Paired Associative Stimulation Research Articles

Applications of cortico-cortical paired associative stimulation for age-related declines of hand function.

Applications of cortico-cortical paired associative stimulation for age-related declines of hand function.

A Novel Paired Somatosensory-Cerebellar Stimulation Induces Plasticity on Cerebellar-Brain Connectivity

The cerebellum receives and integrates a large amount of sensory information that is important for motor coordination and learning. The aim of the present work was to investigate whether peripheral nerve and cerebellum paired associative stimulation (cPAS) could induce plasticity in both the cerebellum and the cortex. In a cross-over design, we delivered right median nerve electrical stimulation 25 or 10 ms before applying transcranial magnetic stimulation over the cerebellum. We assessed changes in motor evoked potentials (MEP), somatosensory evoked potentials (SEP), short-afferent inhibition (SAI), and cerebellum-brain inhibition (CBI) immediately, and 30 min after cPAS. Our results showed a significant reduction in CBI 30 minutes after cPAS, with no discernible changes in MEP, SEP, and SAI. Notably, cPAS10 did not produce any modulatory effects on these parameters. In summary, cPAS25 demonstrated the capacity to induce plasticity effects in the cerebellar cortex, leading to a reduction in CBI. This novel intervention may be used to modulate plasticity mechanisms and motor learning in healthy individuals and patients with neurological conditions.

Disrupted synaptic homeostasis and partial occlusion of associative long-term potentiation in the human cortex during social isolation

Social isolation often occurs in the military mission of soldiers but has increased in the general population since the COVID-19 epidemic. Overall synaptic homeostasis along with associative plasticity for the activity-dependent refinement of transmission across single synapses represent basic neural network function and adaptive behavior mechanisms. Here, we use electrophysiological and behavioral indices to non-invasively study the net synaptic strength and long-term potentiation (LTP)-like plasticity of humans in social isolation environments. The theta activity of electroencephalography (EEG) signals and transcranial magnetic stimulation (TMS) intensity to elicit a predefined amplitude of motor-evoked potential (MEP) demonstrate the disrupted synaptic homeostasis in the human cortex during social isolation. Furthermore, the induced MEP change by paired associative stimulation (PAS) demonstrates the partial occlusion of LTP-like plasticity, further behavior performances in a word-pair task are also identified as a potential index. Our study indicates that social isolation disrupts synaptic homeostasis and occludes associative LTP-like plasticity in the human cortex, decreasing behavior performance related to declarative memory.

Influence of frontal-to-parietal connectivity in pseudoneglect: A cortico-cortical paired associative stimulation study

Pseudoneglect is a set of visuospatial biases that entails a behavioral advantage for stimuli appearing in the left hemifield compared to the right one. Although right hemisphere dominance for visuospatial processing has been invoked to explain this phenomenon, its neurophysiological mechanisms are still debated, and the role of intra- and inter-hemispheric connectivity is yet to be defined. The present study explored the possibility of modulating pseudoneglect in healthy participants through a cortico-cortical paired associative stimulation protocol (ccPAS): a non-invasive brain stimulation protocol that manipulates the interplay between brain regions through the repeated, time-locked coupling of two transcranial magnetic stimulation (TMS) pulses. In the first experiment, healthy participants underwent a frontal-to-parietal (FP) and a parietal-to-frontal (PF) ccPAS. In the FP protocol, the first TMS pulse targeted the right frontal eye field (FEF), and the second pulse the right inferior parietal lobule (IPL), two critical areas for visuospatial and attentional processing. In the PF condition, the order of the pulses was reversed. In both protocols, the inter-stimulus interval (ISI) was 10 ms. Before and after stimulation, pseudoneglect was assessed with a landmark task and a manual line bisection task. A second experiment controlled for ccPAS timing dependency by testing FP-ccPAS with a longer ISI of 100 ms. Results showed that after administering the FP-ccPAS with the ISI of 10 ms, participants’ leftward bias in the landmark task increased significantly, with no effects in the manual line bisection task. The other two protocols tested were ineffective. Our findings showed that ccPAS could be used to modulate pseudoneglect by exploiting frontal-to-parietal connectivity, possibly through increased top-down attentional control. FP-ccPAS could represent a promising tool to investigate connectivity properties within visuospatial and attentional networks in the healthy and as a potential rehabilitation protocol in patients suffering from severe visuospatial pathologies.

Preventive exercise and physical rehabilitation promote long-term potentiation-like plasticity expression in patients with multiple sclerosis.

Loss of long-term potentiation (LTP) expression has been associated with a worse disease course in relapsing-remitting multiple sclerosis (RR-MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP-like plasticity in patients with multiple sclerosis (MS). In 46 newly diagnosed RR-MS patients, we explored the impact of preventive exercise on LTP-like plasticity as assessed by intermittent theta-burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8-week inpatient neurorehabilitation program on clinical scores and LTP-like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects. Reduced LTP expression was found in RR-MS patients compared with controls. Exercising RR-MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity. Both preventive exercise and physical rehabilitation may enhance the expression of LTP-like synaptic plasticity in MS, with potential beneficial effects on disability accumulation.

Cortical paired associative stimulation shows impaired plasticity of inhibition networks as a function of chronic alcohol use.

Response inhibition - or the ability to withhold a suboptimal response - relies on the efficacy of fronto-striatal networks, and is impaired in neuropsychiatric disorders including addiction. Cortical paired associative stimulation (cPAS) is a form of transcranial magnetic stimulation (TMS) which can strengthen neuronal connections via spike-timing-dependent plasticity mechanisms. Here, we used cPAS targeting the fronto-striatal inhibitory network to modulate performance on a response inhibition measure in chronic alcohol use. Fifty-five participants (20 patients with a formal alcohol use disorder (AUD) diagnosis (26-74 years, 6[30%] females) and 20 matched healthy controls (HCs) (27-73 years, 6[30%] females) within a larger sample of 35 HCs (23-84 years, 11[31.4%] females) underwent two randomized sessions of cPAS 1-week apart: right inferior frontal cortex stimulation preceding right presupplementary motor area stimulation by either 4 ms (excitation condition) or 100 ms (control condition), and were subsequently administered the Stop Signal Task (SST) in both sessions. HCs showed decreased stop signal reaction time in the excitation condition (t(19) = -3.01, p = 0.007, [CIs]:-35.6 to -6.42); this facilitatory effect was not observed for AUD (F(1,31) = 9.57, p = 0.004, CIs: -68.64 to -14.11). Individually, rates of SST improvement were substantially higher for healthy (72%) relative to AUD (13.6%) groups (OR: 2.33, p = 0.006, CIs:-3.34 to -0.55). In line with previous findings, cPAS improved response inhibition in healthy adults by strengthening the fronto-striatal network through putative long-term potentiation-like plasticity mechanisms. Furthermore, we identified a possible marker of impaired cortical excitability, and, thus, diminished capacity for cPAS-induced neuroplasticity in AUD with direct implications to a disorder-relevant cognitive process.

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-M1subpopulation might have important translational value for the rehabilitation of hand function.

The effect of paired associative stimulation with a high-intensity cortical component and a high-frequency peripheral component on heart rate and heart rate variability in healthy subjects.

A novel protocol for paired associative stimulation (PAS), called high PAS, consists of high-intensity transcranial magnetic stimulation (TMS) and high-frequency peripheral nerve stimulation (PNS). High PAS was developed for spinal cord injury rehabilitation and targets plastic changes in stimulated pathways in the corticospinal tract, which improves motor function. As therapy interventions can last many weeks, it is important to fully understand the effects of high PAS, including its effect on the cardiovascular system. Heart rate variability (HRV) has been used to measure changes in both sympathetic and parasympathetic systems. We used short-term HRV measurements to evaluate the effects of one 20-min session of high PAS on 17 healthy individuals. HRV was recorded for 5 min before (PRE), during (STIM), immediately after (POST), 30 min after (POST30), and 60 min after (POST60) the stimulation. Five participants repeated the HRV setup with sham stimulation. A significant decrease in low-frequency (LF) power (n.u.) (p = 0.002), low-frequency to high-frequency (HF) ratio (p = 0.017), in Poincaré plot [the standard deviation of RR intervals perpendicular to (SD1) and along (SD2) the line of identity SD2/SD1 ratio p < 0.001], and an increase in HF power (n.u.) (p = 0.002) were observed between PRE and STIM conditions; these changes were fully reversible immediately after stimulation. PRE to POST by 3% (p = 0.015) and continued to decline until POST60 by 5% (p = 0.011). LF power (ms2) (p = 0.017) and SD2 (p = 0.015) decreased from PRE to STIM and increased from PRE to POST (p = 0.025 and p = 0.017, respectively). The results from sham PAS exhibited a trend similar to active high-PAS stimulation. High PAS does not have sustained effects during 60-min follow-up on cardiovascular functions, as measured by HRV. None of the short-term results indicates activation of the sympathetic nervous system in healthy individuals. Observed changes in HRV indicate higher parasympathetic activity during stimulation, which is reversible, and is plausibly explained by the fact that the participants spend 20 min without moving, talking, or using phones while being stimulated.

Can we manipulate brain connectivity? A systematic review of cortico-cortical paired associative stimulation effects

ObjectiveCortico-cortical paired associative stimulation (ccPAS) is a form of dual-site transcranial magnetic stimulation (TMS) entailing a series of single-TMS pulses paired at specific interstimulus intervals (ISI) delivered to distant cortical areas. The goal of this article is to systematically review its efficacy in inducing plasticity in humans focusing on stimulation parameters and hypotheses of underlying neurophysiology. MethodsA systematic review of the literature from 2009–2023 was undertaken to identify all articles utilizing ccPAS to study brain plasticity and connectivity. Six electronic databases were searched and included. Results32 studies were identified. The studies targeted connections within the same hemisphere or between hemispheres. 28 ccPAS studies were in healthy participants, 1 study in schizophrenia, and 1 in Alzheimer’s disease (AD) patients. 2 additional studies used cortico-cortical repetitive paired associative stimulation (cc-rPAS) in generalized anxiety disorder (GAD) patients. Outcome measures include electromyography (EMG), behavioral measures, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). ccPAS seems to be able to modulate brain connectivity depending on the ISI. ConclusionsccPAS can be used to modulate corticospinal excitability, brain activity, and behavior. Although the stimulation parameters used across studies reviewed in this paper are varied, ccPAS is a promising approach for basic research and potential clinical applications. SignificanceRecent advances in neuroscience have caused a shift of interest from the study of single areas to a more complex approach focusing on networks of areas that orchestrate brain activity. Consequently, the TMS community is also witnessing a change, with a growing interest in targeting multiple brain areas rather than a single locus, as evidenced by an increasing number of papers using ccPAS. In light of this new enthusiasm for brain connectivity, this review summarizes existing literature and stimulation parameters that have proven effective in changing electrophysiological, behavioral, or neuroimaging-derived measures.

Exploratory genome-wide analyses of cortical inhibition, facilitation, and plasticity in late-life depression

Late-life depression (LLD) is a heterogenous mood disorder influenced by genetic factors. Cortical physiological processes such as cortical inhibition, facilitation, and plasticity may be markers of illness that are more strongly associated with genetic factors than the clinical phenotype. Thus, exploring the relationship between genetic factors and these physiological processes may help to characterize the biological mechanisms underlying LLD and improve diagnosis and treatment selection. Transcranial magnetic stimulation (TMS) combined with electromyography was used to measure short interval intracortical inhibition (SICI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS) in 79 participants with LLD. We used exploratory genome-wide association and gene-based analyses to assess for genetic correlations of these TMS measures. MARK4 (which encodes microtubule affinity-regulating kinase 4) and PPP1R37 (which encodes protein phosphatase 1 regulatory subunit 37) showed genome-wide significant association with SICI. EGFLAM (which encodes EGF-like fibronectin type III and laminin G domain) showed genome-wide significant association with CSP. No genes met genome-wide significant association with ICF or PAS. We observed genetic influences on cortical inhibition in older adults with LLD. Replication with larger sample sizes, exploration of clinical phenotype subgroups, and functional analysis of relevant genotypes is warranted to better characterize genetic influences on cortical physiology in LLD. This work is needed to determine whether cortical inhibition may serve as a biomarker to improve diagnostic precision and guide treatment selection in LLD.

Motor Cortical Correlates of Paired Associative Stimulation Induced Plasticity: A TMS-EEG Study.

Paired associative stimulation (PAS) is a non-invasive brain stimulation technique that modulates synaptic plasticity in the human motor cortex (M1). Since previous studies have primarily used motor-evoked potentials (MEPs) as outcome measure, cortical correlates of PAS-induced plasticity remain unknown. Therefore, the aim of this observational study was to investigate cortical correlates of a standard PAS induced plasticity in the primary motor cortex by using a combined TMS-EEG approach in a cohort of eighteen healthy subjects. In addition to the expected long-lasting facilitatory modulation of MEPs amplitude, PAS intervention also induced a significant increase in transcranial magnetic stimulation-evoked potentials (TEPs) P30 and P60 amplitude. No significant correlation between the magnitude of PAS-induced changes in TEP components and MEP amplitude were observed. However, the linear regression analysis revealed that the combined changes in P30 and P60 component amplitudes significantly predicted the MEP facilitation after PAS. The findings of our study offer novel insight into the neurophysiological changes associated with PAS-induced plasticity at M1 cortical level and suggest a complex relationship between TEPs and MEPs changes following PAS.

Pathway and directional specificity of Hebbian plasticity in the cortical visual motion processing network

Cortico-cortical paired associative stimulation (ccPAS), which repeatedly pairs single-pulse transcranial magnetic stimulation (TMS) over two distant brain regions, is thought to modulate synaptic plasticity. We explored its spatial selectivity (pathway and direction specificity) and its nature (oscillatory signature and perceptual consequences) when applied along the ascending (Forward) and descending (Backward) motion discrimination pathway. We found unspecific connectivity increases in bottom-up inputs in the low gamma band, probably reflecting visual task exposure. A clear distinction in information transfer occurred in the re-entrant alpha signals, which were only modulated by Backward-ccPAS, and predictive of visual improvements in healthy participants. These results suggest a causal involvement of the re-entrant MT-to-V1 low-frequency inputs in motion discrimination and integration in healthy participants. Modulating re-entrant input activity could provide single-subject prediction scenarios for visual recovery. Visual recovery might indeed partly rely on these residual inputs projecting to spared V1 neurons.

PAS‐MCI: Design and rationale for a randomized controlled trial to enhance prefrontal cortical plasticity and working memory in individuals with amnestic mild cognitive impairment

AbstractAmnestic Mild Cognitive Impairment (aMCI) is a prodromal stage to Alzheimer’s disease dementia (AD). Improving prefrontal cortical function in individuals with MCI could prevent progression from aMCI to AD. A key mechanism that has been linked to memory formation is cortical plasticity. Paired Associative Stimulation (PAS) is an intervention that uses transcranial magnetic stimulation (TMS) to enhance cortical plasticity. When delivered to the prefrontal cortex in individuals with AD, it has shown promise to improve prefrontal cortical plasticity and working memory.PAS‐MCI is a randomized controlled trial (RCT) that aims to assess: (1) dorsolateral prefrontal cortex (DLPFC) plasticity in individuals with aMCI compared to cognitively unimpaired control (CU) participants, (2) the efficacy of PAS delivered for 10 days bilaterally to the DLPFC of individuals with aMCI in enhancing their DLPFC plasticity, working memory, and executive function, and (3) whether changes in DLPFC plasticity mediate changes in working memory and executive function.100 aMCI and 50 CU control participants will be assessed clinically and cognitively, and undergo PAS combined with electroencephalography (PAS‐EEG) to characterize left DLPFC plasticity. The aMCI participants are randomized (1:1) to receive 10 daily sessions of either active or sham PAS delivered to the bilateral DLPFC. On Day 0, 7, and 28 following the PAS course, participants undergo repeat cognitive testing and PAS‐EEG to assess changes in working memory, executive function, and left DLPFC plasticity.As of February 1st, 2022, 14 aMCI and 9 CU participants consented, of which 5 aMCI and 4 CU participants completed the study. 7 aMCI participants were excluded because of: a contraindication for TMS (n = 1), having dementia (n = 1), and having non‐amnestic MCI (n = 5); 1 withdrew due to fatigue; and 1 is pending enrollment. 3 CU participants were excluded because of low cognitive scores; 1 withdrew due to not tolerating TMS; and 1 is pending enrollment.If successful, this RCT will establish the short‐term efficacy of PAS, a new TMS approach to enhance prefrontal cortical function in individuals with aMCI. A follow‐up longer‐term trial will be then needed to assess whether PAS could prevent cognitive decline and progression to AD.

Neurophysiological Markers of Premotor-Motor Network Plasticity Predict Motor Performance in Young and Older Adults.

Aging is commonly associated with a decline in motor control and neural plasticity. Tuning cortico-cortical interactions between premotor and motor areas is essential for controlling fine manual movements. However, whether plasticity in premotor-motor circuits predicts hand motor abilities in young and elderly humans remains unclear. Here, we administered transcranial magnetic stimulation (TMS) over the ventral premotor cortex (PMv) and primary motor cortex (M1) using the cortico-cortical paired-associative stimulation (ccPAS) protocol to manipulate the strength of PMv-to-M1 connectivity in 14 young and 14 elderly healthy adults. We assessed changes in motor-evoked potentials (MEPs) during ccPAS as an index of PMv-M1 network plasticity. We tested whether the magnitude of MEP changes might predict interindividual differences in performance in two motor tasks that rely on premotor-motor circuits, i.e., the nine-hole pegboard test and a choice reaction task. Results show lower motor performance and decreased PMv-M1 network plasticity in elderly adults. Critically, the slope of MEP changes during ccPAS accurately predicted performance at the two tasks across age groups, with larger slopes (i.e., MEP increase) predicting better motor performance at baseline in both young and elderly participants. These findings suggest that physiological indices of PMv-M1 plasticity could provide a neurophysiological marker of fine motor control across age-groups.

Motor Imagery and Paired Associative Stimulation in Poststroke Rehabilitation: Dissociating Motor and Electrophysiological Effects

Paired associative stimulation (PAS) is an intervention that modulates cortical plasticity. Motor imagery (MI) is used in the rehabilitation of stroke patients. We aimed to evaluate the possible synergistic effect of associating both interventions for potentiating motor recovery poststroke. MIPAS is a single-center, randomized controlled trial that enrolled 24 hemiparetic poststroke participants. Three single-session interventions were tested in a crossover design: PAS/MI, PAS, and ShamPAS/MI during which the affected Extensor Carpi Radialis (ECR) muscle was targeted. During MI, the participants were instructed to imagine extending their paretic wrist. We used Sham, subthreshold stimulation during ShamPAS. Changes in ECR Motor-Evoked Potential (MEP) areas and paretic wrist Range of Motion (aROM) during active extension were compared between the interventions. We observed no significant superior effect of any intervention, neither on MEP nor on wrist aROM. A time of assessment effect was highlighted for both outcome measures, with MEP- and aROM-measured post-interventions significantly higher than those measured pre-intervention. Despite the beneficial effect of each intervention on participant paretic wrist motor function, not always associated with MEP change, our results do not highlight a specific advantage in combining PAS and MI interventions in post-stroke motor rehabilitation.

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.MethodThis 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.DiscussionCurrently, 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 registrationThis trial was registered in the Chinese Clinical Trial Registry with code ChiCTR2300067422 and was approved on January 16, 2023.

Modulating motor resonance with paired associativestimulation: Neurophysiological and behavioral outcomes

In the human brain, paired associative stimulation (PAS), a non-invasive brain stimulation technique based on Hebbian learning principles, can be used to model motor resonance, the inner activation of an observer's motor system by action observation. Indeed, the newly developed mirror PAS (m-PAS) protocol, through the repeatedly pairing of transcranial magnetic stimulation (TMS) pulses over the primary motor cortex (M1) and visual stimuli depicting index–finger movements, allows the emergence of a new, atypical pattern of cortico-spinal excitability. In the present study, we performed two experiments to explore (a) the debated hemispheric lateralization of the action-observation network and (b) the behavioral after-effects of m-PAS, particularly concerning a core function of the MNS: automatic imitation.In Experiment 1, healthy participants underwent two sessions of m-PAS, delivered over the right and left M1. Before and after each m-PAS session, motor resonance was assessed by recording motor-evoked potentials induced by single-pulse TMS applied to the right M1 while observing contralateral (left) and ipsilateral (right) index–finger movements or static hands. In Experiment 2, participants performed an imitative compatibility task before and after the m-PAS targeting the right M1. Results showed that only m-PAS targeting the right hemisphere, non-dominant in right-handed people, induced the emergence of motor resonance for the conditioned movement, absent before the stimulation. This effect is not present when m-PAS target the M1 of the left hemisphere. Importantly, the protocol also affects behavior, modulating automatic imitation in a strictly somatotopic fashion (i.e., influencing the imitation of the conditioned finger movement).Overall, this evidence shows that the m-PAS can be used to drive new associations between the perception of actions and their corresponding motor programs, measurable both at a neurophysiological and behavioral level. At least for simple, not goal-directed, movements, the induction of motor resonance and automatic imitation effects are governed by mototopic and somatotopic rules.

321 Paired associative stimulation: a tool for assessing sensorimotor neural signaling and lower limb function post-stroke

OBJECTIVES/GOALS: A stroke can impair neural communication between sensory and motor pathways thus compromising walking function. Paired associative stimulation (PAS) is a useful assay of sensorimotor integration (SMI) with limited use post-stroke. The objective of this study will be to determine lower extremity PAS effectiveness and reliability post-stroke. METHODS/STUDY POPULATION: This study will use a pre-post, cross-sectional design. Ten healthy controls and 10 individuals with chronic stroke (&gt;6 months) will be recruited. PAS protocols will be individualized to account for between-subject variability in sensorimotor signaling by first measuring cortical sensory signaling using electroencephalography. Post-stroke participants will then receive PAS targeting the paretic tibialis anterior muscle; healthy controls will receive PAS targeting the non-dominant TA. Changes in cortically derived muscle responses will be characterized by absolute motor-evoked potential amplitude (MEPAmp) change, elicited by transcranial magnetic stimulation, over two sessions separated by &gt;24 hours. Clinical measures of sensorimotor function and walking ability will also be performed. RESULTS/ANTICIPATED RESULTS: By individualizing PAS protocols, we expect to see significant increases in MEPAmp pre to post PAS, determined using paired t-tests. We also anticipate reliable PAS-induced increases in MEPAmp, which will be assessed using two reliability statistics: intraclass correlation coefficient and coefficients of variation of method error. Lastly, the increases in MEPAmp will be correlated with measures of sensorimotor function and walking ability, anticipating that greater increases in MEPAmp will be related to better walking ability and sensorimotor functioning. Correlations will be assessed via a Pearson’s correlation. A preset alpha = 0.05 will be used to determine significant findings. DISCUSSION/SIGNIFICANCE: The importance of this study is that establishing individualized PAS protocols could potentially provide a reliable and clinically relevant measure of SMI. Understanding post-stroke lower extremity SMI is necessary for furthering targeted and personalized interventions to combat walking deficits.

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 Paired Associative Stimulation on Cortical Plasticity in Agonist–Antagonist Muscle Representations

Paired associative stimulation (PAS) increases and decreases cortical excitability in primary motor cortex (M1) neurons, depending on the spike timing-dependent plasticity, i.e., long-term potentiation (LTP)- and long-term depression (LTD)-like plasticity, respectively. However, how PAS affects the cortical circuits for the agonist and antagonist muscles of M1 is unclear. Here, we investigated the changes in the LTP- and LTD-like plasticity for agonist and antagonist muscles during PAS: 200 pairs of 0.25-Hz peripheral electric stimulation of the right median nerve at the wrist, followed by a transcranial magnetic stimulation of the left M1 with an interstimulus interval of 25 ms (PAS-25 ms) and 10 ms (PAS-10 ms). The unconditioned motor evoked potential amplitudes of the agonist muscles were larger after PAS-25 ms than after PAS-10 ms, while those of the antagonist muscles were smaller after PAS-25 ms than after PAS-10 ms. The γ-aminobutyric acid A (GABAA)- and GABAB-mediated cortical inhibition for the agonist and antagonist muscles were higher after PAS-25 ms than after PAS-10 ms. The cortical excitability for the agonist and antagonist muscles reciprocally and topographically increased and decreased after PAS, respectively; however, GABAA and GABAB-mediated cortical inhibitory functions for the agonist and antagonist muscles were less topographically decreased after PAS-10 ms. Thus, PAS-25 ms and PAS-10 ms differentially affect the LTP- and LTD-like plasticity in agonist and antagonist muscles.