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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. [ABSTRACT FROM AUTHOR]

As a change in the electroencephalogram (EEG) during motor tasks, the phenomenon in the sensorimotor area (SM1) is called event-related desynchronization (ERD). Motor commands are discharged from the primary motor area (M1) to the muscle through the corticospinal pathway and feedback to the primary somatosensory area (S1). This sensory input from the peripheral nerve stimulation to the central nervous system is attenuated during motor tasks by motor commands. This phenomenon is known as movement gating and is observed not only in S1, but also in non-primary motor areas. However, the brain circuits that trigger these motor-related changes and how the brain circuit modulates them as a controller remain unsolved. In this study, we evaluated the effects of spontaneous EEG changes and movement gating of somatosensory evoked potentials (SEPs) during motor execution by modulating cortical excitability with low-frequency repetitive transcranial magnetic stimulation (rTMS) over the PMc. Low frequency rTMS is known as an application where cortical excitability is suppressed after the stimulation. After rTMS, not only the previously known ERD, but also the newly gating of SEPs N30 and corticocortical spontaneous EEG changes were evaluated by Granger causality, which indicates that the time-varying causal relationship from the frontal to parietal area was significantly attenuated among eight healthy participants. These results suggest that spontaneous changes in EEG on SM1 and cortico-cortical connectivity during motor tasks are related to sensory feedback suppression of the frontal cortex.

Transcranial magnetic stimulation (TMS) studies have shown that cortico-cortical paired associative stimulation (ccPAS) can strengthen connectivity between the ventral premotor cortex (PMv) and the primary motor cortex (M1) by modulating convergent input over M1 via Hebbian spike-timing-dependent plasticity (STDP). However, whether ccPAS locally affects M1 activity remains unclear. We tested 60 right-handed young healthy humans in two studies, using a combination of dual coil TMS and ccPAS over the left PMv and M1 to probe and manipulate PMv-to-M1 connectivity, and single- and paired-pulse TMS to assess neural activity within M1. We provide convergent evidence that ccPAS, relying on repeated activations of excitatory PMv-to-M1 connections, acts locally over M1. During ccPAS, motor-evoked potentials (MEPs) induced by paired PMv-M1 stimulation gradually increased. Following ccPAS, the threshold for inducing MEPs of different amplitudes decreased, and the input-output curve (IO) slope increased, highlighting increased M1 corticospinal excitability. Moreover, ccPAS reduced the magnitude of short-interval intracortical inhibition (SICI), reflecting suppression of GABA-ergic interneuronal mechanisms within M1, without affecting intracortical facilitation (ICF). These changes were specific to ccPAS Hebbian strengthening of PMv-to-M1 connectivity, as no modulations were observed when reversing the order of the PMv-M1 stimulation during a control ccPAS protocol. These findings expand prior ccPAS research that focused on the malleability of cortico-cortical connectivity at the network-level, and highlight local changes in the area of convergent activation (i.e., M1) during plasticity induction. These findings provide new mechanistic insights into the physiological basis of ccPAS that are relevant for protocol optimization.

Recent studies have synchronized transcranial magnetic stimulation (TMS) application with pre‐defined brain oscillatory phases showing how brain response to perturbation depends on the brain state. However, none have investigated whether phase‐dependent TMS can possibly modulate connectivity with homologous distant brain regions belonging to the same network. In the framework of network‐targeted TMS, we investigated whether stimulation delivered at a specific phase of ongoing brain oscillations might favour stronger cortico‐cortical (c‐c) synchronization of distant network nodes connected to the stimulation target. Neuronavigated TMS pulses were delivered over the primary motor cortex (M1) during ongoing electroencephalography recording in 24 healthy individuals over two repeated sessions 1 month apart. Stimulation effects were analysed considering whether the TMS pulse was delivered at the time of a positive (peak) or negative (trough) phase of μ‐frequency oscillation, which determines c‐c synchrony within homologous areas of the sensorimotor network. Diffusion weighted imaging was used to study c‐c connectivity within the sensorimotor network and identify contralateral regions connected with the stimulation spot. Depending on when during the μ‐activity the TMS‐pulse was applied (peak or trough), its impact on inter‐hemispheric network synchrony varied significantly. Higher M1–M1 phase‐lock synchronization after the TMS‐pulse (0–200 ms) in the μ‐frequency band was found for trough compared to peak stimulation trials in both study visits. Phase‐dependent TMS delivery might be crucial not only to amplify local effects but also to increase the magnitude and reliability of the response to the external perturbation, with implications for interventions aimed at engaging more distributed functional brain networks. Key points: Synchronized transcranial magnetic stimulation (TMS) pulses with pre‐defined brain oscillatory phases allow evaluation of the impact of brain states on TMS effects.TMS pulses over M1 at the negative peak of the μ‐frequency band induce higher phase‐lock synchronization with interconnected contralateral homologous regions.Cortico‐cortical synchronization changes are linearly predicted by the fibre density and cross‐section of the white matter tract that connects the two brain regions.Phase‐dependent TMS delivery might be crucial not only to amplify local effects but also to increase the magnitude and reliability of within‐network synchronization. [ABSTRACT FROM AUTHOR]

• In patients with progressive myoclonus epilepsy, cortico-muscular coherence significantly decreased during Perampanel treatment. • Out-degree and betweenness centrality increased on contralateral motor cortex during Perampanel treatment. • The improvement of the myoclonus induced by Perampanel resulted from restored leadership of the contralateral motor cortex. To investigate the mechanisms by which Perampanel (PER) reduces the severity of action myoclonus, we studied on MEG signals the changes occurring in cortico-muscular coherence (CMC) and cortico-cortical connectivity in patients with progressive myoclonus epilepsies. The subjects performed an isometric extension of the hand; CMC and cortico-cortical connectivity were assessed using autoregressive models and generalized partial-directed coherence. The contralateral (Co) sensors showing average CMC values >0.7 of the maximum (set to 1) were grouped as central (C) regions of interest (ROI), while adjacent sensors showing CMC values >0.3 were grouped as Surrounding (Sr) ROIs. Under PER treatment, CMC decreased on Co C and Sr ROIs, but also on homologous ipsilateral (Ip) ROIs; out-degrees and betweenness centrality increased in Co ROIs and decreased in Ip ROIs. The flow from Ip to Co ROIs and from activated muscles to Ip C ROI decreased. The improvement of myoclonus corresponded to decreased CMC and recovered leadership of the cortical regions directly involved in the motor task, with a reduced interference of ipsilateral areas. Our study highlights on mechanisms suitable to treating myoclonus and suggests the role of a reduced local synchronization together a better control of distant synaptic effects. [ABSTRACT FROM AUTHOR]

The posterior parietal cortex (PPC) is a multifaceted region of cortex, contributing to several cognitive processes, including sensorimotor integration and spatial navigation. Although recent years have seen a considerable rise in the use of rodents, particularly mice, to investigate PPC and related networks, a coherent anatomical definition of PPC in the mouse is still lacking. To address this, we delineated the mouse PPC, using cyto‐ and chemoarchitectural markers from Nissl‐, parvalbumin‐and muscarinic acetylcholine receptor M2‐staining. Additionally, we performed bilateral triple anterograde tracer injections in primary visual cortex (V1) and prepared flattened tangential sections from one hemisphere and coronal sections from the other, allowing us to co‐register the cytoarchitectural features of PPC with V1 projections. This revealed that extrastriate area A was largely contained within lateral PPC, that medial PPC overlapped with the anterior portion of area AM, and that anterior RL overlapped partially with area PtP. Furthermore, triple anterograde tracer injections in PPC showed strong projections to associative thalamic nuclei as well as higher visual areas, orbitofrontal, cingulate and secondary motor cortices. Retrograde circuit mapping with rabies virus further showed that all cortical connections were reciprocal. These combined approaches provide a coherent definition of mouse PPC that incorporates laminar architecture, extrastriate projections, thalamic, and cortico–cortical connections. [ABSTRACT FROM AUTHOR]

The capacity to produce movements only at appropriate times is fundamental in successful behavior and requires a fine interplay between motor inhibition and facilitation. Evidence in humans indicates that the dorsal premotor cortex (PMCd) is involved in such preparatory and inhibitory processes, but how PMCd modulates motor output in humans is still unclear. We investigated this issue in healthy human volunteers, using a variant of the dual-coil transcranial magnetic stimulation (TMS) technique that allows testing the short-latency effects of conditioning TMS to the left PMCd on test TMS applied to the ipsilateral orofacial primary motor cortex (M1). Participants performed a delayed cued simple reaction time task. They were asked to produce a lip movement cued by an imperative GO-signal presented after a predictable SET-period, during which TMS was applied at different intervals. Results showed that the area of motor evoked potentials (MEPs) to test TMS was modulated by conditioning TMS. A transient inhibition cortico-bulbar excitability by PMCd stimulation was observed around the middle of the SET-period. Conversely, a ramping excitatory effect of PMCd stimulation appeared towards the end of the SET-period, as the time of the predicted GO-signal approached. The time-course of PMCd-M1 activity scaled to the varying SET-period duration. Our data indicate that inhibition and excitation of motor output during a delayed reaction time task are two distinct neural phenomena. They both originate in PMCd and are conveyed via cortico-cortical connections to the ipsilateral M1, where they are integrated to produce harmonic fluctuations of motor output. [ABSTRACT FROM AUTHOR]

• dual coil TMS highlights excitatory PMv-to-M1 neural interactions. • Repeated PMv-M1 TMS coupling enhances motor excitability during ccPAS. • rMT and IO curve show larger M1 corticospinal excitability after ccPAS. • M1 intracortical indices indicate GABA-mediated M1 disinhibition after ccPAS. • These effects are selective to ccPAS targeting of the PMv-to-M1 pathway. Transcranial magnetic stimulation (TMS) studies have shown that cortico-cortical paired associative stimulation (ccPAS) can strengthen connectivity between the ventral premotor cortex (PMv) and the primary motor cortex (M1) by modulating convergent input over M1 via Hebbian spike-timing-dependent plasticity (STDP). However, whether ccPAS locally affects M1 activity remains unclear. We tested 60 right-handed young healthy humans in two studies, using a combination of dual coil TMS and ccPAS over the left PMv and M1 to probe and manipulate PMv-to-M1 connectivity, and single- and paired-pulse TMS to assess neural activity within M1. We provide convergent evidence that ccPAS, relying on repeated activations of excitatory PMv-to-M1 connections, acts locally over M1. During ccPAS, motor-evoked potentials (MEPs) induced by paired PMv-M1 stimulation gradually increased. Following ccPAS, the threshold for inducing MEPs of different amplitudes decreased, and the input-output curve (IO) slope increased, highlighting increased M1 corticospinal excitability. Moreover, ccPAS reduced the magnitude of short-interval intracortical inhibition (SICI), reflecting suppression of GABA-ergic interneuronal mechanisms within M1, without affecting intracortical facilitation (ICF). These changes were specific to ccPAS Hebbian strengthening of PMv-to-M1 connectivity, as no modulations were observed when reversing the order of the PMv-M1 stimulation during a control ccPAS protocol. These findings expand prior ccPAS research that focused on the malleability of cortico-cortical connectivity at the network-level, and highlight local changes in the area of convergent activation (i.e., M1) during plasticity induction. These findings provide new mechanistic insights into the physiological basis of ccPAS that are relevant for protocol optimization. [ABSTRACT FROM AUTHOR]

Objective To investigate functional coupling between brain networks using spectral changes induced by single-pulse electric stimulation (SPES). Method We analyzed 20 patients with focal epilepsy, implanted with depth electrodes. SPES was applied to each pair of adjacent contacts, and responses were recorded from all other contacts. The mean response amplitude value was quantified in three time-periods after stimulation (10–60, 60–255, 255–500 ms) for three frequency-ranges (Gamma, Ripples, Fast-Ripples), and compared to baseline. A total of 30,755 responses were analyzed, taking into consideration three dichotomous pairs: stimulating in primary sensory areas (S1-V1) vs. outside them, to test the interaction in physiologic networks; stimulating in seizure onset zone (SOZ) vs. non-SOZ, to test pathologic interactions; recording in default mode network (DMN) vs. non-DMN. Results Overall, we observed an early excitation (10–60 ms) and a delayed inhibition (60–500 ms). More specifically, in the delayed period, stimulation in S1-V1 produced a higher gamma-inhibition in the DMN, while stimulation in the SOZ induced a higher inhibition in the epilepsy-related higher frequencies (Ripples and Fast-Ripples). Conclusion Physiologic and pathologic interactions can be assessed using spectral changes induced by SPES. Significance This is a promising method for connectivity studies in patients with drug-resistant focal epilepsy. [ABSTRACT FROM AUTHOR]

Background Electroencephalogram (EEG) signals are often contaminated by the electrocardiogram (ECG) interference, which affects quantitative characterization of EEG. New method We propose null-coherence, a frequency-based approach, to attenuate the ECG interference in EEG using simultaneously recorded ECG as a reference signal. After validating the proposed approach using numerically simulated data, we apply this approach to EEG recorded from six newborns receiving therapeutic hypothermia for neonatal encephalopathy. We compare our approach with an independent component analysis (ICA), a previously proposed approach to attenuate ECG artifacts in the EEG signal. The power spectrum and the cortico-cortical connectivity of the ECG attenuated EEG was compared against the power spectrum and the cortico-cortical connectivity of the raw EEG. Results The null-coherence approach attenuated the ECG contamination without leaving any residual of the ECG in the EEG. Comparison with existing method We show that the null-coherence approach performs better than ICA in attenuating the ECG contamination without enhancing cortico-cortical connectivity. Conclusion Our analysis suggests that using ICA to remove ECG contamination from the EEG suffers from redistribution problems, whereas the null-coherence approach does not. We show that both the null-coherence and ICA approaches attenuate the ECG contamination. However, the EEG obtained after ICA cleaning displayed higher cortico-cortical connectivity compared with that obtained using the null-coherence approach. This suggests that null-coherence is superior to ICA in attenuating the ECG interference in EEG for cortico-cortical connectivity analysis. [ABSTRACT FROM AUTHOR]

We analyzed the developmental history of the subplate and related cellular compartments of the prenatal and early postnatal human cerebrum by combining postmortem histological analysis with in vivo MRI. Histological analysis was performed on 21 postmortem brains (age range: 26 postconceptional weeks to 6.5 years) using Nissl staining, AChE-histochemistry, PAS-Alcian blue histochemistry, Gallyas' silver impregnation, and immunocytochemistry for MAP2, synaptophysin, neurofilament, chondroitin sulfate, fibronectin, and myelin basic protein. The histological findings were correlated with in vivo MRI findings obtained in 30 age-matched fetuses, infants, and children. We analyzed developmental reorganization of major cellular (cell bodies, growing axons) and extracellular (extracellular matrix) components of the subplate and the developing cortex/white matter interface. We found that perinatal and postnatal reorganization of these tissue components is protracted (extending into the second year of life) and characterized by well-delineated, transient and previously undescribed structural and molecular changes at the cortex/white matter interface. The findings of this study are clinically relevant because they may inform and guide a proper interpretation of highly dynamic and hitherto puzzling changes of cortical thickness and cortical/white matter interface as described in current in vivo MRI studies. [ABSTRACT FROM AUTHOR]

Abstract: We have recently demonstrated that cortico-cortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Here we further explored the after effects of cc-PAS on fine hand movements. Ten healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1HAND) at an interstimulus interval (ISI) of 8ms. We studied the after effects of cc-PAS on the performance of repetitive finger opposition movements of different complexity on both hands using a sensor-engineered glove. A quantitative evaluation of the following parameters was performed: Touch Duration (TD), Inter Tapping Interval (ITI) and Number of Errors (NE). We confirmed previous data by showing that left-to-right and right-to-left cc-PAS attenuated IHI. The new finding is that both left-to-right and right-to-left cc-PAS were able to influence the performance of a simple finger opposition movement changing the duration of TD and ITI. Interestingly the effect on the two hands was opposite in direction. These results provide further insight that cc-PAS can induce associative plasticity in connections between the targeted cortical areas influencing motor hand performances. These results may be relevant for future rehabilitative applications. [Copyright &y& Elsevier]

Abstract: Repetitive transcranial magnetic stimulation (rTMS) to the human primary motor cortex (M1) causes bidirectional changes in corticospinal excitability depending on the stimulation frequency used. We used functional brain imaging to compare the effects of 5 Hz and 1 Hz-rTMS on local and inter-regional connectivity within the motor system. Regional cerebral blood flow (rCBF) was measured as a marker of synaptic activity at rest and during freely selected finger movements. We hypothesized that increased cortical excitability induced by 5 Hz-rTMS over M1 has an opposite effect on the synaptic activity and the connectivity of the motor network from the decreased cortical excitability induced by 1 Hz-rTMS. rTMS at both frequencies induced similar changes in rCBF at the site of stimulation and within areas of the motor network engaged by the task. The two frequencies showed different effects on movement-related coupling between motor areas. Connectivity analyses also indicated a differential effect of 5 and 1 Hz-rTMS on motor network connectivity, suggesting a role for an inferomedial portion of left M1 and left dorsal premotor cortex in maintaining performance. These results suggest that rapid reorganization of the motor system occurs to maintain task performance during periods of altered cortical excitability. This reorganization differs according to the modulation of excitability which is a function of rTMS frequency. This study extends the work of Lee et al. (Lee, L., Siebner, H.R., Rowe, J.B., Rizzo, V. Rothwell, J.C. Frackowiak, R.S. Friston, K.J., 2003. Acute remapping within the motor system induced by low-frequency repetitive transcranial magnetic stimulation. J. Neurosci. 23, 5308–5318.) by providing evidence that the pattern of acute reorganization in the motor network following rTMS depends on the direction of conditioning. [Copyright &y& Elsevier]

Objective: We examined the interhemispheric functional synchronization of the visual cortex using coherence (Coh) analysis.Methods: Achromatic or isoluminant chromatic sinusoidal grating stimuli were presented to each hemifield at a rate of 8 reversals/s to record steady-state visual-evoked potentials (S-VEPs) in 10 healthy subjects. Four recording electrodes were placed at O1, O2, P3 and P4, referred to an electrode at Cz. A total of 50 responses of 1 s epoch were averaged, and were subjected to discrete fast Fourier transforms to yield the amplitude and phase of the 8 Hz component. Ordinary and partial Coh values were also calculated.Results: For both achromatic and chromatic stimuli, the 8 Hz amplitudes of O1 and O2 were significantly larger than those of P3 and P4 without any significant difference between O1 and O2. The phase lag between O1 and O2 was approximately 30° (latency shift 10.4 ms). Partial Coh between O1 and O2 at 8 Hz was significantly greater than that of the unstimulated condition, and this was only observed at 8 Hz.Conclusions: These results suggest that interhemispheric synchronization in the occipital area occurs despite the nature of the visual stimuli. Therefore, the activation of interhemispheric connection is important for the early stage of the visual information processing.Significance: Our results indicate that the first step of the visual information processing requires interhemispheric functional synchronization. [Copyright &y& Elsevier]

We examined the differences in interhemispheric functional correlation in the somatosensory system using coherence (Coh) analysis. Ten healthy adult volunteers served as subjects for this experiment. Vibratory stimulation (modulation frequency, 21 Hz) was given to each palm to record vibratory steady-state somatosensory evoked potentials (S-SEPs). S-SEPs were recorded from four electrodes placed at 2 cm posterior and anterior to C3 and C4, referred to an electrode at Fpz, respectively. For comparison, unstimulated S-SEPs were also recorded. A total of 50 responses of 1-s epochs was averaged and subjected to discrete fast Fourier transforms to yield the amplitudes of major harmonic components and Coh value. The Coh value between the two signals, x and y at each frequency f, was calculated as [Cohxy(f)]2=[Sxy(f)]2/[Sxx(f)×Syy(f)]. The amplitude at 21 Hz in the contralateral somatosensory area was significantly larger than that in the other electrodes. The interhemispheric Coh of the somatosensory area at 21 Hz was significantly lower than that in the unstimulated condition or intrahemispheric Coh. The initial somatosensory information is desynchronized. These findings indicate less significance of interhemispheric correlation as the first step of the vibratory information processing in the somatosensory cortex. [Copyright &y& Elsevier]

EEG coherence measures the covariation in electrical brain activity between two locations on the scalp and is used to study connectivity between cortical regions. The aim of this study was to determine the heritability of EEG coherence. Coherence was measured in a group of 213 16-yr-old twin pairs. By including male and female twin pairs in the sample, sex differences in genetic architecture were systematically examined. The EEG was obtained during quiet supine resting. Coherence was estimated for short and long distance combinations of electrode pairs along the anterior-posterior axis within a hemisphere for four frequency bands (delta, theta, alpha and beta). Averaged over all electrode combinations about 60% of the variance was explained by genetic factors for coherence in the theta, alpha and beta bands. For the delta band, the heritability was somewhat lower. No systematic sex differences in genetic architecture were found. All environmental influences were nonshared, i.e., unique factors including measurement error. Environmental factors shared by twin siblings did not influence variation in EEG coherence. These results suggest that individual differences in coherence form a potential candidate for (molecular) genetic studies on brain function. [ABSTRACT FROM AUTHOR]

Copy number variant disorders arise from altering the dosage of multiple contiguous genes. In this issue of Neuron, Fernandez et al. (2019) identify haploinsufficiency of mitochondrial Txnrd2 as an important contributor to the hypo-cortico-cortical connectivity of 22q11 deletion syndrome., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The statistical structure of intrinsic parietal and parieto-frontal connectivity in monkeys was studied through hierarchical cluster analysis. Based on their inputs, parietal and frontal areas were grouped into different clusters, including a variable number of areas that in most instances occupied contiguous architectonic fields. Connectivity tended to be stronger locally: that is, within areas of the same cluster. Distant frontal and parietal areas were targeted through connections that in most instances were reciprocal and often of different strength. These connections linked parietal and frontal clusters formed by areas sharing basic functional properties. This led to five different medio-laterally oriented pillar domains spanning the entire extent of the parieto-frontal system, in the posterior parietal, anterior parietal, cingulate, frontal, and prefrontal cortex. Different information processing streams could be identified thanks to inter-domain connectivity. These streams encode fast hand reaching and its control, complex visuomotor action spaces, hand grasping, action/intention recognition, oculomotor intention and visual attention, behavioral goals and strategies, and reward and decision value outcome. Most of these streams converge on the cingulate domain, the main hub of the system. All of them are embedded within a larger eye-hand coordination network, from which they can be selectively set in motion by task demands., Competing Interests: Authors report no conflict of interest.

The computation of texture and shape involves integration of features of various orientations. Orientation networks within V1 tend to involve cells which share similar orientation selectivity. However, emergent properties in V2 require the integration of multiple orientations. We now show that, unlike interactions within V1, V1-V2 orientation interactions are much less synchronized and are not necessarily orientation dependent. We find V1-V2 orientation networks are of two types: a more tightly synchronized, orientation-preserving network and a less synchronized orientation-diverse network. We suggest that such diversity of V1-V2 interactions underlies the spatial and functional integration required for computation of higher order contour and shape in V2., (Copyright © 2015 Elsevier Ltd. All rights reserved.)