Cortical Network Activity Research Articles

Somatostatin-expressing interneurons modulate neocortical network through GABAb receptors in a synapse-specific manner

The firing activity of somatostatin-expressing inhibitory neurons (SST-INs) can suppress network activity via both GABAa and GABAb receptors (Rs). Although SST-INs do not receive GABAaR input from other SST-INs, it is possible that SST-IN-released GABA could suppress the activity of SST-INs themselves via GABAbRs, providing a negative feedback loop. Here we characterized the influence of GABAbR modulation on SST-IN activity in layer 2/3 of the somatosensory cortex in mice. We compared this to the effects of GABAbR activation on parvalbumin-expressing interneurons (PV-INs). Using in vitro whole-cell patch clamp recordings, pharmacological and optogenetic manipulations, we found that the firing activity of SST-INs suppresses excitatory drive to themselves via presynaptic GABAbRs. Postsynaptic GABAbRs did not influence SST-IN spontaneous activity or intrinsic excitability. Although GABAbRs at pre- and postsynaptic inputs to PV-INs are modestly activated during cortical network activity in vitro, the spontaneous firing of SST-INs was not the source of GABA driving this GABAbR activation. Thus, SST-IN firing regulates excitatory synaptic strength through presynaptic GABAbRs at connections between pyramidal neurons (Pyr-Pyr) and synapses between pyramidal neurons and SST-INs (Pyr-SST), but not Pyr-PV and PV-Pyr synapses. Our study indicates that two main types of neocortical inhibitory interneurons are differentially modulated by SST-IN-mediated GABA release.

Functional connectivity of cortical-cerebellar networks in relation to sensorimotor behavior and clinical features in autism spectrum disorder.

Sensorimotor issues are present in the majority of individuals with autism spectrum disorder (ASD) and are associated with core symptoms. The neural systems associated with these impairments remain unclear. Using a visually guided precision gripping task during functional magnetic resonance imaging, we characterized task-based connectivity and activation of cortical, subcortical, and cerebellar visuomotor networks. Participants with ASD (n = 19; ages 10-33) and age- and sex-matched neurotypical controls (n = 18) completed a visuomotor task at low and high force levels. Relative to controls, individuals with ASD showed reduced functional connectivity of right primary motor-anterior cingulate cortex and left anterior intraparietal lobule (aIPL)-right Crus I at high force only. At low force, increased caudate, and cerebellar activation each were associated with sensorimotor behavior in controls, but not in ASD. Reduced left aIPL-right Crus I connectivity was associated with more severe clinically rated ASD symptoms. These findings suggest that sensorimotor problems in ASD, particularly at high force levels, involve deficits in the integration of multimodal sensory feedback and reduced reliance on error-monitoring processes. Adding to literature positing that cerebellar dysfunction contributes to multiple developmental issues in ASD, our data implicate parietal-cerebellar connectivity as a key neural marker underlying both core and comorbid features of ASD.

A case study of left visual neglect after right pontine lesion: pathophysiological evidence for the infratentorial involvement in human visual attention.

Hemispatial neglect, the inability to attend to the contralesional side of space, is the most common disturbance of visuospatial attention. Both hemispatial neglect and visuospatial attention are typically associated with extended cortical networks. Nevertheless, recent accounts challenge this so-called corticocentric view and postulate the participation of structures well beyond the telencephalic cortex, in particular advocating the role of the brainstem. However, to the best of our knowledge, hemispatial neglect after a brainstem lesion has not yet been described. We describe, for the first time in a human, the occurrence and remission of contralesional visual hemispatial neglect after a focal lesion in the right pons. Hemispatial neglect was assessed by means of video-oculography during free visual exploration, a very sensitive and established method, and its remission was followed up until 3 wk after stroke. Moreover, by means of a lesion-deficit approach complemented by imaging, we identify a pathophysiological mechanism involving the disconnection of cortico-ponto-cerebellar and/or tecto-cerebellar-tectal pathways passing through the pons. Our findings offer, for the first time in a human, causal, lesion-based support for recent seminal accounts postulating the role of infratentorial structures participating in the activity of cerebral cortical attentional networks mediating attentional processes.NEW & NOTEWORTHY Visuospatial attention and its most common disturbance, hemispatial neglect, are typically associated with extended cortical networks. However, recent accounts challenge this corticocentric view and advocate the role of infratentorial structures. We describe, for the first time in a human, the occurrence of contralesional visual hemispatial neglect after a focal lesion in the right pons. We provide causal, lesion-based evidence for a pathophysiological mechanism involving the disconnection of cortico-ponto-cerebellar and/or tecto-cerebellar-tectal pathways passing through the pons.

The Functional Aspects of Resting EEG Microstates: A Systematic Review.

A growing body of clinical and cognitive neuroscience studies have adapted a broadband EEG microstate approach to evaluate the electrical activity of large-scale cortical networks. However, the functional aspects of these microstates have not yet been systematically reviewed. Here, we present an overview of the existing literature and systematize the results to provide hints on the functional role of electrical brain microstates. Studies that evaluated and manipulated the temporal properties of resting-state microstates and utilized questionnaires, task-initiated thoughts, specific tasks before or between EEG session(s), pharmacological interventions, neuromodulation approaches, or localized sources of the extracted microstates were selected. Fifty studies that met the inclusion criteria were included. A new microstate labeling system has been proposed for a comprehensible comparison between the studies, where four classical microstates are referred to as A-D, and the others are labeled by the frequency of their appearance. Microstate A was associated with both auditory and visual processing and links to subjects' arousal/arousability. Microstate B showed associations with visual processing related to self, self-visualization, and autobiographical memory. Microstate C was related to processing personally significant information, self-reflection, and self-referential internal mentation rather than autonomic information processing. In contrast, microstate E was related to processing interoceptive and emotional information and to the salience network. Microstate D was associated with executive functioning. Microstate F is suggested to be a part of the Default Mode Network and plays a role in personally significant information processing, mental simulations, and theory of mind. Microstate G is potentially linked to the somatosensory network.

Timing-specific patterns of cerebral activations during motor imagery: A case study of the expert brain signature

Brain activations elicited during motor imagery (MI) in experts are typically reduced compared to novices, which is interpreted as a neurophysiological correlate of increased neural efficiency. However, the modulatory effects of MI speed on expertise-related differences in brain activation remains largely unknown. In the present pilot study, we compared the magnetoencephalographic (MEG) correlates of MI in an Olympic medallist and an amateur athlete under conditions of slow, real-time and fast MI. Data revealed event-related changes in the time course of alpha (8–12 Hz) power of MEG oscillations, for all timing conditions. We found that slow MI was associated with a corollary increase in neural synchronization, in both participants. Sensor-level and source-level analyses however disclosed differences between the two expertise levels. The Olympic medallist achieved greater activation of cortical sensorimotor networks than the amateur athlete, particularly during fast MI. Fast MI elicited the strongest event-related desynchronization of alpha oscillations, which was generated from cortical sensorimotor sources in the Olympic medallist, but not in the amateur athlete. Taken together, data suggest that fast MI is a particularly demanding form of motor cognition, putting a specific emphasis on cortical sensorimotor networks to achieve the formation of accurate motor representations under demanding timing constraints.

Modeling the marmoset brain using embryonic stem cell-derived cerebral assembloids

Studying the non-human primate (NHP) brain is required for the translation of rodent research to humans, but remains a challenge for molecular, cellular, and circuit-level analyses in the NHP brain due to the lack of in vitro NHP brain system. Here, we report an in vitro NHP cerebral model using marmoset (Callithrix jacchus) embryonic stem cell-derived cerebral assembloids (CAs) that recapitulate inhibitory neuron migration and cortical network activity. Cortical organoids (COs) and ganglionic eminence organoids (GEOs) were induced from cjESCs and fused to generate CAs. GEO cells expressing the inhibitory neuron marker LHX6 migrated toward the cortical side of CAs. COs developed their spontaneous neural activity from a synchronized pattern to an unsynchronized pattern as COs matured. CAs containing excitatory and inhibitory neurons showed mature neural activity with an unsynchronized pattern. The CAs represent a powerful in vitro model for studying excitatory and inhibitory neuron interactions, cortical dynamics, and their dysfunction. The marmoset assembloid system will provide an in vitro platform for the NHP neurobiology and facilitate translation into humans in neuroscience research, regenerative medicine, and drug discovery.

The role of selective SATB1 deletion in somatostatin expressing interneurons on endogenous network activity and the transition to epilepsy.

Somatostatin (SST) expressing interneurons are the second most abundant group of inhibitory neurons in the neocortex. They mainly target the apical dendrites of excitatory pyramidal cells and are implicated in feedforward and feedback inhibition. In the present study, we employ a conditional knockout mouse, in which the transcription factor Satb1 is selectively deleted in SST-expressing interneurons resulting to the reduction of their number across the somatosensory barrel field. Our goal was to investigate the effect of the reduced number of Satb1 mutant SST-interneurons on (i) the endogenous cortical network activity (spontaneously recurring Up/Down states), and (ii) the transition to epileptiform activity. By conducting LFP recordings in acute brain slices from young male and female mice, we demonstrate that mutant animals exhibit significant changes in network excitability, reflected in increased Up state occurrence, decreased Up state duration and higher levels of extracellular spiking activity. Epileptiform activity was induced through two distinct and widely used in vitro protocols: the low magnesium and the 4-Aminopyridine (4-AP) model. In the former, slices from mutant animals manifested shorter latency for the expression of stable seizure-like events. In contrast, when epilepsy was induced by 4-AP, no significant differences were reported. We conclude that normal SST-interneuron function has a significant role both in the regulation of the endogenous network activity, and in the transition to seizure-like discharges in a context-dependent manner.

Biophysical Kv channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer’s

AbstractBackgroundIn Alzheimer’s disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability, as they display altered AP firing before neighboring excitatory neurons in prodromal AD.MethodWe used an interneuron‐enhancer AAV labeling technique to specifically target PV interneurons for whole‐cell and outside‐out patch clamp recordings in young 5xFAD mice. Our findings were complemented by PV dyanmic clamp recordings, PV‐specific qPCR, quantitative proteomics, and NEURON modeling.ResultWe report a novel mechanism responsible for cortical PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of K+ channels, but not changes in mRNA expression, are responsible for dampened excitability. These K+ conductances could efficiently regulate near‐threshold AP firing, resulting in gamma‐frequency specific network hyperexcitability.ConclusionOur findings suggest that posttranslational modulation of ion channels can reshape cortical network activity prior to changes in their gene expression in early AD.

Spatiotemporally heterogeneous coordination of cholinergic and neocortical activity.

Variation in an animal's behavioral state is linked to fluctuations in brain activity and cognitive ability. In the neocortex, state-dependent circuit dynamics may reflect neuromodulatory influences such as that of acetylcholine (ACh). Although early literature suggested that ACh exerts broad, homogeneous control over cortical function, recent evidence indicates potential anatomical and functional segregation of cholinergic signaling. In addition, it is unclear whether states as defined by different behavioral markers reflect heterogeneous cholinergic and cortical network activity. Here, we perform simultaneous, dual-color mesoscopic imaging of both ACh and calcium across the neocortex of awake mice to investigate their relationships with behavioral variables. We find that higher arousal, categorized by different motor behaviors, is associated with spatiotemporally dynamic patterns of cholinergic modulation and enhanced large-scale network correlations. Overall, our findings demonstrate that ACh provides a highly dynamic and spatially heterogeneous signal that links fluctuations in behavior to functional reorganization of cortical networks.

Cortical Network Activity Modulation by Breath in the Anesthetized Juvenile Rat

Cortical Network Activity Modulation by Breath in the Anesthetized Juvenile Rat

Clinical thresholds in pain-related facial activity linked to differences in cortical network activation in neonates.

In neonates, a noxious stimulus elicits pain-related facial expression changes and distinct brain activity as measured by electroencephalography, but past research has revealed an inconsistent relationship between these responses. Facial activity is the most commonly used index of neonatal pain in clinical settings, with clinical thresholds determining if analgesia should be provided; however, we do not know if these thresholds are associated with differences in how the neonatal brain processes a noxious stimulus. The objective of this study was to examine whether subclinical vs clinically significant levels of pain-related facial activity are related to differences in the pattern of nociceptive brain activity in preterm and term neonates. We recorded whole-head electroencephalography and video in 78 neonates (0-14 days postnatal age) after a clinically required heel lance. Using an optimal constellation of Neonatal Facial Coding System actions (brow bulge, eye squeeze, and nasolabial furrow), we compared the serial network engagement (microstates) between neonates with and without clinically significant pain behaviour. Results revealed a sequence of nociceptive cortical network activation that was independent of pain-related behavior; however, a separate but interleaved sequence of early activity was related to the magnitude of the immediate behavioural response. Importantly, the degree of pain-related behavior is related to how the brain processes a stimulus and not simply the degree of cortical activation. This suggests that neonates who exhibit clinically significant pain behaviours process the stimulus differently and that neonatal pain-related behaviours reflect just a portion of the overall cortical pain response.

Phase matters when there is power: Phasic modulation of corticospinal excitability occurs at high amplitude sensorimotor mu-oscillations

Prior studies have suggested that oscillatory activity in cortical networks can modulate stimulus-evoked responses through time-varying fluctuations in neural excitation-inhibition dynamics. Studies combining transcranial magnetic stimulation (TMS) with electromyography (EMG) and electroencephalography (EEG) can provide direct measurements to examine how instantaneous fluctuations in cortical oscillations contribute to variability in TMS-induced corticospinal responses. However, the results of these studies have been conflicting, as some reports showed consistent phase effects of sensorimotor mu-rhythms with increased excitability at the negative mu peaks, while others failed to replicate these findings or reported unspecific mu-phase effects across subjects. Given the lack of consistent results, we systematically examined the modulatory effects of instantaneous and pre-stimulus sensorimotor mu-rhythms on corticospinal responses with offline EEG-based motor evoked potential (MEP) classification analyses across five identical visits. Instantaneous sensorimotor mu-phase or pre-stimulus mu-power alone did not significantly modulate MEP responses. Instantaneous mu-power analyses showed weak effects with larger MEPs during high-power trials at the overall group level analyses, but this trend was not reproducible across visits. However, TMS delivered at the negative peak of high magnitude mu-oscillations generated the largest MEPs across all visits, with significant differences compared to other peak-phase combinations. High power effects on MEPs were only observed at the trough phase of ongoing mu oscillations originating from the stimulated region, indicating site and phase specificity, respectively. More importantly, such phase-dependent power effects on corticospinal excitability were reproducible across multiple visits. We provide further evidence that fluctuations in corticospinal excitability indexed by MEP amplitudes are partially driven by dynamic interactions between the magnitude and the phase of ongoing sensorimotor mu oscillations at the time of TMS, and suggest promising insights for (re)designing neuromodulatory TMS protocols targeted to specific cortical oscillatory states.

Modelling of magnetoelectric nanoparticles for non-invasive brain stimulation: a computational study

Objective. Recently developed magnetoelectric nanoparticles (MENPs) provide a potential tool to enable different biomedical applications. They could be used to overcome the intrinsic constraints posed by traditional neurostimulation techniques, namely the invasiveness of electrodes-based techniques, the limited spatial resolution, and the scarce efficiency of magnetic stimulation. Approach. By using computational electromagnetic techniques, we modelled the behaviour of recently designed biocompatible MENPs injected, in the shape of clusters, in specific cortical targets of a highly detailed anatomical head model. The distributions and the tissue penetration of the electric fields induced by MENPs clusters in each tissue will be compared to the distributions induced by traditional transcranial magnetic stimulation (TMS) coils for non-invasive brain stimulation positioned on the left prefrontal cortex (PFC) of a highly detailed anatomical head model. Main results. MENPs clusters can induce highly focused electric fields with amplitude close to the neural activation threshold in all the brain tissues of interest for the treatment of most neuropsychiatric disorders. Conversely, TMS coils can induce electric fields of several tens of V m−1 over a broad volume of the PFC, but they are unlikely able to efficiently stimulate even small volumes of subcortical and deep tissues. Significance. Our numerical results suggest that the use of MENPs for brain stimulation may potentially led to a future pinpoint treatment of neuropshychiatric disorders, in which an impairment of electric activity of specific cortical and subcortical tissues and networks has been assumed to play a crucial role.

Cerebral cortex Functional Networks of Transdermal Electrical Stimulation at Daling (PC7) Acupoint.

The cerebral cortex functional network of Electroencephalogram (EEG) signals during transcutaneous electrical acupoint stimulation (TEAS) on 21 healthy subjects was constructed by using three modules: standard low-resolution brain electromagnetic tomography (sLORETA), phase-locking value (PLV), and complex network. We investigated the brain functional network triggered by PC7 stimulation by comparing with resting state and non-acupoint stimulation. The results showed that the PC7 stimulation mainly activated frontal lobe and temporal lobe including prefrontal cortex (BA10), insular lobe (BA13), temporal gyrus (BA22), anterior cingulate cortex (BA32), temporal pole (BA38), dorsolateral prefrontal cortex (BA46), and inferior frontal cortex (BA47), which are all closely linked to cognition, spirit, and emotion in brain. Furthermore, the degrees of node in frontal, temporal, and whole brain are increased significantly or extreme significantly with p < 0.05, p < 0.05, and p < 0.01, respectively; clustering coefficient in frontal, temporal, and whole brain are all statistically significant (p < 0.05). The information transmission efficiency of cerebral cortex has been greatly improved. During PC7 stimulation, the topological changes in the activation of cerebral regions and cortical functional networks are consistent with the therapeutic effect, which may provide theoretical support for acupoint stimulation to regulate nerve function.

Dose-dependent consequences of sub-chronic fentanyl exposure on neuron and glial co-cultures.

Fentanyl is one of the most common opioid analgesics administered to patients undergoing surgery or for chronic pain management. While the side effects of chronic fentanyl abuse are recognized (e.g., addiction, tolerance, impairment of cognitive functions, and inhibit nociception, arousal, and respiration), it remains poorly understood what and how changes in brain activity from chronic fentanyl use influences the respective behavioral outcome. Here, we examined the functional and molecular changes to cortical neural network activity following sub-chronic exposure to two fentanyl concentrations, a low (0.01 μM) and high (10 μM) dose. Primary rat co-cultures, containing cortical neurons, astrocytes, and oligodendrocyte precursor cells, were seeded in wells on either a 6-well multi-electrode array (MEA, for electrophysiology) or a 96-well tissue culture plate (for serial endpoint bulk RNA sequencing analysis). Once networks matured (at 28 days in vitro), co-cultures were treated with 0.01 or 10 μM of fentanyl for 4 days and monitored daily. Only high dose exposure to fentanyl resulted in a decline in features of spiking and bursting activity as early as 30 min post-exposure and sustained for 4 days in cultures. Transcriptomic analysis of the complex cultures after 4 days of fentanyl exposure revealed that both the low and high dose induced gene expression changes involved in synaptic transmission, inflammation, and organization of the extracellular matrix. Collectively, the findings of this in vitro study suggest that while neuroadaptive changes to neural network activity at a systems level was detected only at the high dose of fentanyl, transcriptomic changes were also detected at the low dose conditions, suggesting that fentanyl rapidly elicits changes in plasticity.

Visual-area-specific tonic modulation of GABA release by endocannabinoids sets the activity and coordination of neocortical principal neurons.

SummaryPerisomatic inhibition of pyramidal neurons (PNs) coordinates cortical network activity during sensory processing, and this role is mainly attributed to parvalbumin-expressing basket cells (BCs). However, cannabinoid receptor type 1 (CB1)-expressing interneurons are also BCs, but the connectivity and function of these elusive but prominent neocortical inhibitory neurons are unclear. We find that their connectivity pattern is visual area specific. Persistently active CB1 signaling suppresses GABA release from CB1 BCs in the medial secondary visual cortex (V2M), but not in the primary visual cortex (V1). Accordingly, in vivo, tonic CB1 signaling is responsible for higher but less coordinated PN activity in the V2M than in the V1. These differential firing dynamics in the V1 and V2M can be captured by a computational network model that incorporates visual-area-specific properties. Our results indicate a differential CB1-mediated mechanism controlling PN activity, suggesting an alternative connectivity scheme of a specific GABAergic circuit in different cortical areas.

Increasing the Excitatory Drive Rescues Excitatory/Inhibitory Imbalance and Mismatch Negativity Deficit Caused by Parvalbumin Specific GluA1 Deletion

Disturbance in synaptic excitatory and inhibitory (E/I) transmission in the prefrontal cortex is considered a critical factor for cognitive dysfunction, a core symptom in schizophrenia. However, the cortical network pathophysiology induced by E/I imbalance is not well characterized, and an effective therapeutic strategy is lacking. In this study, we simulated imbalanced cortical network by using mice with parvalbumin neuron (PV) specific knockout of GluA1 (AMPA receptor subunit 1) (Gria1-PV KO) as an experimental model. Applying high-content confocal imaging and electrophysiological recordings in the medial prefrontal cortex (mPFC), we found structural and functional alterations in the local network of Gria1-PV KO mice. Additionally, we applied electroencephalography (EEG) to assess potential deficits in mismatch negativity (MMN), the standard readout in the clinic for measuring deviance detection and sensory information processing. Gria1-PV KO animals exhibited abnormal theta oscillation and MMN, which is consistent with clinical findings in cognitively impaired patients. Remarkably, we demonstrated that the glycine transporter 1 (GlyT1) inhibitor, Bitopertin, ameliorates E/I imbalance, hyperexcitability, and sensory processing malfunction in Gria1-PV KO mice. Our results suggest that PV-specific deletion of GluA1 might be an experimental approach for back translating the E/I imbalance observed in schizophrenic patients. Our work offers a systematic workflow to understand the effect of GlyT1 inhibition in restoring cortical network activity from single cells to local brain circuitry. This study highlights that selectively boosting NMDA receptor-mediated excitatory drive to enhance the network inhibitory transmission from interneurons to pyramidal neurons (PYs) is a potential therapeutic strategy for restoring E/I imbalance-associated cognitive-related abnormality.

Biophysical Kv3 channel alterations dampen excitability of cortical PV interneurons and contribute to network hyperexcitability in early Alzheimer's.

In Alzheimer's disease (AD), a multitude of genetic risk factors and early biomarkers are known. Nevertheless, the causal factors responsible for initiating cognitive decline in AD remain controversial. Toxic plaques and tangles correlate with progressive neuropathology, yet disruptions in circuit activity emerge before their deposition in AD models and patients. Parvalbumin (PV) interneurons are potential candidates for dysregulating cortical excitability as they display altered action potential (AP) firing before neighboring excitatory neurons in prodromal AD. Here, we report a novel mechanism responsible for PV hypoexcitability in young adult familial AD mice. We found that biophysical modulation of Kv3 channels, but not changes in their mRNA or protein expression, were responsible for dampened excitability in young 5xFAD mice. These K+ conductances could efficiently regulate near-threshold AP firing, resulting in gamma-frequency-specific network hyperexcitability. Thus, biophysical ion channel alterations alone may reshape cortical network activity prior to changes in their expression levels. Our findings demonstrate an opportunity to design a novel class of targeted therapies to ameliorate cortical circuit hyperexcitability in early AD.

Internally generated population activity in cortical networks hinders information transmission.

How neuronal variability affects sensory coding is a central question in systems neuroscience, often with complex and model-dependent answers. Many studies explore population models with a parametric structure for response tuning and variability, preventing an analysis of how synaptic circuitry establishes neural codes. We study stimulus coding in networks of spiking neuron models with spatially ordered excitatory and inhibitory connectivity. The wiring structure is capable of producing rich population-wide shared neuronal variability that agrees with many features of recorded cortical activity. While both the spatial scales of feedforward and recurrent projections strongly affect noise correlations, only recurrent projections, and in particular inhibitory projections, can introduce correlations that limit the stimulus information available to a decoder. Using a spatial neural field model, we relate the recurrent circuit conditions for information limiting noise correlations to how recurrent excitation and inhibition can form spatiotemporal patterns of population-wide activity.

Brain–computer interface-based action observation combined with peripheral electrical stimulation enhances corticospinal excitability in healthy subjects and stroke patients

Objective. Action observation (AO) combined with brain–computer interface (BCI) technology enhances cortical activation. Peripheral electrical stimulation (PES) increases corticospinal excitability, thereby activating brain plasticity. To maximize motor recovery, we assessed the effects of BCI-AO combined with PES on corticospinal plasticity. Approach. Seventeen patients with chronic hemiplegic stroke and 17 healthy subjects were recruited. The participants watched a video of repetitive grasping actions with four different tasks for 15 min: (A) AO alone; (B) AO + PES; (C) BCI-AO + continuous PES; and (D) BCI-AO + triggered PES. PES was applied at the ulnar nerve of the wrist. The tasks were performed in a random order at least three days apart. We assessed the latency and amplitude of motor evoked potentials (MEPs). We examined changes in MEP parameters pre-and post-exercise across the four tasks in the first dorsal interosseous muscle of the dominant hand (healthy subjects) and affected hand (stroke patients). Main results. The decrease in MEP latency and increase in MEP amplitude after the four tasks were significant in both groups. The increase in MEP amplitude was sustained for 20 min after tasks B, C, and D in both groups. The increase in MEP amplitude was significant between tasks A vs. B, B vs. C, and C vs. D. The estimated mean difference in MEP amplitude post-exercise was the highest for A and D in both groups. Significance. The results indicate that BCI-AO combined with PES is superior to AO alone or AO + PES for facilitating corticospinal plasticity in both healthy subjects and patients with stroke. Furthermore, this study supports the idea that synchronized activation of cortical and peripheral networks can enhance neuroplasticity after stroke. We suggest that the BCI-AO paradigm and PES could provide a novel neurorehabilitation strategy for patients with stroke.