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Background: SARS-COV-2 infection has been associated to long-lasting neuropsychiatric sequelae, including cognitive deficits, that persist after one year. However, longitudinal monitoring has been scarcely performed. Here, in a sample of COVID-19 patients, we monitor cognitive, psychological and quality of life-related profiles up to 22 months from resolution of respiratory disease. Methods: Out of 657 COVID-19 patients screened at Manzoni Hospital (Lecco, Italy), 22 underwent neuropsychological testing because of subjective cognitive disturbances at 6 months, 16 months, and 22 months. Tests of memory, attention, and executive functions were administered, along with questionnaires for depressive and Post-traumatic stress disorder (PTSD) symptoms, psychological well-being and quality of life. Cross-sectional descriptives, correlational, as well as longitudinal analyses considering COVID19-severity were carried out. A preliminary comparison with a sample of obstructive sleep apneas patients was also performed. Results: Around 50% of COVID-19 patients presented with cognitive deficits at t0. The most affected domain was verbal memory. Pathological scores diminished over time, but a high rate of borderline scores was still observable. Longitudinal analyses highlighted improvements in verbal and non-verbal long term memory, as well as attention, and executive functioning. Depression and PTSD-related symptoms were present in 30% of patients. The latter decreased over time and were associated to attentional-executive performance. Conclusions: Cognitive dysfunctions in COVID-19 patients may extend over 1 year, yet showing a significant recovery in several cases. Cognitive alterations are accompanied by a significant psychological distress. Many patients displaying borderline scores, especially those at higher risk of dementia, deserve clinical monitoring.

BackgroundWe investigated whether transcranial magnetic stimulation (rTMS) over the primary somatosensory cortex (S1) and sensory stimulation (SS) could promote upper limb recovery in participants with subacute stroke.MethodsParticipants were randomized into four groups: rTMS/Sham SS, Sham rTMS/SS, rTMS/SS, and control group (Sham rTMS/Sham SS). Participants underwent ten sessions of sham or active rTMS over S1 (10 Hz, 1,500 pulses, 120% of resting motor threshold, 20 min), followed by sham or active SS. The SS involved active sensory training (exploring features of objects and graphesthesia, proprioception exercises), mirror therapy, and Transcutaneous electrical nerve stimulation (TENS) in the region of the median nerve in the wrist (stimulation intensity as the minimum intensity at which the participants reported paresthesia; five electrical pulses of 1 ms duration each at 10 Hz were delivered every second over 45 min). Sham stimulations occurred as follows: Sham rTMS, coil was held while disconnected from the stimulator, and rTMS noise was presented with computer loudspeakers with recorded sound from a real stimulation. The Sham SS received therapy in the unaffected upper limb, did not use the mirror and received TENS stimulation for only 60 seconds. The primary outcome was the Body Structure/Function: Fugl-Meyer Assessment (FMA) and Nottingham Sensory Assessment (NSA); the secondary outcome was the Activity/Participation domains, assessed with Box and Block Test, Motor Activity Log scale, Jebsen-Taylor Test, and Functional Independence Measure.ResultsForty participants with stroke ischemic (n = 38) and hemorrhagic (n = 2), men (n = 19) and women (n = 21), in the subacute stage (10.6 ± 6 weeks) had a mean age of 62.2 ± 9.6 years, were equally divided into four groups (10 participants in each group). Significant somatosensory improvements were found in participants receiving active rTMS and active SS, compared with those in the control group (sham rTMS with sham SS). Motor function improved only in participants who received active rTMS, with greater effects when active rTMS was combined with active SS.ConclusionThe combined use of SS with rTMS over S1 represents a more effective therapy for increasing sensory and motor recovery, as well as functional independence, in participants with subacute stroke.Clinical Trial Registration[clinicaltrials.gov], identifier [NCT03329807].

The Mirror Neuron System (MNS) is endowed with an action-observation network whereby the movement observation leads to greater excitability of the primary motor area (M1) (motor resonance). The activity in MNS seems to be modulated by learning new visuo-motor associations, i.e., Hebbian associative plasticity. A method to induce such plasticity and reshape motor resonance is the so-called mirror Paired Associative Stimulation (PAS) protocol, in which a transcranial magnetic stimulation (TMS) pulse over the M1 is paired to a visual stimulus showing ipsilateral hand movements. Further, observing virtual movements while being embodied in a virtual body impacts motor learning. Here, we carried out a mirror-PAS protocol in immersive virtual reality (VR) (i.e., Head Mounted Display) to investigate the impact of body representation on motor resonance when observing a grasping movement from a first-person perspective (1PP) while being embodied in a virtual body. A control group observed the same movement from a 1PP in a non-immersive setting (i.e., computer monitor). During the virtual mirror-PAS, a single-pulse TMS was applied over the right M1 paired to the observation of an ipsilateral grasping movement. Moreover, we recorded Motor Evoked Potentials induced by single-pulse TMS over the right M1 during the observation of grasping movements made with both hands. Following the virtual mirror-PAS protocol, we found differences between groups in motor resonance, sense of ownership, and agency toward the virtual arm performing the grasping movement. These results show the pivotal role of virtual embodiment in modulating the mirror-PAS's effects on corticomotor excitability.

Introduction : In the last years, the evidence that the primary somatosensory cortex (S1) is activated not only during the perception of tactile stimuli but also during their observation, has been widely investigated. A highly influential hypothesis suggests that the cross-modal, mirror-like, activity of S1 may arise from Hebbian associative plasticity: the contingency of seeing a touch and the feeling of a tactile sensation on one’s own body may reinforce synapses between visual and somatosensory neurons. However, to date, a causal demonstration is still lacking. To test this hypothesis, we developed a novel cross-modal Paired Associative Stimulation protocol (cm-PAS) where a visual stimulus depicting the palm of a left hand being touched is repeatedly presented (i.e. visual-touch stimulus), time-locked with a Transcranial Magnetic Stimulation (TMS) pulse over right S1. Methods : In 4 within-subjects experiments, we tested temporal (Experiment 1), cortical (Experiment 2) and visual (Experiment 3) specificity of cm-PAS by assessing its effects on tactile acuity. Experiment 3 explored neurophysiological changes in S1 by recording Somatosensory Evoked Potentials (SEPs). The last study (Experiment 4) investigated the role of predictive coding mechanisms through a jittered, unpredictable, cm-PAS version where the frequency between trials was not fixed (at variance with the fixed frequency of 0.1 Hz employed in previous experiments). Temporal constraints were explored by varying the inter-(paired) stimulus interval (ISI), according to different chronometry of S1 activation by touch processing and touch observation (i.e., 20 and 150 ms). Results : Results show that cm-PAS is effective in inducing Hebbian Long-Term Potentiation-like plasticity, increasing tactile acuity at the observer’s hand. Importantly, this effect is present only when (a) the ISI between the two stimuli (i.e., the visual-touch stimulus and the TMS pulse) is of 20 ms (Experiment 1), (b) the TMS pulse is delivered over S1 (Experiment 2) and (c) the visual stimulus depicts an hand being touched, not a mere hand action (Experiment 3). The cm-PAS also increases SEPs (i.e., the P40 component peak). Finally, Experiment 4 showed that the unpredictability of temporal occurrence of the paired stimuli changes the temporal window required for integrating the visual-touch stimulus with the cortical activation of S1, now requiring an ISI of 150 ms. Discussion : Our study provides novel insight into the cross-modal, mirroring, activity of S1, and the chance of inducing changes in this area by activating spike-timing-dependent plasticity and, in a broader perspective, Hebbian associative plasticity. Our original protocol, the cm-PAS, effectively modulates S1 functioning, improving tactile acuity and increasing SEPs. Interestingly, the cm-PAS recruits predictive coding mechanisms that act by pre-activating S1, anticipating the upcoming touch. Taken together, our results show how the cm-PAS can be a very useful non-invasive stimulation protocol to cross-modally induce neuroplasticity in the human brain, as well as uncovering the underpinning of mirroring mechanisms and the shaping role of predictive coding.

Hebbian associative plasticity and, in detail, spike-timing dependent plasticity (STDP) has been implied in the formation of the association between sensory and motor representations of actions in the Mirror Neuron System (MNS); however, such inductor role of STDP still needs empirical support1. To address this issue, we have assessed whether a novel paired associative stimulation (PAS) protocol, a non-invasive brain stimulation protocol known to activate STDP2, can induce the formation of atypical (i.e., absent in normal conditions), visuo-motor associations, in turn reshaping motor resonance. Twenty healthy participants underwent our novel mirror-PAS protocol (m-PAS) during which they were exposed to 180 repeated pairings of transcranial magnetic stimulation (TMS) pulses, applied over the right primary motor cortex (M1), time-locked with the view of index-finger movements of the right (ipsilateral) hand at a frequency of 0.2 Hz. In two different sessions, the inter-stimulus interval (ISI) between the onset of the visual action stimulus and TMS pulse was varied following the chronometry of motor control (25 ms) or that of MNS activation (250 ms). Before and after each m-PAS session, motor resonance was assessed by recording Motor Evoked Potentials (MEPs) induced by single-pulse TMS applied to the right M1, during the observation of both contralateral (left) and ipsilateral (right) index-finger movements or static hands. As expected from literature3, before m-PAS, a facilitation of cortico-spinal excitability (MEPs) occurred only during the view of left, contralateral (with respect to the TMS side) index-finger movements. The m-PAS successfully induced new ipsilateral motor resonance responses, indexed by an atypical facilitation of cortico-spinal excitability by the view of ipsilateral (i.e., right) hand movements. Crucially, this effect occurred only if the associative stimulation followed the chronometry of motor control (ISI of 25 ms). The present findings provide empirical evidence that Hebbian associative plasticity, and thus STDP, shapes the visual-motor matching properties of the MNS, which could be modulable by our PAS protocol. The m-PAS represents a promising non-invasive protocol to shed light on the neurofunctional bases of the human MNS.

Mirror therapy (MT) has been proposed as an effective rehabilitative strategy to alleviate pain symptoms in amputees with phantom limb pain (PLP). However, establishing the neural correlates associated with MT therapy have been challenging given that it is difficult to administer the therapy effectively within a magnetic resonance imaging (MRI) scanner environment. To characterize the functional organization of cortical regions associated with this rehabilitative strategy, we have developed a combined behavioral and functional neuroimaging protocol that can be applied in participants with a leg amputation. This novel approach allows participants to undergo MT within the MRI scanner environment by viewing real-time video images captured by a camera. The images are viewed by the participant through a system of mirrors and a monitor that the participant views while lying on the scanner bed. In this manner, functional changes in cortical areas of interest (e.g., sensorimotor cortex) can be characterized in response to the direct application of MT.

Background. Recently, the existence of serial order retention mechanisms shared across different Short-Term Memory (STM) domains has been hypothesized (1), however, the neural correlates of these mechanisms are still debated (1). Concerning auditory-verbal STM, the left Supramarginal Gyrus (SMG) has been identified as responsible for storing order information (2), but so far there is no study that has investigated whether this area could retain order information regardless of the nature of the stored material (i.e. verbal, spatial or motor). To test this hypothesis, we interfered with the left SMG activity by means of low-frequency repetitive Transcranial Magnetic Stimulation (rTMS), while testing STM in different domains. Methods. In three experiments, we explored the role of the left SMG in verbal (Experiment 1), visuospatial (Experiment 2) and motor (Experiment 3) STM by administering a verbal, a spatial, and a motor version of the span task, respectively, after 10 minutes of offline 1 Hz rTMS. Twenty subjects took part in each experiment, undergoing three sessions: a baseline session without rTMS, and two sessions during which rTMS was applied over the left SMG and the left Inferior Frontal Gyrus (IFG). In a fourth experiment (Control Experiment), a group of 15 subjects was tested in a visual pattern STM task, to assess left SMG selectivity for serial order retention. Number and types of errors were scored. Results. Results from the three experiments show that rTMS applied to the left SMG worsens participants’ accuracy in serial order maintenance, by selectively increasing the proportion of order errors with respect to both the baseline (rTMS-free) performance and the stimulation of the left IFG. Conversely, when the STM task does not require retention of sequential information (Control Experiment), rTMS to the left SMG has no significant effect on performance (i.e., accuracy or reaction times). Interestingly, the stimulation of the left IFG increases the rate of item errors only in the verbal span task (Experiment 1), hence confirming the involvement of this area in storing verbal information. Discussion. Our results show that the left SMG retains order information in STM independently from the information type. This evidence brings new light on the anatomic bases of STM network and to the functioning of the network itself. Furthermore, it also offers novel insights in clinical disorders where order information is prominent.

Background. The primary somatosensory cortex (S1), once thought to be only modality-specific, is involved in higher level functions like emotion recognition and motor learning by observation. S1’ functions may extend even to memory: some theories speculate that these areas may be involved not only in the perception of intrinsic features of the percept but also in the retention of that information. In a recent EEG study, Galvez-Pol suggested that the neural responses of somatosensory cortices to visually perceived body-related information probably reflected their involvement in short-term memory (STM). Aim. The present experiment looks for causal evidence that S1 is implicated in the retention of visual information that may be salient for this cortical area 1. To this purpose we interfered with S1 activity by means of repetitive Transcranial Magnetic Stimulation (rTMS) during a STM task where body-related information had to be retained. Methods. Eighteen healthy volunteers took part in a three sessions within-subjects experiment. The STM task (i.e., delayed match-to-sample task) consisted in the rapid presentation of two lateralized arrays, each one depicting three body-related stimuli (i.e., pictures of hands in different position, taken from previous literature. In the task, half of the trials were identical and half were different for only one stimulus. In each session, every subject performed the task with and without rTMS, with the latter condition serving as a baseline. The rTMS protocol consisted in a train of 3 TMS-pulses (at 10 Hz frequency, fixed intensity of 60% of the maximum stimulator output) delivered after 200 ms from the offset of the first array (i.e. during the retention phase). As control sites for rTMS effects, we stimulated two other cortical areas: the dorsolateral prefrontal cortex (dlPFC; an area commonly activated during working memory tasks) and the lateral occipital cortex (lOC; an area activated in feature-based analysis of visual stimuli). Only the right hemisphere was targeted. Results. We analyzed the sensitivity detection index (d') in the STM task through a 2 X 3 repetitive-measures ANOVA with the within-subjects factors “Condition” (baseline/rTMS) and “Area” (S1/dlPFC/lOC). We found a significant interaction between these two factors (p=0.036). Planned comparisons revealed an improvement of subjects’ performance in the STM task only when rTMS is delivered over S1 (vs. baseline, p

Background. Spike-timing-dependent plasticity (STDP), the neurophysiological basis of Hebbian learning, has been implied in the formation of the association between sensory and motor representations of actions in the Mirror Neuron System (MNS); however, such inductor role of STDP still needs empirical support. Aims. To address this issue, we have assessed whether a paired associative stimulation (PAS) protocol, a non-invasive brain stimulation protocol known to activate STDP, can induce the formation of atypical (i.e., absent in normal conditions), visuomotor associations, in turn reshaping motor resonance. Methods. Twenty healthy participants underwent our novel mirror-PAS protocol (m-PAS) during which they were exposed to 180 repeated pairings of transcranial magnetic stimulation (TMS) pulses, applied over the right primary motor cortex (M1), time-locked with the view of index-finger movements of the right (ipsilateral) hand at a frequency of 0.2 Hz. In two different sessions, the inter-stimulus interval (ISI) between the onset of the visual action stimulus and TMS pulse was varied following the chronometry of motor control (25 ms) or that of MNS activation (250 ms). Before and after each m-PAS session, motor resonance was assessed by recording Motor Evoked Potentials (MEPs) induced by single pulse TMS applied to the right M1, during the observation of both contralateral (left) and ipsilateral (right) index-finger movements or static hands. Results. As expected from literature3, before m-PAS, a facilitation of cortico-spinal excitability (MEPs) occurred only during the view of left, contralateral (with respect to the TMS side) index-finger movements. The m-PAS successfully induced new ipsilateral motor resonance responses, indexed by an atypical facilitation of corticospinal excitability by the view of ipsilateral (i.e., right) hand movements. Crucially, this effect occurred only if the associative stimulation followed the chronometry of motor control (ISI of 25 ms). Conclusion. The present findings provide empirical evidence that STDP, and thus Hebbian learning, shapes the visual-motor matching properties of the MNS, which could be modulable by PAS. The m-PAS represents a promising non-invasive protocol to shed light on the neurofunctional bases of the human MNS.

Background & object. The primary somatosensory cortex (S1), once thought to be only modality-specific, is involved in higher level functions like emotion recognition and motor learning by observation. S1 functions may extend even to memory: some theories speculate that sensorimotor areas may be involved not only in the perception of intrinsic features of the percept but also in the retention of that information. In a recent EEG study, it has been suggested that the neural responses of somatosensory cortices to visually perceived body-related information probably reflect their involvement in short-term memory (STM). The present experiment looks for causal evidence that S1 is implicated in the retention of visual information that may be salient for this cortical area1. To this purpose we interfered with S1 activity by means of repetitive Transcranial Magnetic Stimulation (rTMS) during a STM task where body-related information had to be retained. Methods & materials. Eighteen healthy volunteers took part in a three sessions within-subjects experiment. The STM task (i.e., delayed match-to-sample task) consisted in the rapid presentation of two lateralized arrays, each one depicting three body-related stimuli (i.e., pictures of hands in different position, taken from previous literature2). In the task, half of the trials were identical and half were different for only one stimulus. In each session, every subject performed the task with and without rTMS, with the latter condition serving as a baseline. The rTMS protocol consisted in a train of 3 TMS-pulses (at 10 Hz frequency, fixed intensity of 60% of the maximum stimulator output) delivered after 200 ms from the offset of the first array (i.e. during the retention phase). As control sites for rTMS effects, we stimulated two other cortical areas: the dorsolateral prefrontal cortex (dlPFC; an area commonly activated during WM tasks) and the lateral occipital cortex (lOC; an area activated in feature-based analysis of visual stimuli). Only the right hemisphere was targeted. Results. We analyzed the sensitivity detection index (d') in the STM task through a 2 X 3 repetitive-measures ANOVA with the within-subjects factors “Condition” (baseline vs. rTMS) and “Area” (S1, dlPFC, lOC). We found a statistically significant interaction between these two factors (p=0.036). Planned comparisons revealed an improvement of subjects’ performance in the STM task only when rTMS is delivered over S1 (vs. baseline, p

Objectives. Hebbian learning, and spike-timing-dependent plasticity (STDP), its neurophysiological basis, has been implied in the formation of the association between sensory and motor representations of actions in the Mirror Neuron System (MNS). At date, such inductor role of STDP still needs empirical support1. To address this issue, we have assessed whether a paired associative stimulation (PAS) protocol, a protocol known to activate STDP2, can induce the formation of atypical (i.e., absent in normal conditions), visuo-motor associations, in turn reshaping motor resonance. Methods & Materials. Twenty healthy participants underwent our novel mirror-PAS (m-PAS) protocol during which they were exposed to 180 repeated pairings of transcranial magnetic stimulation (TMS) pulses, applied over the right primary motor cortex (M1), time-locked with the view of index-finger movements of the right (ipsilateral) hand at a frequency of 0.2 Hz. In two different sessions, the inter-stimulus interval (ISI) between the onset of the visual action stimulus and TMS pulse was varied following the chronometry of motor control (25 ms) or that of MNS activation (250 ms). Before and after each m-PAS session, motor resonance was assessed by recording Motor Evoked Potentials (MEPs) induced by single-pulse TMS applied to the right M1, during the observation of both contralateral (left) and ipsilateral (right) index-finger movements or static hands. Results. As expected from literature3, before m-PAS, a facilitation of cortico-spinal excitability (i.e., MEPs) occurred only during the view of left, contralateral (with respect to the TMS side) index-finger movements. Importantly, the m-PAS successfully induced new ipsilateral motor resonance responses, indexed by an atypical facilitation of cortico-spinal excitability by the view of ipsilateral (i.e., right) hand movements. Crucially, this effect occurred only if the associative stimulation followed the chronometry of motor control (ISI of 25 ms). Discussion & Conclusions. The present findings provide empirical evidence that STDP, and thus Hebbian learning, shapes the visuo-motor matching properties of the MNS, which could be modulable by PAS. The m-PAS represents a promising non-invasive protocol to shed light on the neurofunctional bases of the human MNS.

In the last few years, the existence of a Tactile Mirror System in the human brain has been hypothesized: in this system, the same cortical areas implicated in tactile perception, namely the primary somatosensory cortex (S1), also respond to the mere observation of tactile events. In a seminal work, Keysers and Gazzola (2014) suggested that such cross-modal, mirror-like, responses of S1 may arise from Hebbian associative plasticity: the contingency of seeing a touch and the feeling of a tactile sensation on one’s own body may reinforce synapses between visual and somatosensory neurons. We tested this hypothesis by developing a novel cross-modal Paired Associative Stimulation (cmPAS) protocol. In the cmPAS, a visual stimulus (instead of the standard peripheral stimulation) depicting the palm of a left hand being touched is repeatedly presented, paired with a Transcranial Magnetic Stimulation (TMS) pulse over right S1. In Experiment 1, we tested the temporal and the cortical specificity of the plasticity effects induced by the cmPAS. Results show that the cmPAS is effective in eliciting Hebbian Long-Term Potentiation (LTP), modulating tactile acuity (measured by means of a 2-Points Discrimination Task) at the observer’s hand. Importantly, the effect is present only when the Inter-Stimulus Interval (ISI) between the two stimuli is 20 ms and the TMS pulse is delivered over S1. In Experiment 2, we aimed to uncover possible neurophysiological changes in S1 by combining the measurement of subjects’ tactile acuity with the recording of Somatosensory Evoked Potentials (SEPs). We also looked for evidence for a selectivity of the visual responsiveness of S1 by replacing the visual stimulus of a touch with one of a static hand (i.e., no-touch condition). Besides confirming the improvement of tactile acuity, preliminary results from the analysis of SEPs showed an increase of the SEPs’ P40 component peak after the delivery of the cmPAS. Consistently with the literature on the Tactile Mirror System, both these findings were present only when the visual stimulus depicted a touch. To sum up, our study provides novel insight of the cross-modal, visual, responsiveness of S1, showing that our cmPAS can induce plastic changes in S1 that follows the Hebbian associative learning rule. Such changes were detected both at a behavioral and at a neurophysiological level. This evidence offers new insights on the neural substrates of the Tactile Mirror System and, in a broader perspective, of early visuo-tactile interactions in the primary stages of somatosensory processing.

In a seminal work, Hurlstone, Hitch and Baddeley (2014) have proposed the existence of serial order mechanisms shared across different Short-Term Memory (STM) domains. However, the neural correlates of these mechanisms are still undiscovered and debated. Recently, in the case of auditory-verbal STM, a cortical area that seems responsible for storing order information has been identified, namely the left Supramarginal Gyrus (SMG). We speculate that the left SMG could retain order information regardless of presentation modality. Our study investigates this hypothesis by modulating the activity of the SMG with inhibitory repetitive Transcranial Magnetic Stimulation (rTMS). In a series of three experiments, we explored the role of the left SMG in the following STM domains: (a) verbal domain, with an auditory-verbal digit span task (Experiment 1); (b) visuo-spatial domain, with a computerized version of the Corsi span task (Experiment 2) and (c) motor domain, with a finger tapping span task (Experiment 3). Furthermore, we tested the selectivity of left SMG function (i.e., maintaining serial order and not a more general attentional role) using a visual pattern span task, a task where no order information has to be retained (Experiment 4). Twenty healthy volunteers took part in each of the three main experiments. The design of these experiments was within-subjects. Each experiment included three randomized sessions. In two stimulation sessions, before the experimental task, ten minutes of 1 Hz rTMS was applied either over the left SMG or over the left Inferior Frontal Gyrus (IFG). This second cortical area served as a control site. The third session was behavioural-only, serving as a baseline measurement. In Experiment 4 (control experiment) fifteen subjects were tested in a two-sessions within-subjects experiment. In this case, rTMS was applied only over the left SMG. Results of the three main experiments show that for all the STM tasks that required serial order maintenance, the inhibition of SMG selectively impaired the proportion of order errors made by the subjects with respect to both the stimulation-free condition and IFG inhibition. Conversely, when the STM task did not require a sequential information to retain, as in Experiment 4, the stimulation of SMG exerted no significant effect on the performance. Interestingly, the inhibition of IFG produced an increased rate of item errors only in the digit span task revealing how, in line with previous literature, IFG stores verbal information. Taken together our results suggest that left SMG retains order information in STM independently from the material type. This evidence not only brings new light to the anatomic bases of STM network and to the functioning of the network itself but could also offer novel insights in clinical disorders where order information is crucial.

For decades visual illusions have been used as a tool to investigate the properties of the visual system. In parallel, the neural bases of visual illusions have been investigated. Two principal methods have been used: the modification of perception in brain damage patients and the recording of brain activity induced by illusion perception. In general terms, the neuropsychological and imaging techniques suggest that the perception of illusions takes place at low level in the human brain. Here we use a non-invasive brain stimulation technique (tDCS, transcranial Direct Current Stimulation) to verify the bottom-up arising and the top-down modulation of a visuo-spatial illusion (Brentano illusion, BI) and of a brightness illusion (Glare effect, GE). Two groups of healthy subjects were tested with BI and GE while receiving cathodal or sham tDCS to the right or left posterior parietal cortex (PPC) or to the right or left occipital cortex (OC). Results show different effects for the two illusions. For BI, there is an increase of the illusory effect after cathodal tDCS of the right PPC and a decrease after the stimulation of the left PPC. No changes were found for OC stimulations. On the contrary GE was not modulated neither by PPC nor by OC stimulations. These evidences uphold the involvement of attention and its hemispheric asymmetry in modulating the perceptual processing underlying the BI, mediated by PPC and not by OC. GE as a pure luminance gradient illusion does not seem to be modulated by tDCS.

Introduction : Despite tDCS is increasingly used in experimental and clinical settings, its precise mechanisms remain largely unknown. At a neuronal level, tDCS modulates the cortical excitability by shifting the resting membrane potential in a polarity-dependent way: anodal stimulation increases the spontaneous firing rate, while cathodal decreases it. So far, the neurophysiological underpinnings of the immediate and delayed effects of tDCS are still unclear, as well as, how the stimulation of a given cerebral region may affect the activity of anatomically connected regions. In a previous study it has been investigated the tDCS anodal’s effect on the cortical excitability, by the means of TMS-EEG, showing a diffuse rise of cortical excitability in a bilateral fronto-parietal networks. Methods : Fifteen healthy, right-handed volunteers participated in the study. Single pulse TMS was delivered over the left posterior parietal cortex (PPC), before, during, and after a 10 minutes long session of cathodal tDCS stimulation over the right PPC, while EEG was recorded from 60 channels. For each TMS session, indexes of global and local cerebral excitability were obtained, computed as global and local mean field power (Global Mean Field Power, GMFP and Local Mean Field Power, LMFP) on the mean TMS-evoked potentials (TEPs) for three temporal windows: 0-50, 50-100 and 100-150 ms. The global index was computed on all the 60 channels. While, the local indexes were computed in four different clusters of electrodes: left and right, in frontal and parietal regions. Results : The preliminary results show no differences in both the TMS sessions during and after cathodal tDCS compared to pre-stimulation one, both at global and local level. A further test using bayesian analysis was performed, providing a moderate indication toward null hypothesis. Discussion : These results are consistent with the literature in which the coupling of anodal-excitatory and cathodal-inhibitory effects are well established in the sensory and motor domains, both at physiological and behavioral levels, while the evidence is more controversial for higher-level mental activity. References : Bindman L. et al. Nature. (1962) 196:584e585. Jacobson L.et al. Exp Brain Res. (2012) 216(1):1-10. Romero Lauro L. J. Et al. Cortex, (2014) 58:99e111

Recently, the existence of serial order retention mechanisms shared across different Short-Term Memory (STM) domains has been hypothesized; however, the neural correlates of these mechanisms are debated and partially undiscovered. In auditory-verbal STM, one cortical area that seems responsible for storing order information is the left Supramarginal Gyrus (SMG) but so far, it’s unknown whether this area could retain order information regardless of the nature of the stored material (i.e. verbal, spatial or motor). To investigate this hypothesis, in three experiments, we interfered with the left SMG activity by means of low-frequency (1 Hz) repetitive Transcranial Magnetic Stimulation (rTMS), while testing STM in different domains, namely in the verbal, visuospatial and motor domains, using different versions of the span task. Twenty subjects took part in each experiment, undergoing three sessions: a baseline session without rTMS, and two sessions during which rTMS was applied over the left SMG and the left Inferior Frontal Gyrus (IFG), serving as a control site. Results show that in all the STM domains tested, rTMS applied to the left SMG worsens subjects’ accuracy in serial order maintenance by selectively increasing the proportion of order errors with respect to both the baseline performance and the stimulation of the left IFG. Our finding is the first causal demonstration that left SMG retains order information in STM independently from the information type. This evidence brings new light on the anatomo-functional bases of STM network and could also offer novel insights in clinical disorders where order information is crucial.

Background: A growing body of evidence suggests the existence of a Tactile Mirror System in the human brain: the observation of tactile events activates the same cortical network implicated in tactile perception, including the primary somatosensory cortex (S1). It has been suggested that such crossmodal, mirror-like, responses of S1 may arise from Hebbian association learning plasticity: the contingency of seeing a touch and the feeling of a tactile sensation may reinforce synapses between visual and somatosensory neurons. We tested this hypothesis with a novel crossmodal Paired Associative Stimulation (PAS). Methods: In the crossmodal PAS, a visual stimulus depicting a hand being touched is repeatedly presented, paired with a Transcranical Magnetic Stimulation (TMS) pulse over S1. We investigated the efficacy of this protocol in inducing timing-dependent crossmodal plasticity, assessed in terms of changes of tactile acuity. Eighteen healthy participants took part in a within-subjects experiment: the inter-stimulus interval (ISI) between the seen touch and the TMS pulse varied across PAS sessions. Results: A significant improvement in tactile acuity was induced by the cross-modal PAS only at a selective (20 ms) ISI. The present result shows that associative plasticity within S1 can be effectively induced through vision, highlighting the existence of crossmodal plastic mechanisms.

An increasing number of evidence suggests the existence of a Tactile Mirror System in the human brain: the same cortical network implicated in tactile perception, which comprises the primary somatosensory cortex (S1), also responds to the mere observation of tactile events. It has been suggested that such cross-modal, mirror-like, responses of S1 may arise from Hebbian associative plasticity: the contingency of seeing a touch and the feeling of a tactile sensation on one’s own body may reinforce synapses between visual and somatosensory neurons. We tested this hypothesis introducing a novel cross-modal Paired Associative Stimulation (PAS) protocol. In the cross-modal PAS, a visual stimulus depicting a hand being touched is repeatedly presented, paired with a Transcranial Magnetic Stimulation (TMS) pulse over S1. In experiment 1, we tested both the temporal and the cortical specificity of the plasticity effects induced by the protocol. Results showed that cross-modal PAS was effective in eliciting Hebbian associative plasticity, modulating subjects’ tactile acuity (measured with a 2-Point Discrimination Task) selectively when the Inter-Stimulus Interval (ISI) between the two paired stimulations was 20 ms and the TMS pulse is delivered over S1. In experiment 2, we looked for evidence for a selectivity of the visual responsiveness of S1 and the role of expectancy during the cross-modal PAS. We also aimed to uncover possible neurophysiological changes in S1 by pairing the measurement of subjects’ tactile acuity with the recording of Somatosensory-Evoked Potentials (SEPs). To sum up, our study provides novel insight of the visual activity of S1, showing that our cross-modal PAS can induce plastic changes in S1, in line with an Hebbian associative learning rule. This evidence also offers new insights on the neural substrates of the Tactile Mirror System and, in a broader perspective, of early visuo-tactile interactions in the primary (low-level) stages of sensory processing.

Despite transcranial direct current stimulation (tDCS) is increasingly used in experimental and clinical settings, its precise mechanisms of action remain largely unknown. At a neuronal level, tDCS modulates the cortical excitability by shifting the resting membrane potential in a polarity-dependent way: anodal stimulation increases the spontaneous firing rate in the stimulated region, while cathodal decreases it. So far, the neurophysiological underpinnings of the immediate and delayed effects of tDCS are still unclear, as well as, it is not fully understood how the stimulation of a given cerebral region may affect the activity of anatomically connected regions. In a previous study it has been investigated the tDCS anodal’s role in the cortical excitability, by a combination of Transcranial Magnetic Stimulation (TMS) and Electroencephalography (EEG). Results showed a diffuse rise of cortical excitability in a bilateral fronto-parietal networks. In the present study, we used the same technique and methodological setting in order to explore local and global cortical excitability modulation during and after cathodal tDCS. Single pulse TMS was delivered over the left posterior parietal cortex (PPC), before, during, and after 10 minutes of tDCS over the right PPC, while EEG was recorded from 60 channels. For each session, indexes of global and local cerebral excitability were obtained, computed as global and local mean field power (Global Mean Field Power, GMFP and Local Mean Field Power, LMFP) on mean TMS-evoked potentials (TEPs) for four temporal windows: 0-50, 50-100, 100-150 and 150-200 milliseconds. The global index was computed on all 60 channels. The local indexes were computed in four clusters of electrodes: left and right, in frontal and parietal regions. The preliminary results on nine subjects show no differences in both sessions during and after cathodal tDCS compared to pre-stimulation session. These preliminary results suggest the existence of a difference effect due to anodal and cathodal tDCS stimulation, also in other areas, different from the motor cortex.

La stimolazione elettrica transcranica (tDCS) è sempre più impiegata sia in ambito clinico sia sperimentale, nonostante questo i suoi precisi meccanismi di funzionamento rimangono in gran parte sconosciuti. È noto che a livello neuronale, la tDCS modula l’eccitabilità corticale modificando il potenziale di membrana a riposo in modo polarità-dipendente: la stimolazione anodica aumenta il firing rate spontaneo delle regioni direttamente stimolate, al contrario quella catodica lo diminuisce (Bindman et Al, 1964). Tuttavia, le basi neurofisiologiche degli effetti della tDCS, diretti e post-stimolazione, sono ancora poco chiare, così come non si è ancora del tutto compreso come la stimolazione di una data area possa indurre degli effetti anche in regioni anatomicamente connesse a essa (Jacobson et al. 2012). In un precedente lavoro sono stati esplorati gli effetti della stimolazione tDCS anodica sull’eccitabilità corticale tramite l’utilizzo di una tecnica che combina la Stimolazione Magnetica Transcranica (TMS) alla registrazione Elettroencefalografica (EEG). I risultati hanno mostrato un diffuso aumento dell’eccitabilità corticale in un network bilaterale fronto-parietale (Romero Lauro et al., 2014). Nel presente studio è stata utilizzata la stessa tecnica e il medesimo setting sperimentale al fine di esplorare gli effetti di modulazione dell’eccitabilità corticale indotti dalla stimolazione tDCS catodica, sia a livello globale sia a livello locale. Materiali e Metodi È stata applicata la TMS a impulso singolo sulla corteccia parietale posteriore (PPC) sinistra, prima, durante e dieci minuti dopo la stimolazione tDCS in corrispondenza della PPC destra. Durante le tre sessioni di stimolazione sono stati registrati i potenziali evocati dalla TMS (TEPs) mediante una cuffia a sessanta canali. Dei TEPs sono state considerate per l’analisi quattro diverse finestre temporali: 0 (onset TMS) -50, 50-100, 100-150 and 150-200 millisecondi. Per ognuna di esse sono stati ricavati gli indici di eccitabilità corticale, sia globale sia locale, calcolando rispettivamente il Global e Local Mean Field Power (GMFP e LMFP) sulla media dei TEPs. Il GMFP è stato ottenuto analizzando il segnale derivante da tutti i sessanta canali EEG. Il LMFP, invece, è stato calcolato su quattro clusters di elettrodi: parietale destro (CP2, CP4, P2, e P4), parietale sinistro (CP1, CP3, P1, e P3), frontale destro (F2, F6, FC2, e FC6) e frontale sinistro (F1, F5, FC1, e FC3). Risultati e Discussione I risultati preliminari mostrano un’assenza di differenze significative tra le tre condizioni di stimolazione. Un’analisi bayesiana mostra un’indicazione moderata per l’ipotesi nulla. Questi risultati sono in linea con gli studi in letteratura che riportano come gli effetti della tDCS catodica risultino piuttosto controversi quando sono interessate aree che sottendono a funzioni cognitive di ordine superiore (Jacobson et al., 2012). Bibliografia 1. Bindman, L. J., Lippold, O. C., & Redfearn, J. W. (1962). Long-lasting changes in the level of the electrical activity of the cerebral cortex produced by polarizing currents. Nature, 196, 584e585. 2. Jacobson, L., Koslowsky, M., & Lavidor, M. (2012). tDCS polarity effects in motor and cognitive domains: a meta-analytical review. Experimental brain research, 216(1), 1-10. 3. Romero Lauro, L. J., Rosanova, M., Mattavelli, G., Convento, S., Pisoni, A., Opitz, A., et al. (2014). TDCS increases cortical excitability: direct evidence from TMS-EEG. Cortex, 58, 99e111.

The Müller-Lyer figure is a visual illusion in which two identical horizontal lines are perceived as different in their physical length because of the presence of fins (inducers) at the line ends. The Brentano illusion combines the two configurations of the Müller-Lyer illusion in one figure on the horizontal planum. In healthy subjects this configuration generates a displacement of the subjective midpoint of the horizontal line. In brain-damaged patients, with unilateral spatial neglect (USN+) without hemianopia (H-), the Brentano illusion is preserved, with illusory effects even enlarged in the contralesional hemispace. This finding suggests an inhibitory modulation of the top-down mechanisms on the bottom-up processing at the basis of such illusory phenomenon, likely mediated by the right posterior parietal cortex (PPC), which represents the main neural substrate of neglect. In order to verify the hypothesis that the attentional system can modulate the Brentano illusion and that this modulation is lateralized, a group of healthy subjects was tested with the Brentano Hemianopia Test (BHT) while receiving cathodal or sham transcranial Direct Current Stimulation (tDCS) to the right or left PPC. The results show an increase of the illusory effect after cathodal tDCS of the right PPC and a decrease after the stimulation of the left PPC. This evidence uphold the involvement of attention and its hemispheric asymmetry in modulating the perceptual processing underlying the Brentano illusion of length.

La figura di Müller-Lyer è un’illusione visiva in cui due linee orizzontali identiche sono viste come di diversa lunghezza fisica a causa della presenza di “induttori” agli estremi delle linee. L’illusione di Brentano è una variante in cui le due parti che compongono la figura di Müller-Lyer sono affiancate a formare un’unica configurazione, nella quale, in soggetti normali vi è uno spostamento del punto medio percepito della linea orizzontale. Precedenti studi, utilizzando il compito di bisezione, hanno evidenziato come l’illusione sia correttamente elaborata da pazienti affetti da negligenza spaziale unilaterale (NSU) senza emianopsia, mostrando un ampliamento dell’effetto illusorio nella parte di spazio controlaterale alla lesione. Tale risultato è stato interpretato come una modulazione dei processi top-down sull’elaborazione bottom-up, alla base del fenomeno illusorio. La NSU è una sindrome neuropsicologica associata a lesioni che colpiscono soprattutto l’emisfero destro e che coinvolgono in molti casi la corteccia parietale posteriore. Al fine di verificare il ruolo dell’attenzione e il coinvolgimento della corteccia parietale posteriore (PPC) nel modulare l’illusione di Brentano, un gruppo di soggetti neurologicamente indenni è stato sottoposto a stimolazione transcranica a corrente continua (tDCS), con polarità catodica, mentre veniva loro somministrato il Brentano Hemianopia Test. La procedura sperimentale prevedeva tre sessioni di stimolazione, con tDCS applicata su: PPC destra, PPC sinistra o in modalità sham (i.e. placebo). I risultati mostrano un aumento dell’effetto illusorio in seguito a tDCS catodica di PPC destra, e una riduzione dell’effetto illusorio in seguito a stimolazione di PPC sinistra. Tali risultati confermano sia il ruolo dell’attenzione che l’asimmetria emisferica della PPC nel regolare i processi di organizzazione percettiva responsabili dell’illusione di Brentano.