The cerebellum and the Mirror Neuron System: A matter of inhibition? From neurophysiological evidence to neuromodulatory implications. A narrative review.

Mirror neurons show activity during both the execution (AE) and observation of actions (AO). The Mirror Neuron System (MNS) could be involved during motor imagery (MI) as well. Extensive research suggests that the cerebellum is interconnected with the MNS and may be critically involved in its activities. We gathered evidence on the cerebellum's role in MNS functions, both theoretically and experimentally. Evidence shows that the cerebellum plays a major role during AO and MI and that its lesions impair MNS functions likely because, by modulating the activity of cortical inhibitory interneurons with mirror properties, the cerebellum may contribute to visuomotor matching, which is fundamental for shaping mirror properties. Indeed, the cerebellum may strengthen sensory-motor patterns that minimise the discrepancy between predicted and actual outcome, both during AE and AO. Furthermore, through its connections with the hippocampus, the cerebellum might be involved in internal simulations of motor programs during MI. Finally, as cerebellar neuromodulation might improve its impact on MNS activity, we explored its potential neurophysiological and neurorehabilitation implications.

Excitatory/inhibitory motor balance reflects individual differences during joint action coordination.

Joint action (JA) is a continuous process of motor co-regulation based on the integration of contextual (top-down) and kinematic (bottom-up) cues from partners. The fine equilibrium between excitation and inhibition in sensorimotor circuits is, thus, central to such a dynamic process of action selection and execution. In a bimanual task adapted to become a unimanual JA task, the participant held a bottle (JA), while a confederate had to reach and unscrew either that bottle or another stabilized by a mechanical clamp (No_JA). Prior knowledge was manipulated in each trial such that the participant knew (K) or not (No_K) the target bottle in advance. Online transcranial magnetic stimulation (TMS) was administered at action-relevant landmarks to explore corticospinal excitability (CSE) and inhibition (cortical silent period [cSP]). CSE was modulated early on before the action started if prior information was available. In contrast, cSP modulation emerged later during the reaching action, regardless of prior information. These two indexes could thus reflect the concurrent elaboration of contextual priors (top-down) and the online sampling of partner's kinematic cues (bottom-up). Furthermore, participants selected either one of two possible behavioural strategies, preferring early or late force exertion on the bottle. One translates into a reduced risk of motor coordination failure and the other into reduced metabolic expenditure. Each strategy was characterised by a specific excitatory/inhibitory profile. In conclusion, the study of excitatory/inhibitory balance paves the way for the neurophysiological determination of individual differences in the combination of top-down and bottom-up processing during JA coordination.

Motor or non-motor speech interference? A multimodal fMRI and direct cortical stimulation mapping study.

We retrospectively analyzed data from 15 patients, with a normal pre-operative cognitive performance, undergoing awake surgery for left fronto-temporal low-grade glioma. We combined a pre-surgical measure (fMRI maps of motor- and language-related centers) with intra-surgical measures (MNI-registered cortical sites data obtained during intra-operative direct electrical stimulation, DES, while they performed the two most common language tasks: number counting and picture naming). Selective DES effects along the precentral gyrus/inferior frontal gyrus (and/or the connected speech articulation network) were obtained. DES of the precentral gyrus evoked the motor speech arrest, i.e., anarthria (with apparent mentalis muscle movements). We calculated the number of shared voxels between the lip-tongue and overt counting related- and silent naming-related fMRI maps and the Volumes of Interest (VOIs) obtained by merging together the MNI sites at which a given speech disturbance was observed, normalized on their mean the values (i.e., Z score). Both tongue- and lips-related movements fMRI maps maximally overlapped (Z = 1.05 and Z = 0.94 for lips and tongue vs. 0.16 and -1.003 for counting and naming) with the motor speech arrest seed. DES of the inferior frontal gyrus, pars opercularis and the rolandic operculum induced speech arrest proper (without apparent mentalis muscle movements). This area maximally overlapped with overt counting-related fMRI map (Z = -0.11 and Z = 0.09 for lips and tongue vs. 0.9 and 0.0006 for counting and naming). Interestingly, our fMRI maps indicated reduced Broca's area activity during silent speech compared to overt speech. Lastly, DES of the inferior frontal gyrus, pars opercularis and triangularis evoked variations of the output, i.e., dysarthria, a motor speech disorder occurring when patients cannot control the muscles used to produce articulated sounds (phonemes). Silent object naming-related fMRI map maximally overlapped (Z = -0.93 and Z = -1.04 for lips and tongue vs. -1.07 and 0.99 for counting and naming) with this seed. Speech disturbances evoked by DES may be thought of as selective interferences with specific recruitment of left inferior frontal gyrus and precentral cortex which are differentiable in terms of the specific interference induced.

A new perspective on positive symptoms: expression of damage or self-defence mechanism of the brain?

Usually, positive neurological symptoms are considered as the consequence of a mere, afinalistic and abnormal increase in function of specific brain areas. However, according to the Theory of Active Inference, which argues that action and perception constitute a loop that updates expectations according to a Bayesian model, the brain is rather an explorer that formulates hypotheses and tests them to assess the correspondence between internal models and reality. Moreover, the cerebral cortex is characterised by a continuous "conflict" between different brain areas, which constantly attempt to expand in order to acquire more of the limited available computational resources, by means of their dopamine-induced neuroplasticity. Thus, it has recently been suggested that dreams, during rapid eye movement sleep (REMS), protect visual brain areas (deprived of their stimuli during rest) from being conquered by other normally stimulated ones. It is therefore conceivable that positive symptoms also have a functional importance for the brain. We evaluate supporting literature data of a 'defensive' role of positive symptoms and the relevance of dopamine-induced neuroplasticity in the context of neurodegenerative and psychiatric diseases. Furthermore, the possible functional significance of idiopathic REMS-related behavioural disorder as well as phantom limb syndrome is examined. We suggest that positive neurological symptoms are not merely a passive expression of a damage, but active efforts, related to dopamine-induced plasticity, to maintain a correct relationship between the external world and its brain representation, thus preventing healthy cortical areas from ousting injured ones.

Submovement interpersonal coupling is associated to audio-motor coordination performance.

Acting in concert with others, a key aspect of our social life, requires behavioral coordination between persons on multiple timescales. When zooming in on the kinematic properties of movements, it appears that small speed fluctuations, called submovements, are embedded within otherwise smooth end-point trajectories. Submovements, by occurring at a faster timescale than that of movements, offer a novel window upon the functional relationship between distinct motor timescales. In this regard, it has previously been shown that when partners visually synchronize their movements, they also coordinate the timing of their submovement by following an alternated pattern. However, it remains unclear whether the mechanisms behind submovement coordination are domain-general or specific to the visual modality, and whether they have relevance for interpersonal coordination also at the scale of whole movements. In a series of solo and dyadic tasks, we show that submovements are also present and coordinated across partners when sensorimotor interactions are mediated by auditory feedback only. Importantly, the accuracy of task-instructed interpersonal coordination at the movement level correlates with the strength of submovement coordination. These results demonstrate that submovement coordination is a potentially fundamental mechanism that participates in interpersonal motor coordination regardless of the sensory domain mediating the interaction.

The role of dorsal premotor cortex in joint action inhibition.

Behavioral interpersonal coordination requires smooth negotiation of actions in time and space (joint action-JA). Inhibitory control may play a role in fine-tuning appropriate coordinative responses. To date, little research has been conducted on motor inhibition during JA and on the modulatory influence that premotor areas might exert on inhibitory control. Here, we used an interactive task in which subjects were required to reach and open a bottle using one hand. The bottle was held and stabilized by a co-actor (JA) or by a mechanical holder (vice clamp, no-JA). We recorded two TMS-based indices of inhibition (short-interval intracortical inhibition-sICI; cortical silent period-cSP) during the reaching phase of the task. These reflect fast intracortical (GABAa-mediated) and slow corticospinal (GABAb-mediated) inhibition. Offline continuous theta burst stimulation (cTBS) was used to interfere with dorsal premotor cortex (PMd), ventral premotor cortex (PMv), and control site (vertex) before the execution of the task. Our results confirm a dissociation between fast and slow inhibition during JA coordination and provide evidence that premotor areas drive only slow inhibitory mechanisms, which in turn may reflect behavioral co-adaptation between trials. Exploratory analyses further suggest that PMd, more than PMv, is the key source of modulatory drive sculpting movements, according to the socio-interactive context.

Speech perception difficulty modulates theta-band encoding of articulatory synergies.

The human brain tracks available speech acoustics and extrapolates missing information such as the speaker's articulatory patterns. However, the extent to which articulatory reconstruction supports speech perception remains unclear. This study explores the relationship between articulatory reconstruction and task difficulty. Participants listened to sentences and performed a speech-rhyming task. Real kinematic data of the speaker's vocal tract were recorded via electromagnetic articulography (EMA) and aligned to corresponding acoustic outputs. We extracted articulatory synergies from the EMA data with principal component analysis (PCA) and employed partial information decomposition (PID) to separate the electroencephalographic (EEG) encoding of acoustic and articulatory features into unique, redundant, and synergistic atoms of information. We median-split sentences into easy (ES) and hard (HS) based on participants' performance and found that greater task difficulty involved greater encoding of unique articulatory information in the theta band. We conclude that fine-grained articulatory reconstruction plays a complementary role in the encoding of speech acoustics, lending further support to the claim that motor processes support speech perception.NEW & NOTEWORTHY Top-down processes originating from the motor system contribute to speech perception through the reconstruction of the speaker's articulatory movement. This study investigates the role of such articulatory simulation under variable task difficulty. We show that more challenging listening tasks lead to increased encoding of articulatory kinematics in the theta band and suggest that, in such situations, fine-grained articulatory reconstruction complements acoustic encoding.

Action prediction in psychosis.

Aberrant motor-sensory predictive functions have been linked to symptoms of psychosis, particularly reduced attenuation of self-generated sensations and misattribution of self-generated actions. Building on the parallels between prediction of self- and other-generated actions, this study aims to investigate whether individuals with psychosis also demonstrate abnormal perceptions and predictions of others' actions. Patients with psychosis and matched controls completed a two-alternative object size discrimination task. In each trial, they observed reaching actions towards a small and a large object, with varying levels of temporal occlusion ranging from 10% to 80% of movement duration. Their task was to predict the size of the object that would be grasped. We employed a novel analytic approach to examine how object size information was encoded and read out across progressive levels of occlusion with single-trial resolution. Patients with psychosis exhibited an overall pattern of reduced and discontinuous evidence integration relative to controls, characterized by a period of null integration up to 20% of movement duration, during which they did not read any size information. Surprisingly, this drop in accuracy in the initial integration period was not accompanied by a reduction in confidence. Difficulties in action prediction were correlated with the severity of negative symptoms and impaired functioning in social relationships.

Scale-invariant changes in corticospinal excitability reflect multiplexed oscillations in the motor output.

In the absence of disease, humans produce smooth and accurate movement trajectories. Despite such 'macroscopic' aspect, the 'microscopic' structure of movements reveals recurrent (quasi-rhythmic) discontinuities. To date, it is unclear how the sensorimotor system contributes to the macroscopic and microscopic architecture of movement. Here, we investigated how corticospinal excitability changes in relation to microscopic fluctuations that are naturally embedded within larger macroscopic variations in motor output. Participants performed a visuomotor tracking task. In addition to the 0.25 Hz modulation that is required for task fulfilment (macroscopic scale), the motor output shows tiny but systematic fluctuations at ∼2 and 8 Hz (microscopic scales). We show that motor-evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) during task performance are consistently modulated at all (time) scales. Surprisingly, MEP modulation covers a similar range at both micro- and macroscopic scales, even though the motor output differs by several orders of magnitude. Thus, corticospinal excitability finely maps the multiscale temporal patterning of the motor output, but it does so according to a principle of scale invariance. These results suggest that corticospinal excitability indexes a relatively abstract level of movement encoding that may reflect the hierarchical organisation of sensorimotor processes. KEY POINTS: Motor behaviour is organised on multiple (time)scales. Small but systematic ('microscopic') fluctuations are engrained in larger and slower ('macroscopic') variations in motor output, which are instrumental in deploying the desired motor plan. Corticospinal excitability is modulated in relation to motor fluctuations on both macroscopic and microscopic (time)scales. Corticospinal excitability obeys a principle of scale invariance, that is, it is modulated similarly at all (time)scales, possibly reflecting hierarchical mechanisms that optimise motor encoding.

Synergy of Nanotopography and Electrical Conductivity of PEDOT/PSS for Enhanced Neuronal Development.

Biomaterials able to promote neuronal development and neurite outgrowth are highly desired in neural tissue engineering for the repair of damaged or disrupted neural tissue and restoring the axonal connection. For this purpose, the use of either electroactive or micro- and nanostructured materials has been separately investigated. Here, the use of a nanomodulated conductive poly(3,4-ethylendioxithiophene) poly(styrenesulfonate) (PEDOT/PSS) substrate that exhibits instructive topographical and electrical cues at the same time was investigated for the first time. In particular, thin films featuring grooves with sizes comparable with those of neuronal neurites (NanoPEDOT) were fabricated by electrochemical polymerization of PEDOT/PSS on a nanomodulated polycarbonate template. The ability of NanoPEDOT to support neuronal development and direct neurite outgrowth was demonstrated by assessing cell viability and proliferation, expression of neuronal markers, average neurite length, and direction of neuroblastoma N2A cells induced to differentiate on this novel support. In addition to the beneficial effect of the nanogrooved topography, a 30% increase was shown in the average length of neurites when differentiating cells were subjected to an electrical stimulation of a few microamperes for 6 h. The results reported here suggest a favorable effect on the neuronal development of the synergistic combination of nanotopography and electrical stimulation, supporting the use of NanoPEDOT in neural tissue engineering to promote physical and functional reconnection of impaired neural networks.

The microstructure of intra- and interpersonal coordination.

Movements are naturally composed of submovements, i.e. recurrent speed pulses (2-3 Hz), possibly reflecting intermittent feedback-based motor adjustments. In visuomotor (unimanual) synchronization tasks, partners alternate submovements over time, indicating mutual coregulation. However, it is unclear whether submovement coordination is organized differently between and within individuals. Indeed, different types of information may be variably exploited for intrapersonal and interpersonal coordination. Participants performed a series of bimanual tasks alone or in pairs, with or without visual feedback (solo task only). We analysed the relative timing of submovements between their own hands or between their own hands and those of their partner. Distinct coordinative structures emerged at the submovement level depending on the relevance of visual feedback. Specifically, the relative timing of submovements (between partners/effectors) shifts from alternation to simultaneity and a mixture of both when coordination is achieved using vision (interpersonal), proprioception/efference-copy only (intrapersonal, without vision) or all information sources (intrapersonal, with vision), respectively. These results suggest that submovement coordination represents a behavioural proxy for the adaptive weighting of different sources of information within action-perception loops. In sum, the microstructure of movement reveals common principles governing the dynamics of sensorimotor control to achieve both intra- and interpersonal coordination.

Cortico-cortical paired associative stimulation conditioning superficial ventral premotor cortex-primary motor cortex connectivity influences motor cortical activity during precision grip.

The ventral premotor cortex (PMv) and primary motor cortex (M1) represent critical nodes of a parietofrontal network involved in grasping actions, such as power and precision grip. Here, we investigated how the functional PMv-M1 connectivity drives the dissociation between these two actions. We applied a PMv-M1 cortico-cortical paired associative stimulation (cc-PAS) protocol, stimulating M1 in both postero-anterior (PA) and antero-posterior (AP) directions, in order to induce long-term changes in the activity of different neuronal populations within M1. We evaluated the motor-evoked potential (MEP) amplitude, MEP latency and cortical silent period, in both PA and AP, during the isometric execution of precision and power grip, before and after the PMv-M1 cc-PAS. The repeated activation of the PMv-M1 cortico-cortical network with PA orientation over M1 did not change MEP amplitude or cortical silent period duration during both actions. In contrast, the PMv-M1 cc-PAS stimulation of M1 with an AP direction led to a specific modulation of precision grip motor drive. In particular, MEPs tested with AP stimulation showed a selective increase of corticospinal excitability during precision grip. These findings suggest that the more superficial M1 neuronal populations recruited by the PMv input are involved preferentially in the execution of precision grip actions. KEY POINTS: Ventral premotor cortex (PMv)-primary motor cortex (M1) cortico-cortical paired associative stimulation (cc-PAS) with different coil orientation targets dissociable neural populations. PMv-M1 cc-PAS with M1 antero-posterior coil orientation specifically modulates corticospinal excitability during precision grip. Superficial M1 populations are involved preferentially in the execution of precision grip. A plasticity induction protocol targeting the specific PMv-M1 subpopulation might have important translational value for the rehabilitation of hand function.

Modulatory Effects of Communicative Gaze on Attentional Orienting Are Driven by Dorsomedial Prefrontal Cortex but Not Right Temporoparietal Junction.

Communicative gaze (e.g., mutual or averted) has been shown to affect attentional orienting. However, no study to date has clearly separated the neural basis of the pure social component that modulates attentional orienting in response to communicative gaze from other processes that might be a combination of attentional and social effects. We used TMS to isolate the purely social effects of communicative gaze on attentional orienting. Participants completed a gaze-cueing task with a humanoid robot who engaged either in mutual or in averted gaze before shifting its gaze. Before the task, participants received either sham stimulation (baseline), stimulation of right TPJ (rTPJ), or dorsomedial prefrontal cortex (dmPFC). Results showed, as expected, that communicative gaze affected attentional orienting in baseline condition. This effect was not evident for rTPJ stimulation. Interestingly, stimulation to rTPJ also canceled out attentional orienting altogether. On the other hand, dmPFC stimulation eliminated the socially driven difference in attention orienting between the two gaze conditions while maintaining the basic general attentional orienting effect. Thus, our results allowed for separation of the pure social effect of communicative gaze on attentional orienting from other processes that are a combination of social and generic attentional components.

The time scales of irreversibility in spontaneous brain activity are altered in obsessive compulsive disorder.

We study how obsessive-compulsive disorder (OCD) affects the complexity and time-reversal symmetry-breaking (irreversibility) of the brain resting-state activity as measured by magnetoencephalography (MEG). Comparing MEG recordings from OCD patients and age/sex matched control subjects, we find that irreversibility is more concentrated at faster time scales and more uniformly distributed across different channels of the same hemisphere in OCD patients than in control subjects. Furthermore, the interhemispheric asymmetry between homologous areas of OCD patients and controls is also markedly different. Some of these differences were reduced by 1-year of Kundalini Yoga meditation treatment. Taken together, these results suggest that OCD alters the dynamic attractor of the brain's resting state and hint at a possible novel neurophysiological characterization of this psychiatric disorder and how this therapy can possibly modulate brain function.

The effect of the preferred hand on drawing movement.

The observation that different effectors can execute the same movement suggests functional equivalences driven by limb independent representation of action in the central nervous system. A common invariant motor behavior is the speed and curvature coupling (the 1/3 power law), a low dimensional (abstract) descriptor of movement which is resilient to different sensorimotor contexts. Our purpose is to verify the consistency of such motor equivalence during a drawing task, by testing the effect of manual dominance and movement speed on motor performance. We hypothesize that abstract kinematic variables are not the most resistant to speed or limb effector changes. The results show specific effects of speed and hand side on the drawing task. Movement duration, speed-curvature covariation, and maximum velocity were not significantly affected by hand side, while geometrical features were strongly speed and limb dependent. However, intra-trial analysis performed over the successive drawing movements reveals a significant hand side effect on the variability of movement vigor and velocity-curvature relationship (the 1/3 PL). The identified effects of speed and hand dominance on the kinematic parameters suggest different neural strategies, in a pattern that does not go from the most abstract to the least abstract component, as proposed by the traditional hierarchical organization of the motor plan.

Action Observation Therapy for Arm Recovery after Stroke: A Preliminary Investigation on a Novel Protocol with EEG Monitoring.

This preliminary study introduces a novel action observation therapy (AOT) protocol associated with electroencephalographic (EEG) monitoring to be used in the future as a rehabilitation strategy for the upper limb in patients with subacute stroke. To provide initial evidence on the usefulness of this method, we compared the outcome of 11 patients who received daily AOT for three weeks with that of patients who undertook two other approaches recently investigated by our group, namely intensive conventional therapy (ICT), and robot-assisted therapy combined with functional electrical stimulation (RAT-FES). The three rehabilitative interventions showed similar arm motor recovery as indexed by Fugl-Meyer's assessment of the upper extremity (FMA_UE) and box and block test (BBT). The improvement in the FMA_UE was yet more favourable in patients with mild/moderate motor impairments who received AOT, in contrast with patients carrying similar disabilities who received the other two treatments. This suggests that AOT might be more effective in this subgroup of patients, perhaps because the integrity of their mirror neurons system (MNS) was more preserved, as indexed by EEG recording from central electrodes during action observation. In conclusion, AOT may reveal an effective rehabilitative tool in patients with subacute stroke; the EEG evaluation of MNS integrity may help to select patients who could maximally benefit from this intervention.

Placental DNA methylation profile as predicting marker for autism spectrum disorder (ASD).

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that impairs normal brain development and socio-cognitive abilities. The pathogenesis of this condition points out the involvement of genetic and environmental factors during in-utero life. Placenta, as an interface tissue between mother and fetus, provides developing fetus requirements and exposes it to maternal environment as well. Therefore, the alteration of DNA methylation as epigenetic consequence of gene-environmental interaction in the placenta could shed light on ASD pathogenesis. In this study, we reviewed the current findings on placental methylation status and its association with ASD. Differentially methylated regions (DMRs) in ASD-developing placenta were found to be mainly enriched in ASD gene loci affecting synaptogenesis, microtubule dynamics, neurogenesis and neuritogenesis. In addition, non-genic DMRs in ASD-placenta proposes an alternative contributing mechanism for ASD development. Our study highlights the importance of placental DNA methylation signature as a biomarker for ASD prediction.

Motor invariants in action execution and perception.

The nervous system is sensitive to statistical regularities of the external world and forms internal models of these regularities to predict environmental dynamics. Given the inherently social nature of human behavior, being capable of building reliable predictive models of others' actions may be essential for successful interaction. While social prediction might seem to be a daunting task, the study of human motor control has accumulated ample evidence that our movements follow a series of kinematic invariants, which can be used by observers to reduce their uncertainty during social exchanges. Here, we provide an overview of the most salient regularities that shape biological motion, examine the role of these invariants in recognizing others' actions, and speculate that anchoring socially-relevant perceptual decisions to such kinematic invariants provides a key computational advantage for inferring conspecifics' goals and intentions.