Effects of transcranial magnetic stimulation (TMS) current direction and pulse waveform on cortico-cortical connectivity: A registered report TMS-EEG study.

Transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) are a promising proxy for measuring effective connectivity, that is, the directed transmission of physiological signals along cortico-cortical tracts, and for developing connectivity-based biomarkers. A crucial point is how stimulation parameters may affect TEPs, as they may contribute to the general variability of findings across studies. Here, we manipulated two TMS parameters (i.e. current direction and pulse waveform) while measuring (a) an early TEP component reflecting contralateral inhibition of motor areas, namely, M1-P15, as an operative model of interhemispheric cortico-cortical connectivity, and (b) motor-evoked potentials (MEP) for the corticospinal pathway. Our results showed that these two TMS parameters are crucial to evoke the M1-P15, influencing its amplitude, latency, and replicability. Specifically, (a) M1-P15 amplitude was strongly affected by current direction in monophasic stimulation; (b) M1-P15 latency was significantly modulated by current direction for monophasic and biphasic pulses. The replicability of M1-P15 was substantial for the same stimulation condition. At the same time, it was poor when stimulation parameters were changed, suggesting that these factors must be controlled to obtain stable single-subject measures. Finally, MEP latency was modulated by current direction, whereas non-statistically significant changes were evident for amplitude. Overall, our study highlights the importance of TMS parameters for early TEP responses recording and suggests controlling their impact in developing connectivity biomarkers from TEPs. Moreover, these results point out that the excitability of the corticospinal tract, which is commonly used as a reference to set TMS intensity, may not correspond to the excitability of cortico-cortical pathways.

Rhythmic TMS as a Feasible Tool to Uncover the Oscillatory Signatures of Audiovisual Integration.

Multisensory integration is quintessential to adaptive behavior, with clinical populations showing significant impairments in this domain, most notably hallucinatory reports. Interestingly, altered cross-modal interactions have also been reported in healthy individuals when engaged in tasks such as the Sound-Induced Flash-Illusion (SIFI). The temporal dynamics of the SIFI have been recently tied to the speed of occipital alpha rhythms (IAF), with faster oscillations entailing reduced temporal windows within which the illusion is experienced. In this regard, entrainment-based protocols have not yet implemented rhythmic transcranial magnetic stimulation (rhTMS) to causally test for this relationship. It thus remains to be evaluated whether rhTMS-induced acoustic and somatosensory sensations may not specifically interfere with the illusion. Here, we addressed this issue by asking 27 volunteers to perform a SIFI paradigm under different Sham and active rhTMS protocols, delivered over the occipital pole at the IAF. Although TMS has been proven to act upon brain tissues excitability, results show that the SIFI occurred for both Sham and active rhTMS, with the illusory rate not being significantly different between baseline and stimulation conditions. This aligns with the discrete sampling hypothesis, for which alpha amplitude modulation, known to reflect changes in cortical excitability, should not account for changes in the illusory rate. Moreover, these findings highlight the viability of rhTMS-based interventions as a means to probe the neuroelectric signatures of illusory and hallucinatory audiovisual experiences, in healthy and neuropsychiatric populations.

M1-P15 as a cortical marker for transcallosal inhibition: A preregistered TMS-EEG study.

In a recently published study combining transcranial magnetic stimulation and electroencephalography (TMS-EEG), an early component of TMS-evoked potentials (TEPs), i.e., M1-P15, was proposed as a measure of transcallosal inhibition between motor cortices. Given that early TEPs are known to be highly variable, further evidence is needed before M1-P15 can be considered a reliable index of effective connectivity. Here, we conceived a new preregistered TMS-EEG study with two aims. The first aim was validating the M1-P15 as a cortical index of transcallosal inhibition by replicating previous findings on its relationship with the ipsilateral silent period (iSP) and with performance in bimanual coordination. The second aim was inducing a task-dependent modulation of transcallosal inhibition. A new sample of 32 healthy right-handed participants underwent behavioral motor tasks and TMS-EEG recording, in which left and right M1 were stimulated both during bimanual tasks and during an iSP paradigm. Hypotheses and methods were preregistered before data collection. Results show a replication of our previous findings on the positive relationship between M1-P15 amplitude and the iSP normalized area. Differently, the relationship between M1-P15 latency and bimanual coordination was not confirmed. Finally, M1-P15 amplitude was modulated by the characteristics of the bimanual task the participants were performing, and not by the contralateral hand activity during the iSP paradigm. In sum, the present results corroborate our previous findings in validating the M1-P15 as a cortical marker of transcallosal inhibition and provide novel evidence of its task-dependent modulation. Importantly, we demonstrate the feasibility of preregistration in the TMS-EEG field to increase methodological rigor and transparency.

The hand motor hotspot for seed-based functional connectivity of hand motor networks at rest.

In the seed-based method for studying functional connectivity (FC), seed selection is relevant. Here, we propose a new methodological approach for resting-state FC analysis of hand motor networks using the individual hand motor hotspot (hMHS) as seed. Nineteen right-handed healthy volunteers underwent a transcranial magnetic stimulation (TMS) session and resting-state fMRI. For each subject, the hMHS in both hemispheres was identified by TMS with the contralateral abductor pollicis brevis muscle as the target, the site eliciting the highest and most reliable motor-evoked potentials. Seed regions were built on coordinates on the cortex corresponding to the individual left and right hMHSs. For comparison, the left and right Brodmann's area 4 (BA4) masks extracted from a standard atlas were used as seed. The left and right hMHSs showed FC patterns at rest mainly including sensorimotor regions, with a bilateral connectivity only for the left hMHS. The statistical contrast BA4 > hMHS for both hemispheres showed different extension and lateralization of the functionally connected cortical regions. On the contrary, no voxels survived the opposite contrast (hMHS > BA4). This suggests that detection of individual hand motor seeds by TMS allows to identify functionally connected motor networks that are more specific with respect to those obtained starting from the a priori atlas-based identification of the primary motor cortex.

Sharing motor plans while acting jointly: A TMS study.

When acting together, we may represent not only our own individual goals but also a collective goal. Although behavioural evidence suggests that agents' motor plans might be related to collective goals, direct neurophysiological evidence of whether collective goals are motorically represented is still scarce. The aim of the present transcranial magnetic stimulation (TMS) study is to begin to fill this gap. A participant and a confederate were asked to sequentially perform a two-choice reaction time task by acting on pressure sensors. In their own turn, they saw a cue indicating whether to lift their fingers from (or to press them on) a pressure sensor to shoot a ball across the screen as fast as possible. The confederate responded with the right hand, the participant with the left hand. While the confederate acted on the sensor, the participant's motor evoked potentials (MEPs) were collected from the right Extensor Carpi Ulnaris. If participants represent their own and the confederate's actions as being directed to a collective goal, MEPs amplitude should be modulated according to the action the confederate should perform. To test this conjecture, we contrasted three conditions: a Joint condition, in which both players worked together with their collective goal being to shoot the ball to get it to a common target, a Parallel condition, in which the players performed exactly the same task but received independent outcomes for their performance, and a Competitive condition, in which the outcome of the game still depended on the other player performance, but without the collective goal feature. Results showed no MEPs modulation according to the confederate's action in the Joint condition. Post-hoc exploratory analyses both provide some hints about this negative finding and also suggest possible improvements (i.e., adopting a different dependent variable, avoiding task-switching between conditions) for testing our hypothesis that collective goal can be represented motorically.

Pre-stimulus alpha-band power and phase fluctuations originate from different neural sources and exert distinct impact on stimulus-evoked responses.

Ongoing oscillatory neural activity before stimulus onset influences subsequent visual perception. Specifically, both the power and the phase of oscillations in the alpha-frequency band (9-13 Hz) have been reported to predict the detection of visual stimuli. Up to now, the functional mechanisms underlying pre-stimulus power and phase effects on upcoming visual percepts are debated. Here, we used magnetoencephalography recordings together with a near-threshold visual detection task to investigate the neural generators of pre-stimulus power and phase and their impact on subsequent visual-evoked responses. Pre-stimulus alpha-band power and phase opposition effects were found consistent with previous reports. Source localization suggested clearly distinct neural generators for these pre-stimulus effects: Power effects were mainly found in occipital-temporal regions, whereas phase effects also involved prefrontal areas. In order to be functionally relevant, the pre-stimulus correlates should influence post-stimulus processing. Using a trial-sorting approach, we observed that only pre-stimulus power modulated the Hits versus Misses difference in the evoked response, a well-established post-stimulus neural correlate of near-threshold perception, such that trials with stronger pre-stimulus power effect showed greater post-stimulus difference. By contrast, no influence of pre-stimulus phase effects were found. In sum, our study shows distinct generators for two pre-stimulus neural patterns predicting visual perception, and that only alpha power impacts the post-stimulus correlate of conscious access. This underlines the functional relevance of prestimulus alpha power on perceptual awareness, while questioning the role of alpha phase.

Alpha-band cortico-cortical phase synchronization is associated with effective connectivity in the motor network.

OBJECTIVE: Communication-through-coherence proposes that the phase synchronization (PS) of neural oscillations between cortical areas supports neural communication. In this study, we exploited transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) to test this hypothesis at the macroscale level, i.e., whether PS between cortical areas supports interarea communication. TEPs are electroencephalographic (EEG) responses time-locked to TMS pulses reflecting interarea communication, as they are generated by the transmission of neural activity from the stimulated area to connected regions. If interarea PS is important for communication, it should be associated with the TEP amplitude in the connected areas. METHODS: TMS was delivered over the left primary motor cortex (M1) of fourteen healthy volunteers, and 70-channel EEG was recorded. Early TEP components were source-localized to identify their generators, i.e., distant brain regions activated by M1 through effective connections. Next, linear regressions were used to test the relationship between the TEP amplitude and the pre-stimulus PS between the M1 and the connected regions in four frequency bands (range 4-45 Hz). RESULTS: Pre-stimulus interarea PS in the alpha-band was positively associated with the amplitude of early TEP components, namely, the N15 (ipsilateral supplementary motor area), P25 (contralateral M1) and P60 (ipsilateral parietal cortex). CONCLUSIONS: Alpha-band PS predicts the response amplitude of the distant brain regions effectively connected to M1. SIGNIFICANCE: Our study supports the role of EEG-PS in interarea communication, as theorized by communication-through-coherence.

Asymmetric transcallosal conduction delay leads to finer bimanual coordination.

It has been theorized that hemispheric dominance and more segregated information processing have evolved to overcome long conduction delays through the corpus callosum (transcallosal conduction delay - TCD) but that this may still impact behavioral performance, mostly in tasks requiring high timing accuracy. Nevertheless, a thorough understanding of the temporal features of interhemispheric communication is lacking. Here, we aimed to assess the relationship between TCD and behavioral performance with a noninvasive directional cortical measure of TCD obtained from transcranial magnetic stimulation (TMS)-evoked potentials (TEPs) in the motor system. Twenty-one healthy right-handed subjects were tested. TEPs were recorded during an ipsilateral silent period (iSP) paradigm and integrated with diffusion tensor imaging (DTI) and an in-phase bimanual thumb-opposition task. Linear mixed models were applied to test relationships between measures. We found TEP indexes of transcallosal communication at ∼15 ms both after primary motor cortex stimulation (M1-P15) and after dorsal premotor cortex stimulation (dPMC-P15). Both M1-and dPMC-P15 were predicted by mean diffusivity in the callosal body. Moreover, M1-P15 was positively related to iSP. Importantly, M1-P15 latency was linked to bimanual coordination with direction-dependent effects, so that asymmetric TCD was the best predictor of bimanual coordination. Our findings support the idea that transcallosal timing in signal transmission is essential for interhemispheric communication and can impact the final behavioral outcome. However, they challenge the view that a short conduction delay is always beneficial. Rather, they suggest that the effect of the conduction delay may depend on the direction of information flow.

Oscillatory Bursts in Parietal Cortex Reflect Dynamic Attention between Multiple Objects and Ensembles.

The visual system uses two complimentary strategies to process multiple objects simultaneously within a scene and update their spatial positions in real time. It either uses selective attention to individuate a complex, dynamic scene into a few focal objects (i.e., object individuation), or it represents multiple objects as an ensemble by distributing attention more globally across the scene (i.e., ensemble grouping). Neural oscillations may be a key signature for focal object individuation versus distributed ensemble grouping, because they are thought to regulate neural excitability over visual areas through inhibitory control mechanisms. We recorded whole-head MEG data during a multiple-object tracking paradigm, in which human participants (13 female, 11 male) switched between different instructions for object individuation and ensemble grouping on different trials. The stimuli, responses, and the demand to keep track of multiple spatial locations over time were held constant between the two conditions. We observed increased α-band power (9-13 Hz) packed into oscillatory bursts in bilateral inferior parietal cortex during multiple-object processing. Single-trial analysis revealed greater burst occurrences on object individuation versus ensemble grouping trials. By contrast, we found no differences using standard analyses on across-trials averaged α-band power. Moreover, the bursting effects occurred only below/at, but not above, the typical capacity limits for multiple-object processing (at ∼4 objects). Our findings reveal the real-time neural correlates underlying the dynamic processing of multiple-object scenarios, which are modulated by grouping strategies and capacity. They support a rhythmic, α-pulsed organization of dynamic attention to multiple objects and ensembles.SIGNIFICANCE STATEMENT Dynamic multiple-object scenarios are an important problem in real-world and computer vision. They require keeping track of multiple objects as they move through space and time. Such problems can be solved in two ways: One can individuate a scene object by object, or alternatively group objects into ensembles. We observed greater occurrences of α-oscillatory burst events in parietal cortex for processing objects versus ensembles and below/at versus above processing capacity. These results demonstrate a unique top-down mechanism by which the brain dynamically adjusts its computational level between objects and ensembles. They help to explain how the brain copes with its capacity limitations in real-time environments and may lead the way to technological innovations for time-critical video analysis in computer vision.

Touch anticipation mediates cross-modal Hebbian plasticity in the primary somatosensory cortex.

Paired associative stimulation (PAS) protocols can be used to induce Hebbian plasticity in the human brain. A modified, cross-modal version, of the PAS (cross-modal PAS, cm-PAS) has been recently developed. The cm-PAS consists in the repetitive pairings of a transcranial magnetic stimulation (TMS) pulse over the primary somatosensory cortex (S1) and a visual stimulus depicting a hand being touched; a 20 ms of inter-stimulus interval (ISI) is required to affect S1 plasticity, in turn modulating tactile acuity and somatosensory evoked potentials. The present study explores the role of anticipatory simulation in the cm-PAS efficacy, which could be responsible for such a short ISI. To this aim, we compared the effect of the original, fixed-frequency, cm-PAS to that of a jittered version, in which the time interval between trials was not steady but jittered, hence avoiding the anticipation of the upcoming visual-touch stimulus. Moreover, in the jittered PAS, the ISI between the paired stimulations was varied: it could match the early, somatosensory-driven, activation of S1 (20 ms), or the mirror recruitment of S1 by touch observation (150 ms). Results showed that tactile acuity is enhanced by the fixed-frequency cm-PAS, with an ISI of 20 ms between paired stimulation (visual-touch stimulus and TMS pulse over S1), and also by the jittered cm-PAS but only if the ISI is of 150 ms. These findings suggest that the cm-PAS with a jittered frequency, by preventing an anticipatory pre-activation of S1, delays the timing of the interaction between the visual-touch stimulus and the cortical pulse. On a broader perspective, our study highlights the possible involvement of sensory anticipation, likely through mirror-like simulation mechanisms, in tactile mirroring, as well as its influence of the optimal interval between the afferent and the magnetic pulse during PAS protocols.

Modelling the effects of ongoing alpha activity on visual perception: The oscillation-based probability of response.

Substantial evidence has shown that ongoing neural activity significantly contributes to how the brain responds to upcoming stimuli. In visual perception, a considerable portion of trial-to-trial variability can be accounted for by prestimulus magneto/electroencephalographic (M/EEG) alpha oscillations, which play an inhibitory function by means of cross-frequency interactions with gamma-band oscillations. Despite the fundamental theories on the role of oscillations in perception and cognition, the current literature lacks a clear theorization of the neural mechanisms underlying the effects of prestimulus activity, including electrophysiological phenomena at different scales (e.g., local field potentials and macro-scale M/EEG). Here, we present a model called the oscillation-based probability of response (OPR), which directly assesses the link between meso-scale neural mechanisms, macro-scale M/EEG, and behavioural outcome. The OPR includes distinct meso-scale mechanisms through which alpha oscillations modulate M/EEG gamma activity, namely, by decreasing a) the amplitude and/or b) neural synchronization of gamma oscillations. Crucially, the OPR makes specific predictions on the effects of these mechanisms on visual perception, as assessed through the psychometric function. SIGNIFICANCE STATEMENT: The oscillation-based probability of response (OPR) is grounded on a psychophysical approach focusing on the psychometric function estimation and may be highly informative in the study of ongoing brain activity, because it provides a tool for distinguishing different neural mechanisms of alpha-driven modulation of sensory processing.

Hebbian associative plasticity in the visuo-tactile domain: A cross-modal paired associative stimulation protocol.

We developed and assessed the effects of a novel cross-modal protocol aimed at inducing associative (Hebbian-like) plasticity in the somatosensory cortical system through vision. Associative long-term potentiation can be induced in the primary somatosensory cortex (S1) by means of paired associative stimulation (PAS), in which a peripheral electrical stimulation of the median nerve is repeatedly paired with a transcranial magnetic stimulation (TMS) pulse over S1. Considering the mirror proprieties of S1, the cross-modal PAS (cm-PAS) consists of repetitive observation of bodily tactile stimulations, paired with TMS pulses over the contralateral S1. Through three experiments in healthy participants, we demonstrate that the cm-PAS is able to induce excitatory plastic effects with functional significance in S1, improving somatosensory processing at both behavioral (tactile acuity) and neurophysiological (somatosensory-evoked potentials) levels. The plastic effects induced by cm-PAS depend on the interval (20 ms) between the visual stimulus and the magnetic pulse, the targeted cortical site (S1), and the tactile content of the visual stimulus, which must represent a touch event. Such specificity implies the involvement of cross-modal, mirror-like, mechanisms in S1, which are able to visually promote associative synaptic plasticity in S1 likely through the recruitment of predictive coding processes.

Perceptual and Physiological Consequences of Dark Adaptation: A TMS-EEG Study.

Existing literature on sensory deprivation suggests that short-lasting periods of dark adaptation (DA) can cause changes in visual cortex excitability. DA cortical effects have previously been assessed through phosphene perception, i.e., the ability to report visual sensations when a transcranial magnetic stimulation (TMS) pulse is delivered over the visual cortex. However, phosphenes represent an indirect measure of visual cortical excitability which relies on a subjective report. Here, we aimed at overcoming this limitation by assessing visual cortical excitability by combining subjective (i.e., TMS-induced phosphenes) and objective (i.e., TMS-evoked potentials - TEPs) measurements in a TMS-EEG protocol after 30 min of DA. DA effects were compared to a control condition, entailing 30 min of controlled light exposure. TMS was applied at 11 intensities in order to estimate the psychometric function of phosphene report and explore the relationship between TEPs and TMS intensity. Compared to light adaptation, after DA the slope of the psychometric function was significantly steeper, and the amplitude of a TEP component (P60) was lower, only for high TMS intensities. The perceptual threshold was not affected by DA. These results support the idea that DA leads to a change in the excitability of the visual cortex, accompanied by a behavioral modification of visual perception. Furthermore, this study provides a first valuable description of the relationship between TMS intensity and visual TEPs.