Giacomo Guidali

Unveiling the plastic mechanisms of the primary visual cortex (V1) is crucial for understanding how visual processing can change and adapt, ultimately informing interventions to promote functional recovery following visual system damage. Paired associative stimulation (PAS) protocols can induce associative plasticity within the human V1. However, previous paradigms used full-field visual stimulation, engaging both hemispheres simultaneously, leaving unclear whether plasticity can be selectively targeted to a single visual pathway and whether it can modulate the non-stimulated hemisphere. Across three experiments in healthy participants, we investigated the neurophysiological, behavioural, and interhemispheric outcomes of a novel lateralized visual PAS protocol (vPAS). Pattern-reversal checkerboards were presented in a single visual hemifield and time-locked to transcranial magnetic stimulation (TMS) pulses delivered over the contralateral V1. Experiment 1 assessed neurophysiological effects by recording hemifield-lateralized visual-evoked potentials (VEPs) and testing three inter-stimulus intervals (ISIs: 75, 100, and 125 ms) between vPAS-paired stimuli. Experiment 2 evaluated perceptual changes in contrast detection, while Experiment 3 examined vPAS hemispheric specificity and aftereffects on interhemispheric visuomotor transfer. Only the 75-ms ISI consistently modulated visual processing in the non-conditioned hemisphere, reducing N75 amplitude and improving contrast detection for visual stimuli presented contralateral to the TMS side. Longer ISIs were not effective. Furthermore, this protocol altered interhemispheric transfer exclusively when the left, but not the right, V1 was targeted during vPAS. In conclusion, lateralized vPAS induces timing-dependent changes beyond the stimulated cortex, suggesting that associative plasticity can engage contralateral visual circuits and modulate visual processing.

Observing another person's action recruits the action observation network (AON). Evidence suggests that distinct AON pathways are engaged depending on action features, such as their transitivity or the movement's target; however, the spatiotemporal dynamics of these circuitries remain unclear and debated. In the present study, to further explore this aspect, healthy participants completed two experiments involving the passive observation of distinct grasping actions: intransitive (isolated grasp), object‐directed (hand grasping a bottle), and socially‐directed (hand grasping another person's hand). In Experiment 1 , using electroencephalography (EEG), we examined whole‐brain temporal patterns of AON activation during the observation of these stimuli through event‐related potentials and microstate analyses. In Experiment 2 , informed by EEG results, we used transcranial magnetic stimulation (TMS) to assess the temporal dynamics of motor resonance, a corticospinal marker of AON recruitment. Experiment 1 showed that observing transitive and intransitive grasping activates the same core circuit within the AON, albeit with distinct spatiotemporal dynamics emerging in two separate time windows, peaking at approximately 200 and 350 ms after action onset. Specifically, observation of object‐directed grasping relies more on the engagement of posterior brain regions. In contrast, intransitive and socially‐directed movements recruit anterior areas more quickly, with the activation pattern of the latter class of stimuli likely reflecting the additional visuo‐tactile processing associated with the observed action. Experiment 2 showed muscle‐specific motor resonance at 200 ms only for intransitive and object‐directed grasping, but no corticospinal facilitation at later latencies, where inhibitory patterns instead emerged, suggesting that EEG and TMS capture complementary dynamics underlying action observation and understanding. Overall, our findings suggest that observing transitive and intransitive movements modulates AON activity through shared pathways expressed in specific spatiotemporal gradients, corresponding to distinct cortical and corticospinal signatures that encode the features of the observed action.

Background: Signature production represents a complex motor and cognitive behavior, highly automatized and repeated countless times throughout life. It ranks among the most durable graphic forms, often preserved even when writing processes are impaired. Studies examining signature characteristics in clinical cohorts are limited. The available evidence raises questions about its potential as a behavioral marker of neurological and psychiatric disorders. Methods: We conducted a PRISMA-compliant systematic review up to 4th December 2025 to summarize evidence on how neurological and psychiatric conditions may affect signature features. Eligible articles on this topic were searched in Scopus, Web of Science, and PubMed databases. Sixteen papers were included, and their results were systematically described and qualitatively analyzed. Results: The available literature suggests that signature production appears relatively independent of global cognitive decline, although it is sensitive to specific pathological conditions (e.g., micrographia in Parkinson’s disease, increased tortuosity in cerebral small vessel disease, and alterations observed in mania, delirium, obsessive-compulsive disorder, and major depressive disorder). Alterations commonly affect kinematic parameters, as well as visuospatial and constructional features. However, no disorder-specific signature pattern emerges from current evidence, largely due to the methodological heterogeneity across studies. Conclusions: The handwritten signature holds promise as a behavioral marker of brain disorders, serving as a potentially useful, complementary - rather than a stand-alone - indicator of neurological and psychiatric conditions, which could be potentially useful in clinical settings. The implications for forensic applications remain largely theoretical and have not yet been standardized.

Background: Retrograde trans‐synaptic degeneration (RTSD) refers to the progressive loss of retinal cells following damage to the post‐geniculate visual pathway. The advent of optical coherence tomography (OCT) has allowed the measurement and quantification of retinal layers, in turn providing compelling evidence of RTSD in stroke patients and highlighting that assessing the temporal and functional evolution of RTSD has important clinical implications. Methods: We conducted a systematic review up until 7th July 2025 to summarize the OCT evidence on post‐stroke RTSD. Eligible articles on this topic were searched in PubMed, Web of Science, and Scopus databases. Twenty‐eight papers, involving 888 patients and 624 healthy controls, were included, and their results were systematically described and qualitatively analyzed. Results: Overall, literature shows that RTSD is a frequent outcome of post‐chiasmatic strokes. RTSD is operationalized by measuring the thickness of the peripapillary retinal nerve fiber and macular layers. The latter appears to be a more robust structural biomarker, showing more consistent findings across studies, with its magnitude better correlating with patients' visual field defects. RTSD starts early after the stroke's onset and progresses for several years, with severity depending on lesion location and extension. Future investigations are needed to draw more robust conclusions on RTSD temporal dynamics, clarifying the relation between structural and functional loss. Conclusions: Current literature highlights the need to consider the RTSD among the primary outcomes of post‐chiasmatic stroke, given its implications on clinical management and neurorehabilitation, making the longitudinal assessment of this degenerative process crucial for prevention.

Individuals with borderline personality disorder (BPD) show alterations in empathic abilities, potentially involving automatic simulation processes supported by mirror-like mechanisms in the somatosensory domain. Within the tactile mirror system (TaMS), observing touch on another person’s body activates cortical regions involved in tactile perception, including the primary somatosensory cortex (S1). Although mirror-like alterations have been suggested in BPD, the underlying mechanisms of plasticity remain underexplored. Here, we used a cross-modal paired associative stimulation (cm-PAS) protocol to investigate the plasticity mechanisms of TaMS functioning in BPD. Twenty-four individuals with BPD and 24 healthy controls (HCs) were included. Empathic abilities were assessed using self-report questionnaires. Participants performed tactile acuity and visuo-tactile spatial congruity (VTSC) tasks before and after a cm-PAS protocol. During cm-PAS, images of a hand being touched were paired with transcranial magnetic stimulation over the S1. The effects of cm-PAS were assessed on tactile acuity, as an index of S1 activity, and VTSC performance, as an index of TaMS functioning. Preregistered analyses revealed that patients with BPD tended to have lower cognitive empathy than HCs, with no significant cm-PAS effects on tactile acuity or VTSC performance in HCs, precluding between-group comparisons of plasticity effects. Exploratory analyses were conducted to further investigate potential sources of variability in the effects of cm-PAS, as well as the relationship between cognitive empathy and visuo-tactile processing as measure of TaMS functioning. Preregistered Stage 1 protocol: https://osf.io/sqnwd (date of in-principle acceptance: 25/06/2023).

Paired associative stimulation (PAS), a neuromodulation protocol combining transcranial magnetic stimulation (TMS) pulses to the primary motor cortex (M1) with electrical median nerve stimulation, promotes synaptic plasticity (long-term potentiation—LTP, long-term depression—LTD) in the human motor system following Hebbian associative plasticity induction. To date, PAS effects have been mainly investigated at the corticospinal level. In the present Registered Report, we leveraged TMS and electroencephalography (TMS-EEG) co-registration to track the cortical dynamics related to M1-PAS, aiming to better characterize the neurophysiological substrates, grounding the effectiveness of such protocol. In two within-subject sessions, 30 healthy participants underwent the standard M1-PAS protocols inducing LTP (PASLTP) and LTD (PASLTD) while measuring motor-evoked potentials (MEPs) and TMS-evoked potentials (TEPs) from M1 stimulation before, immediately after, and 30 minutes after the end of the PAS, applied both at supra- (i.e., 110%) and sub- (i.e., 90%) resting motor threshold intensities. Besides replicating MEP enhancement and inhibition after PASLTP and PASLTD, our results showed that the P30 and N100 M1-TEP components were significantly modulated immediately following PASLTP and PASLTD administration. These effects were detectable only in suprathreshold conditions, suggesting that M1 subthreshold stimulation could not be optimal for tracking cortical effects of PAS. Furthermore, exploratory analyses showed that P60 amplitude at baseline successfully predicted the magnitude of P30 modulations after PASLTP administration. Our findings provide compelling evidence regarding the specificity of early TEP components in reflecting changes in M1 reactivity that underpin PAS effects and associative plasticity induction within the motor system. From a broader perspective, our study fosters evidence about using TMS-EEG biomarkers to track complex plastic changes induced in the human brain, exploiting neuromodulatory non-invasive brain stimulation protocols based on associative mechanisms, like PAS. Preregistered Stage 1 protocol: https://osf.io/detjc (date of in-principle acceptance: January 15, 2024). Recommended Stage 2 manuscript:https://rr.peercommunityin.org/articles/rec?id=1031.

Background/Objectives: Empathy is essential for successful social functioning, mediating different aspects of social cognition in everyday life. An intriguing aspect is the involvement of empathy even in basic neural mechanisms of action perception, thanks to its association with the Mirror Neuron System (MNS). The present retrospective study explores whether individual differences in cognitive and affective empathy, measured by the Interpersonal Reactivity Index (IRI) questionnaire, can predict motor resonance—the enhancement of motor cortex reactivity during the observation of biological movements—during transitive and intransitive action observation. Methods: Data from 160 healthy subjects who participated in transcranial magnetic stimulation (TMS) experiments assessing corticospinal excitability during action observation were retrospectively analyzed using multiple linear regression models. Participants filled the IRI and observed intransitive single-digit finger movements (n = 80) or grasping actions directed at different targets (intransitive, object-directed, social-directed; n = 80) synchronized with TMS over the primary motor cortex, allowing the investigation of how action features modulate the relationship between participants’ empathic traits and motor resonance magnitude. Results: Results show that empathic traits do not affect motor resonance during intransitive movements, whereas they do when motor resonance is measured during the observation of transitive actions. Cognitive empathy, particularly the perspective-taking scale, significantly predicts motor resonance magnitude when observing goal-directed actions. Meanwhile, affective empathy, specifically the empathic concern scale, predicts motor resonance while observing social action. Conclusions: These findings highlight that different facets of empathy are significantly related to humans’ ability to understand others’ actions through inner simulation mechanisms, particularly concerning action goals and social relevance.