundaries. However, they are often studied in isolated pockets, and this fact makes it difficult to parse the unique influence of specific cultural psychologies. To help fill in this gap, the present study applies existing cultural theories via linear mixed modeling to test the influence of unique cultural factors in a multi-national sample (that moves beyond Western nations) on the effects of age, biological sex, and political beliefs on pandemic outcomes that include adverse financial impacts, adverse resource impacts, adverse psychological impacts, and the health impacts of COVID. Our study spanned 19 nations (participant N = 14,133) and involved translations into 9 languages. Linear mixed models revealed similarities across cultures, with both young persons and women reporting worse outcomes from COVID across the multi-national sample. However, these effects were generally qualified by culture-specific variance, and overall more evidence emerged for effects unique to each culture than effects similar across cultures. Follow-up analyses suggested this cultural variability was consistent with models of pre-existing inequalities and socioecological stressors exacerbating the effects of the pandemic. Collectively, this evidence highlights the importance of developing culturally flexible models for understanding the cross-cultural nature of pandemic psychology beyond typical WEIRD approaches

Enhanced action performance following TMS manipulation of associative plasticity in ventral premotor-motor pathway

Skillful goal-directed manual actions such as grasping and manipulating objects are supported by a large sensorimotor network. Within this network, the ventral premotor cortex (PMv) transforms visual information about objects into motor commands that are conveyed to the primary motor cortex (M1), allowing fine control of finger movements. However, it is unknown whether transcranial magnetic stimulation (TMS) of this PMv-to-M1 hierarchical pathway improves action performance. To fill in this gap, here, we used cortico-cortical paired associative stimulation (ccPAS) with the aim of manipulating synaptic efficacy in the human PMv-to-M1 pathway. We found that repeatedly pairing TMS of pre-and post-synaptic nodes of the PMv-to-M1 pathway (i.e., PMv-to-M1 ccPAS) increased motor excitability and enhanced performance on the 9-Hole Peg Test (9-HPT), which taps into PMv-M1 functioning. These effects were specific to the ccPAS protocol consistent with the direction of the PMv-to-M1 hierarchy, as no effects were observed when reversing the order of the paired TMS pulses (i.e., following a M1-to-PMv ccPAS) or when administering sham ccPAS. Additionally, the effect of PMv-to-M1 ccPAS appeared functionally specific, as no behavioral enhancement was observed in a visuomotor control task. We therefore provide novel causal evidence that the PMv-to-M1 pathway, which is instrumental to object-oriented hand actions, is sensitive to TMS manipulations of associative plasticity. Our study highlights the causal role of the PMv-to-M1 pathway in controlling skillful object-oriented hand actions and suggests that ccPAS might be a useful tool for investigating the functional relevance of directional connectivity in humans. These findings may have implications for designing novel therapeutic strategies based on the manipulation of associative plasticity in cortico-cortical networks

Driving associative plasticity in premotor-motor connections through a novel paired associative stimulation based on long-latency cortico-cortical interactions

There is no evidence that ccPAS protocols based on long-latency interactions (i.e., ll-ccPAS) can induce associative plasticity in humans. Here we empirically address this question by testing the effect of 3 ll-ccPAS protocols on PMv-M1 interactions in healthy volunteers