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.

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Cortico-cortical paired associative stimulation (ccPAS) is a recently established offline dual-coil transcranial magnetic stimulation (TMS) protocol [1-3] based on the Hebbian principle of associative plasticity and designed to transiently enhance synaptic efficiency in neural pathways linking two interconnected (targeted) brain regions [4,5]. Here, we present a new 'function-tuning ccPAS' paradigm in which, by pairing ccPAS with the presentation of a specific visual feature, for example a specific motion direction, we can selectively target and enhance the synaptic efficiency of functionally specific, but spatially overlapping, pathways. We report that ccPAS applied in a state-dependent manner and at a low intensity selectively enhanced detection of the specific motion direction primed during the combined visual-TMS manipulations. This paradigm significantly enhances the specificity of TMS-induced plasticity, by allowing the targeting of cortico-cortical pathways associated with specific functions.

The primary motor cortex (M1) is highly influenced by premotor/motor areas both within and across hemispheres. Dual site transcranial magnetic stimulation (dsTMS) has revealed interhemispheric interactions mainly at early latencies. Here, we used dsTMS to systematically investigate long-latency causal interactions between right-hemisphere motor areas and the left M1 (lM1). We stimulated lM1 using a suprathreshold test stimulus (TS) to elicit motor-evoked potentials (MEPs) in the right hand. Either a suprathreshold or a subthreshold conditioning stimulus (CS) was applied over the right M1 (rM1), the right ventral premotor cortex (rPMv), the right dorsal premotor cortex (rPMd) or the supplementary motor area (SMA) prior to the TS at various CS-TS inter-stimulus intervals (ISIs: 40–150 ms). The CS strongly affected lM1 excitability depending on ISI, CS site and intensity. Inhibitory effects were observed independently of CS intensity when conditioning PMv, rM1 and SMA at a 40-ms ISI, with larger effects after PMv conditioning. Inhibition was observed with suprathreshold PMv and rM1 conditioning at a 150-ms ISI, while site-specific, intensity-dependent facilitation was detected at an 80-ms ISI. Thus, long-latency interhemispheric interactions, likely reflecting indirect cortico-cortical/cortico-subcortical pathways, cannot be reduced to nonspecific activation across motor structures. Instead, they reflect intensity-dependent, connection- and time-specific mechanisms.

The primary motor cortex (M1) is strongly influenced by several frontal regions. Dual-site transcranial magnetic stimulation (dsTMS) has highlighted the timing of early (<40 ms) prefrontal/premotor influences over M1. Here we used dsTMS to investigate, for the first time, longer-latency causal interactions of the posterior inferior frontal gyrus (pIFG) and pre-supplementary motor area (pre-SMA) with M1 at rest. A suprathreshold test stimulus (TS) was applied over M1 producing a motor-evoked potential (MEP) in the relaxed hand. Either a subthreshold or a suprathreshold conditioning stimulus (CS) was administered over ipsilateral pIFG/pre-SMA sites before the TS at different CS-TS inter-stimulus intervals (ISIs: 40–150 ms). Independently of intensity, CS over pIFG and pre-SMA (but not over a control site) inhibited MEPs at an ISI of 40 ms. The CS over pIFG produced a second peak of inhibition at an ISI of 150 ms. Additionally, facilitatory modulations were found at an ISI of 60 ms, with supra- but not subthreshold CS intensities. These findings suggest differential modulatory roles of pIFG and pre-SMA in M1 excitability. In particular, the pIFG –but not the pre-SMA– exerts intensity-dependent modulatory influences over M1 within the explored time window of 40-150 ms, evidencing fine-tuned control of M1 output.

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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.

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.