Symmetry in Frontal But Not Motor and Somatosensory Cortical Projections.

The neocortex and striatum are topographically organized for sensory and motor functions. While sensory and motor areas are lateralized for touch and motor control, respectively, frontal areas are involved in decision-making, where lateralization of function may be less important. This study contrasted the topographic precision of cell-type-specific ipsilateral and contralateral cortical projections while varying the injection site location in transgenic mice of both sexes. While sensory cortical areas had strongly topographic outputs to the ipsilateral cortex and striatum, they were weaker and not as topographically precise to contralateral targets. The motor cortex had somewhat stronger projections but still relatively weak contralateral topography. In contrast, frontal cortical areas had high degrees of topographic similarity for both ipsilateral and contralateral projections to the cortex and striatum. Corticothalamic organization is mainly ipsilateral, with weaker, more medial contralateral projections. Corticostriatal computations might integrate input outside closed basal ganglia loops using contralateral projections, enabling the two hemispheres to act as a unit to converge on one result in motor planning and decision-making.

Real-time monitoring of cortical brain activity in response to acute pain using wide-area Ca2+ imaging.

Previous human and rodent studies indicated that nociceptive stimuli activate many brain regions that is involved in the somatosensory and emotional sensation. Although these studies have identified several important brain regions involved in pain perception, it has been a challenge to observe neural activity directly and simultaneously in these multiple brain regions during pain perception. Using a transgenic mouse expressing G-CaMP7 in majority of astrocytes and a subpopulation of excitatory neurons, we recorded the brain activity in the mouse cerebral cortex during acute pain stimulation. Both of hind paw pinch and intraplantar administration of formalin caused strong transient increase of the fluorescence in several cortical regions, including primary somatosensory, motor and retrosplenial cortex. This increase of the fluorescence intensity was attenuated by the pretreatment with morphine. The present study provides important insight into the cortico-cortical network during pain perception.

Cortico-cortical paired associative stimulation conditioning superficial ventral premotor cortex-primary motor cortex connectivity influences motor cortical activity during precision grip.

The ventral premotor cortex (PMv) and primary motor cortex (M1) represent critical nodes of a parietofrontal network involved in grasping actions, such as power and precision grip. Here, we investigated how the functional PMv-M1 connectivity drives the dissociation between these two actions. We applied a PMv-M1 cortico-cortical paired associative stimulation (cc-PAS) protocol, stimulating M1 in both postero-anterior (PA) and antero-posterior (AP) directions, in order to induce long-term changes in the activity of different neuronal populations within M1. We evaluated the motor-evoked potential (MEP) amplitude, MEP latency and cortical silent period, in both PA and AP, during the isometric execution of precision and power grip, before and after the PMv-M1 cc-PAS. The repeated activation of the PMv-M1 cortico-cortical network with PA orientation over M1 did not change MEP amplitude or cortical silent period duration during both actions. In contrast, the PMv-M1 cc-PAS stimulation of M1 with an AP direction led to a specific modulation of precision grip motor drive. In particular, MEPs tested with AP stimulation showed a selective increase of corticospinal excitability during precision grip. These findings suggest that the more superficial M1 neuronal populations recruited by the PMv input are involved preferentially in the execution of precision grip actions. KEY POINTS: Ventral premotor cortex (PMv)-primary motor cortex (M1) cortico-cortical paired associative stimulation (cc-PAS) with different coil orientation targets dissociable neural populations. PMv-M1 cc-PAS with M1 antero-posterior coil orientation specifically modulates corticospinal excitability during precision grip. Superficial M1 populations are involved preferentially in the execution of precision grip. A plasticity induction protocol targeting the specific PMv-M1 subpopulation might have important translational value for the rehabilitation of hand function.

Mechanisms of Hebbian-like plasticity in the ventral premotor - primary motor network.

The functional connection between ventral premotor cortex (PMv) and primary motor cortex (M1) is critical for the organization of goal-directed actions. Repeated activation of this connection by means of cortico-cortical paired associative stimulation (cc-PAS), a transcranial magnetic stimulation (TMS) protocol, may induce Hebbian-like plasticity. However, the physiological modifications produced by Hebbian-like plasticity in the PMv-M1 network are poorly understood. To fill this gap, we investigated the effects of cc-PAS on PMv-M1 circuits. We hypothesized that specific interactions would occur with I2 -wave interneurons as measured by the short intracortical facilitation protocol (SICF). We used different paired-pulse TMS protocols to examine the effects of PMv-M1 cc-PAS on SICF, on GABAergic circuits as measured by short (SICI) and long (LICI) intracortical inhibition protocols, and varied the current direction in M1 to target different M1 neuronal populations. Finally, we examined the effects of cc-PAS on PMv-M1 connectivity using a dual coil approach. We found that PMv-M1 cc-PAS induces both a long-term potentiation (LTP)- or long-term depression (LTD)-like after-effect in M1 neuronal activity that is strongly associated with a bidirectional-specific change in I2 -wave activity (SICF = 2.5 ms ISI). Moreover, cc-PAS induces a specific modulation of the LICI circuit and separately modulates PMv-M1 connectivity. We suggest that plasticity within the PMv-M1 circuit is mediated by a selective mechanism exerted by PMv on M1 by targeting I2 -wave interneurons. These results provide new mechanistic insights into how PMv modulates M1 activity that are relevant for the design of brain stimulation protocols in health and disease. KEY POINTS: The I2 -wave is specifically modulated by the induction of ventral premotor cortex - primary motor cortex (PMv-M1) plasticity. After PMv-M1 cortico-cortical paired associative stimulation (cc-PAS), corticospinal excitability correlates negatively with I2 -wave amplitude. Different cc-PAS coil orientations can lead to a long-term potentiation- or long-term depression-like after-effect in M1.

Cortico-cortical paired associative stimulation (ccPAS) over premotor-motor areas affects local circuitries in the human motor cortex via Hebbian plasticity.

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.

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.

Quantifying trial-by-trial variability during cortico-cortical evoked potential mapping of epileptogenic tissue.

OBJECTIVE: Measuring cortico-cortical evoked potentials (CCEPs) is a promising tool for mapping epileptic networks, but it is not known how variability in brain state and stimulation technique might impact the use of CCEPs for epilepsy localization. We test the hypotheses that (1) CCEPs demonstrate systematic variability across trials and (2) CCEP amplitudes depend on the timing of stimulation with respect to endogenous, low-frequency oscillations. METHODS: We studied 11 patients who underwent CCEP mapping after stereo-electroencephalography electrode implantation for surgical evaluation of drug-resistant epilepsy. Evoked potentials were measured from all electrodes after each pulse of a 30 s, 1 Hz bipolar stimulation train. We quantified monotonic trends, phase dependence, and standard deviation (SD) of N1 (15-50 ms post-stimulation) and N2 (50-300 ms post-stimulation) amplitudes across the 30 stimulation trials for each patient. We used linear regression to quantify the relationship between measures of CCEP variability and the clinical seizure-onset zone (SOZ) or interictal spike rates. RESULTS: We found that N1 and N2 waveforms exhibited both positive and negative monotonic trends in amplitude across trials. SOZ electrodes and electrodes with high interictal spike rates had lower N1 and N2 amplitudes with higher SD across trials. Monotonic trends of N1 and N2 amplitude were more positive when stimulating from an area with higher interictal spike rate. We also found intermittent synchronization of trial-level N1 amplitude with low-frequency phase in the hippocampus, which did not localize the SOZ. SIGNIFICANCE: These findings suggest that standard approaches for CCEP mapping, which involve computing a trial-averaged response over a .2-1 Hz stimulation train, may be masking inter-trial variability that localizes to epileptogenic tissue. We also found that CCEP N1 amplitudes synchronize with ongoing low-frequency oscillations in the hippocampus. Further targeted experiments are needed to determine whether phase-locked stimulation could have a role in localizing epileptogenic tissue.

Neocortical and medial temporal seizures have distinct impacts on brain responsiveness.

Focal epileptic seizures are characterized by abnormal neuronal discharges that can spread to other cortical areas and interfere with brain activity, thereby altering the patient's experience and behavior. The origin of these pathological neuronal discharges encompasses various mechanisms that converge toward similar clinical manifestations. Recent studies have suggested that medial temporal lobe (MTL) and neocortical (NC) seizures are often underpinned by two characteristic onset patterns, which, respectively, affect and spare synaptic transmission in cortical slices. However, these synaptic alterations and their effects have never been confirmed or studied in intact human brains. To fill this gap, we here evaluate whether responsiveness of MTL and NC are differentially affected by focal seizures, using a unique data set of cortico-cortical evoked potentials (CCEPs) collected during seizures triggered by single-pulse electrical stimulation (SPES). We find that responsiveness is abruptly reduced by the onset of MTL seizures, despite increased spontaneous activity, whereas it is preserved in the case of NC seizures. The present results provide an extreme example of dissociation between responsiveness and activity and show that brain networks are diversely affected by the onset of MTL and NC seizures, thus extending at the whole brain level the evidence of synaptic alteration found in vitro.

Effects of cortico-cortical paired associative stimulation based on multisensory integration to brain network connectivity in stroke patients: study protocol for a randomized doubled blind clinical trial.

INTRODUCTION: Brain has a spontaneous recovery after stroke, reflecting the plasticity of the brain. Currently, TMS is used for studies of single-target brain region modulation, which lacks consideration of brain networks and functional connectivity. Cortico-cortical paired associative stimulation (ccPAS) promotes recovery of motor function. Multisensory effects in primary visual cortex(V1) directly influence behavior and perception, which facilitate motor functional recovery in stroke patients. Therefore, in this study, dual-targeted precise stimulation of V1 and primary motor cortex(M1) on the affected hemisphere of stroke patients will be used for cortical visuomotor multisensory integration to improve motor function. METHOD: This study is a randomized, double-blind controlled clinical trial over a 14-week period. 69 stroke subjects will be enrolled and divided into sham stimulation group, ccPAS low frequency group, and ccPAS high frequency group. All groups will receive conventional rehabilitation. The intervention lasted for two weeks, five times a week. Assessments will be performed before the intervention, at the end of the intervention, and followed up at 6 and 14 weeks. The primary assessment indicator is the 'Fugl-Meyer Assessment of the Upper Extremity ', secondary outcomes were 'The line bisection test', 'Modified Taylor Complex Figure', 'NIHSS' and neuroimaging assessments. All adverse events will be recorded. DISCUSSION: Currently, ccPAS is used for the modulation of neural circuits. Based on spike-timing dependent plasticity theory, we can precisely intervene in the connections between different cortices to promote the recovery of functional connectivity on damaged brain networks after stroke. We hope to achieve the modulation of cortical visuomotor interaction by combining ccPAS with the concept of multisensory integration. We will further analyze the correlation between analyzing visual and motor circuits and explore the alteration of neuroplasticity by the interactions between different brain networks. This study will provide us with a new clinical treatment strategy to achieve precise rehabilitation for patient with motor dysfunction after stroke. TRIAL REGISTRATION: This trial was registered in the Chinese Clinical Trial Registry with code ChiCTR2300067422 and was approved on January 16, 2023.

Stimulating native seizures with neural resonance: a new approach to localize the seizure onset zone.

Successful outcomes in epilepsy surgery rely on the accurate localization of the seizure onset zone. Localizing the seizure onset zone is often a costly and time-consuming process wherein a patient undergoes intracranial EEG monitoring, and a team of clinicians wait for seizures to occur. Clinicians then analyse the intracranial EEG before each seizure onset to identify the seizure onset zone and localization accuracy increases when more seizures are captured. In this study, we develop a new approach to guide clinicians to actively elicit seizures with electrical stimulation. We propose that a brain region belongs to the seizure onset zone if a periodic stimulation at a particular frequency produces large amplitude oscillations in the intracranial EEG network that propagate seizure activity. Such responses occur when there is 'resonance' in the intracranial EEG network, and the resonant frequency can be detected by observing a sharp peak in the magnitude versus frequency response curve, called a Bode plot. To test our hypothesis, we analysed single-pulse electrical stimulation response data in 32 epilepsy patients undergoing intracranial EEG monitoring. For each patient and each stimulated brain region, we constructed a Bode plot by estimating a transfer function model from the intracranial EEG 'impulse' or single-pulse electrical stimulation response. The Bode plots were then analysed for evidence of resonance. First, we showed that when Bode plot features were used as a marker of the seizure onset zone, it distinguished successful from failed surgical outcomes with an area under the curve of 0.83, an accuracy that surpassed current methods of analysis with cortico-cortical evoked potential amplitude and cortico-cortical spectral responses. Then, we retrospectively showed that three out of five native seizures accidentally triggered in four patients during routine periodic stimulation at a given frequency corresponded to a resonant peak in the Bode plot. Last, we prospectively stimulated peak resonant frequencies gleaned from the Bode plots to elicit seizures in six patients, and this resulted in an induction of three seizures and three auras in these patients. These findings suggest neural resonance as a new biomarker of the seizure onset zone that can guide clinicians in eliciting native seizures to more quickly and accurately localize the seizure onset zone.

A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials.

Epilepsy presurgical investigation may include focal intracortical single-pulse electrical stimulations with depth electrodes, which induce cortico-cortical evoked potentials at distant sites because of white matter connectivity. Cortico-cortical evoked potentials provide a unique window on functional brain networks because they contain sufficient information to infer dynamical properties of large-scale brain connectivity, such as preferred directionality and propagation latencies. Here, we developed a biologically informed modelling approach to estimate the neural physiological parameters of brain functional networks from the cortico-cortical evoked potentials recorded in a large multicentric database. Specifically, we considered each cortico-cortical evoked potential as the output of a transient stimulus entering the stimulated region, which directly propagated to the recording region. Both regions were modelled as coupled neural mass models, the parameters of which were estimated from the first cortico-cortical evoked potential component, occurring before 80 ms, using dynamic causal modelling and Bayesian model inversion. This methodology was applied to the data of 780 patients with epilepsy from the F-TRACT database, providing a total of 34 354 bipolar stimulations and 774 445 cortico-cortical evoked potentials. The cortical mapping of the local excitatory and inhibitory synaptic time constants and of the axonal conduction delays between cortical regions was obtained at the population level using anatomy-based averaging procedures, based on the Lausanne2008 and the HCP-MMP1 parcellation schemes, containing 130 and 360 parcels, respectively. To rule out brain maturation effects, a separate analysis was performed for older (>15 years) and younger patients (<15 years). In the group of older subjects, we found that the cortico-cortical axonal conduction delays between parcels were globally short (median = 10.2 ms) and only 16% were larger than 20 ms. This was associated to a median velocity of 3.9 m/s. Although a general lengthening of these delays with the distance between the stimulating and recording contacts was observed across the cortex, some regions were less affected by this rule, such as the insula for which almost all efferent and afferent connections were faster than 10 ms. Synaptic time constants were found to be shorter in the sensorimotor, medial occipital and latero-temporal regions, than in other cortical areas. Finally, we found that axonal conduction delays were significantly larger in the group of subjects younger than 15 years, which corroborates that brain maturation increases the speed of brain dynamics. To our knowledge, this study is the first to provide a local estimation of axonal conduction delays and synaptic time constants across the whole human cortex in vivo, based on intracerebral electrophysiological recordings.

Variability of Single Pulse Electrical Stimulation Responses Recorded with Intracranial Electroencephalography in Epileptic Patients.

Cohort studies of brain stimulations performed with stereo-electroencephalographic (SEEG) electrodes in epileptic patients allow to derive large scale functional connectivity. It is known, however, that brain responses to electrical or magnetic stimulation techniques are not always reproducible. Here, we study variability of responses to single pulse SEEG electrical stimulation. We introduce a second-order probability analysis, i.e. we extend estimation of connection probabilities, defined as the proportion of responses trespassing a statistical threshold (determined in terms of Z-score with respect to spontaneous neuronal activity before stimulation) over all responses and derived from a number of individual measurements, to an analysis of pairs of measurements.Data from 445 patients were processed. We found that variability between two equivalent measurements is substantial in particular conditions. For long ( > ~ 90 mm) distances between stimulating and recording sites, and threshold value Z = 3, correlation between measurements drops almost to zero. In general, it remains below 0.5 when the threshold is smaller than Z = 4 or the stimulating current intensity is 1 mA. It grows with an increase of either of these factors. Variability is independent of interictal spiking rates in the stimulating and recording sites.We conclude that responses to SEEG stimulation in the human brain are variable, i.e. in a subject at rest, two stimulation trains performed at the same electrode contacts and with the same protocol can give discrepant results. Our findings highlight an advantage of probabilistic interpretation of such results even in the context of a single individual.

Corticocortical innervation subtypes of layer 5 intratelencephalic cells in the murine secondary motor cortex.

Feedback projections from the secondary motor cortex (M2) to the primary motor and sensory cortices are essential for behavior selection and sensory perception. Intratelencephalic (IT) cells in layer 5 (L5) contribute feedback projections to diverse cortical areas. Here we show that L5 IT cells participating in feedback connections to layer 1 (L1) exhibit distinct projection patterns, genetic profiles, and electrophysiological properties relative to other L5 IT cells. An analysis of the MouseLight database found that L5 IT cells preferentially targeting L1 project broadly to more cortical regions, including the perirhinal and auditory cortices, and innervate a larger volume of striatum than the other L5 IT cells. We found experimentally that in upper L5 (L5a), ER81 (ETV1) was found more often in L1-preferring IT cells, and in IT cells projecting to perirhinal/auditory regions than those projecting to primary motor or somatosensory regions. The perirhinal region-projecting L5a IT cells were synaptically connected to each other and displayed lower input resistance than contra-M2 projecting IT cells including L1-preferring and nonpreferring cells. Our findings suggest that M2-L5a IT L1-preferring cells exhibit stronger ER81 expression and broader cortical/striatal projection fields than do cells that do not preferentially target L1.

Layer 6A Pyramidal Cell Subtypes Form Synaptic Microcircuits with Distinct Functional and Structural Properties.

Neocortical layer 6 plays a crucial role in sensorimotor co-ordination and integration through functionally segregated circuits linking intracortical and subcortical areas. We performed whole-cell recordings combined with morphological reconstructions to identify morpho-electric types of layer 6A pyramidal cells (PCs) in rat barrel cortex. Cortico-thalamic (CT), cortico-cortical (CC), and cortico-claustral (CCla) PCs were classified based on their distinct morphologies and have been shown to exhibit different electrophysiological properties. We demonstrate that these three types of layer 6A PCs innervate neighboring excitatory neurons with distinct synaptic properties: CT PCs establish weak facilitating synapses onto other L6A PCs; CC PCs form synapses of moderate efficacy, while synapses made by putative CCla PCs display the highest release probability and a marked short-term depression. For excitatory-inhibitory synaptic connections in layer 6, both the presynaptic PC type and the postsynaptic interneuron type govern the dynamic properties of the respective synaptic connections. We have identified a functional division of local layer 6A excitatory microcircuits which may be responsible for the differential temporal engagement of layer 6 feed-forward and feedback networks. Our results provide a basis for further investigations on the long-range CC, CT, and CCla pathways.

Variations in Commissural Input Processing Across Different Types of Cortical Projection Neurons.

To understand how incoming cortical inputs are processed by different types of cortical projection neurons in the medial prefrontal cortex, we compared intrinsic physiological properties of and commissural excitatory/inhibitory influences on layer 5 intratelencephalic (IT), layer 5 pyramidal tract (PT), and layers 2/3 IT projection neurons. We found that intrinsic physiological properties and commissural synaptic transmission varied across the three types of projection neurons. The rank order of intrinsic excitability was layer 5 PT > layer 5 IT > layers 2/3 IT neurons. Commissural connectivity was higher in layers 2/3 than layer 5 projection neurons, but commissural excitatory influence was stronger on layer 5 than layers 2/3 pyramidal neurons. Paired-pulse ratio was also greater in PT than IT neurons. These results indicate that commissural inputs activate deep layer PT neurons most preferentially and superficial layer IT neurons least preferentially. Deep layer PT neurons might faithfully transmit cortical input signals to downstream subcortical structures for reliable control of behavior, whereas superficial layer IT neurons might integrate cortical input signals from diverse sources in support of higher-order cognitive functions.

Effects of Muscle Fatigue and Recovery on the Neuromuscular Network after an Intermittent Handgrip Fatigue Task: Spectral Analysis of Electroencephalography and Electromyography Signals.

Mechanisms underlying exercise-induced muscle fatigue and recovery are dependent on peripheral changes at the muscle level and improper control of motoneurons by the central nervous system. In this study, we analyzed the effects of muscle fatigue and recovery on the neuromuscular network through the spectral analysis of electroencephalography (EEG) and electromyography (EMG) signals. A total of 20 healthy right-handed volunteers performed an intermittent handgrip fatigue task. In the prefatigue, postfatigue, and postrecovery states, the participants contracted a handgrip dynamometer with sustained 30% maximal voluntary contractions (MVCs); EEG and EMG data were recorded. A considerable decrease was noted in EMG median frequency in the postfatigue state compared with the findings in other states. Furthermore, the EEG power spectral density of the right primary cortex exhibited a prominent increase in the gamma band. Muscle fatigue led to increases in the beta and gamma bands of contralateral and ipsilateral corticomuscular coherence, respectively. Moreover, a decrease was noted in corticocortical coherence between the bilateral primary motor cortices after muscle fatigue. EMG median frequency may serve as an indicator of muscle fatigue and recovery. Coherence analysis revealed that fatigue reduced the functional synchronization among bilateral motor areas but increased that between the cortex and muscle.

Targeted Modulation of Human Brain Interregional Effective Connectivity With Spike-Timing Dependent Plasticity.

OBJECTIVE: The ability to selectively up- or downregulate interregional brain connectivity would be useful for research and clinical purposes. Toward this aim, cortico-cortical paired associative stimulation (ccPAS) protocols have been developed in which two areas are repeatedly stimulated with a millisecond-level asynchrony. However, ccPAS results in humans using bifocal transcranial magnetic stimulation (TMS) have been variable, and the mechanisms remain unproven. In this study, our goal was to test whether ccPAS mechanism is spike-timing-dependent plasticity (STDP). MATERIALS AND METHODS: Eleven healthy participants received ccPAS to the left primary motor cortex (M1) → right M1 with three different asynchronies (5 milliseconds shorter, equal to, or 5 milliseconds longer than the 9-millisecond transcallosal conduction delay) in separate sessions. To observe the neurophysiological effects, single-pulse TMS was delivered to the left M1 before and after ccPAS while cortico-cortical evoked responses were extracted from the contralateral M1 using source-resolved electroencephalography. RESULTS: Consistent with STDP mechanisms, the effects on synaptic strengths flipped depending on the asynchrony. Further implicating STDP, control experiments suggested that the effects were unidirectional and selective to the targeted connection. CONCLUSION: The results support the idea that ccPAS induces STDP and may selectively up- or downregulate effective connectivity between targeted regions in the human brain.

Phase-dependent local brain states determine the impact of image-guided transcranial magnetic stimulation on motor network electroencephalographic synchronization.

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.

Distinct connectivity patterns in human medial parietal cortices: Evidence from standardized connectivity map using cortico-cortical evoked potential.

The medial parietal cortices are components of the default mode network (DMN), which are active in the resting state. The medial parietal cortices include the precuneus and the dorsal posterior cingulate cortex (dPCC). Few studies have mentioned differences in the connectivity in the medial parietal cortices, and these differences have not yet been precisely elucidated. Electrophysiological connectivity is essential for understanding cortical function or functional differences. Since little is known about electrophysiological connections from the medial parietal cortices in humans, we evaluated distinct connectivity patterns in the medial parietal cortices by constructing a standardized connectivity map using cortico-cortical evoked potential (CCEP). This study included nine patients with partial epilepsy or a brain tumor who underwent chronic intracranial electrode placement covering the medial parietal cortices. Single-pulse electrical stimuli were delivered to the medial parietal cortices (38 pairs of electrodes). Responses were standardized using the z-score of the baseline activity, and a response density map was constructed in the Montreal Neurological Institutes (MNI) space. The precuneus tended to connect with the inferior parietal lobule (IPL), the occipital cortex, superior parietal lobule (SPL), and the dorsal premotor area (PMd) (the four most active regions, in descending order), while the dPCC tended to connect to the middle cingulate cortex, SPL, precuneus, and IPL. The connectivity pattern differs significantly between the precuneus and dPCC stimulation (p<0.05). Regarding each part of the medial parietal cortices, the distributions of parts of CCEP responses resembled those of the functional connectivity database. Based on how the dPCC was connected to the medial frontal area, SPL, and IPL, its connectivity pattern could not be explained by DMN alone, but suggested a mixture of DMN and the frontoparietal cognitive network. These findings improve our understanding of the connectivity profile within the medial parietal cortices. The electrophysiological connectivity is the basis of propagation of electrical activities in patients with epilepsy. In addition, it helps us to better understand the epileptic network arising from the medial parietal cortices.

Functional connectivity and epileptogenicity of nodular heterotopias: A single-pulse stimulation study.

OBJECTIVE: Nodular heterotopias (NHs) are malformations of cortical development associated with drug-resistant focal epilepsy with frequent poor surgical outcome. The epileptogenic network is complex and can involve the nodule, the overlying cortex, or both. Single-pulse electrical stimulation (SPES) during stereo-electroencephalography (SEEG) allows the investigation of functional connectivity between the stimulated and responsive cortices by eliciting cortico-cortical evoked potentials (CCEPs). We used SPES to analyze the NH connectome and its relation to the epileptogenic network organization. METHODS: We retrospectively studied 12 patients with NH who underwent 1 Hz or 0.2 Hz SPES of NH during SEEG. Outbound connectivity (regions where CCEPs were elicited by NH stimulation) and inbound connectivity (regions where stimulation elicited CCEPs in the NH) were searched. SEEG channels were then classified as "heterotopic" (located within the NH), "connected" (located in normotopic cortex and showing connectivity with the NH), and "unconnected." We used the epileptogenicity index (EI) to quantify implication of channels in the seizure-onset zone and to classify seizures as heterotopic, normotopic, and normo-heterotopic. RESULTS: One hundred thirty-five outbound and 72 inbound connections were found. Three patients showed connectivity between hippocampus and NH, and seven patients showed strong internodular connectivity. A total of 39 seizures were analyzed: 23 normo-heterotopic, 12 normotopic, and 4 heterotopic. Logistic regression found that "connected" channels were significantly (p = 8.4e-05) more likely to be epileptogenic than "unconnected" channels (odds ratio 4.71, 95% confidence interval (CI) [2.17, 10.21]) and heterotopic channels were also significantly (p = .024) more epileptogenic than "unconnected" channels (odds ratio 3.29, 95% CI [1.17, 9.23]). SIGNIFICANCE: SPES reveals widespread connectivity between NH and normotopic regions. Those connected regions show higher epileptogenicity. SPES might be useful to assess NH epileptogenic network.