Paired Associative Stimulation Paradigm Research Articles

Transcranial magnetic stimulation combined with endogenous human hippocampal and motor cortical activity enhances memory.

The hippocampus is a fundamental cortical structure in the memory process of encoding, retaining, and recalling information. Transcranial Magnetic Stimulation (TMS) following a Paired Associative Stimulation (PAS) enhances nervous system excitability and promotes cortical plasticity mechanisms by synchronizing two stimuli in the same neural pathway. However, PAS has not been shown to improve memorization capacity yet. Here, we present an innovative protocol stemming from the PAS paradigm, which combines single-pulse TMS to the hippocampus with endogenous hippocampal activity during a working memory (WM) task. 96 volunteers were randomized across one experimental group and three parallel groups (motor cortex stimulation, sham stimulation, and no stimulation) in a single session. This combined-stimuli configuration resulted in an increased memorization capacity in the WM task, which was dependent on the stimulated brain location and subjects' basal memory performance. These results are potentially significant for clinical research on memory dysfunction and its related neurological disorders. Future research on paired associative or combined stimulation is required to unveil stimulation-derived neural mechanisms that enhance the ability to memorize.

Impaired neuroplasticity in the dorsolateral prefrontal cortex of patients with treatment-resistant depression indexed by paired associative stimulation paradigm and a combined TMS-EEG measurements

Impaired neuroplasticity in the dorsolateral prefrontal cortex of patients with treatment-resistant depression indexed by paired associative stimulation paradigm and a combined TMS-EEG measurements

Paired Associative Stimulation Rewired: A Novel Paradigm to Modulate Resting-State Intracortical Connectivity

Recent neuroimaging research has demonstrated that resting-state intracortical connectivity (i.e., the shared communication between two brain regions) can serve as a robust predictor of motor performance and learning. Theoretically, direct modulation of resting-state intracortical connectivity within the motor system could then improve motor performance and learning. However, previous neuromodulation techniques such as repetitive Transcranial Magnetic Stimulation may be limited in the capacity to modulate targeted intracortical connectivity. Paired Associative Stimulation (PAS) has shown efficacy in facilitating connectivity primarily between the central and peripheral nervous system based on the neuroplasticity mechanism of Spike Timing Dependent Plasticity. It may therefore be plausible for a reconfigured corticocortical PAS paradigm to modulate resting-state intracortical connectivity using a dual stimulator methodology over specific cortical nodes. However, potential theoretical and technological considerations of such a paradigm first need to be addressed prior to application for the purposes of manipulating motor behavior. We posit a corticocortical PAS paradigm used in conjunction with resting-state electroencephalography to demonstrate efficacy of potentiating motor learning associated resting-state intracortical connectivity within the human brain. Here we provide a precise PAS/EEG experimental design, details on data analysis, recommendations for maintaining scientific rigor, and preliminary proof of principle within a single-subject.

FV 1 Cholinergic brain structure and sensory-afferent modulation of motor cortex excitability

Introduction The basal forebrain provides important output within the cholinergic system. The cholinergic system may also influence the effects of paired associative stimulation (PAS), a plasticity inducing protocol involving paired median nerve and motor cortex stimulation, and short latency afferent inhibition (SAI) in which a median nerve sensory afferent stimulus induces short lasting conditioning effects on motor cortex excitability. The responses to either PAS or SAI can be variable. Here we hypothesized that the basal forebrain structural characteristics, or those of the thalamus as important sensory-afferent relay station with cholinergic input, relate to the functional influence of the cholinergic system measured using PAS or SAI. We therefore asked whether structural variability in these cholinergic brain areas could explain some of that functional variability observed with PAS or SAI. Material and methods Forty healthy volunteers (12 male; mean age 60, range 26–81) underwent a facilitatory PAS protocol with an inter-stimulus interval (ISI) of around 25 ms. An LTP-like facilitatory response was defined as an increase post-PAS of MEP amplitude of at least 10% relative to pre-PAS MEP size. SAI employed median nerve condition of motor cortex stimulation with inhibitory as well as facilitatory ISIs. We obtained T1 MPRAGE sequences on a 3T MRI scanner. MRI data were processed using Statistical Parametric Mapping and the CAT12 Toolbox (http://www.neuro.uni-jena.de/cat/) implemented in Matlab 2015a. Volumes of the basal forebrain were determined using a stereotactic atlas based on combined postmortem MRI and histological examination of cholinergic nuclei. As it is based on the histological examination of a single brain specimen and may not generalize across individuals, we also used volumes of right and left BFCS as obtained from the CAT12 toolbox. We used ANOVA models for group comparisons of responders and non-responders to PAS or SAI. Results Nineteen participants (48%) had an LTP-like response to PAS. Age, sex, or motor thresholds did not predict the PAS response. SAI had inhibitory effects in 80% of participants (n = 32). There was no association between the amount of PAS effects and the SAI response. Basal forebrain and right thalamus volumes were larger in SAI responders while volumes were similar in PAS responders and non-responders. Discussion The results suggest that a larger basal forebrain cholinergic output system, and a larger thalamus as sensory-afferent relay station that receives cholinergic input facilitate the short lasting modulation of motor cortex excitability in the SAI paradigm. This could be because of higher cholinergic tone. The cholinergic system may be less important in longer lasting modulation of motor cortex excitability in the PAS paradigm where an LTP-like response may involve more GABA-ergic neurotransmission.

On the Concurrent Use of Self-System Therapy and Functional Magnetic Resonance Imaging-Guided Transcranial Magnetic Stimulation as Treatment for Depression.

Despite the growing use of repetitive transcranial magnetic stimulation (rTMS) as a treatment for unipolar depression, its typical effect sizes have been modest, and methodological and conceptual challenges remain regarding how to optimize its efficacy. Linking rTMS to a model of the neurocircuitry underlying depression and applying such a model to personalize the site of stimulation may improve the efficacy of rTMS. Recent developments in the psychology and neurobiology of self-regulation offer a conceptual framework for identifying mechanisms of action in rTMS for depression, as well as for developing guidelines for individualized rTMS treatment. We applied this framework to develop a multimodal treatment for depression by pairing self-system therapy (SST) with simultaneously administered rTMS delivered to an individually targeted region of dorsolateral prefrontal cortex identified via functional magnetic resonance imaging (fMRI). In this proof-of-concept study, we examined the acceptability, feasibility, and preliminary efficacy of combining individually fMRI-targeted rTMS with SST. Using the format of a cognitive paired associative stimulation paradigm, the treatment was administered to 5 adults with unipolar depression in an open-label trial. The rTMS/SST combination was well tolerated, feasible, and acceptable. Preliminary evidence of efficacy also was promising. We hypothesized that both treatment modalities were targeting the same neural circuitry through cognitive paired associative stimulation, and observed changes in task-based fMRI were consistent with our model. These neural changes were directly related to improvements in depression severity. The new combination treatment represents a promising exemplar for theory-based, individually targeted, multimodal intervention in mood disorders.

Impaired neuroplasticity in the prefrontal cortex in depression indexed through paired associative stimulation.

Dysfunctional neuroplasticity may be one of the pathophysiological mechanisms underlying major depression. We have previously established methods to assess neuroplasticity from the dorsolateral prefrontal cortex (DLPFC) using a paired associative stimulation (PAS) paradigm, which pairs a preceding peripheral nerve stimulation with subsequent transcranial magnetic stimulation (TMS) combined with electroencephalography (EEG). We aimed to investigate neuroplasticity through the PAS paradigm in the DLPFC in patients with depression compared to healthy subjects. Twenty-nine patients with depression and 28 healthy controls participated in this study. There were no significant age or sex differences between the two groups. All participants received PAS paradigm in the DLPFC. We analyzed PAS induced potentiation from the DLPFC in both groups calculating the power of TMS-evoked potentials (TEP). A two-way ANOVA with PAS effect as a within-subject factor and diagnostic group as a between-subject factor was performed to examine the group differences in the PAS paradigm. DLPFC-PAS induced a significant potentiation at the stimulation site in both patients and healthy subjects (mean±SD: 1.24±0.33 [μV] vs. 1.48±0.28 [μV]). However, when we compared PAS potentiation between patients and healthy subjects, there were significant main effects of PAS (F1,53 =68.63, p<0.0001) and PAS-by-diagnostic group interaction (F1,53 =25.05, p<0.0001). Post hoc analysis demonstrated that patients had a significantly lower PAS potentiation compared to healthy subjects (t55 =3.128, p=0.003). Our findings provide evidence for impaired neuroplasticity in DLPFC in patients with depression compared to healthy subjects. Such findings may ultimately help us understand the pathophysiology of MDD and mechanisms involved in its treatment.

Pallidal deep brain stimulation modulates cortical excitability and plasticity.

Internal globus pallidus (GPi) deep brain stimulation (DBS) relieves symptoms in dystonia patients. However, the physiological effects produced by GPi DBS are not fully understood. In particular, how a single-pulse GPi DBS changes cortical circuits has never been investigated. We studied the modulation of motor cortical excitability and plasticity with single-pulse GPi DBS in dystonia patients with bilateral implantation of GPi DBS. The cortical evoked potentials from DBS were recorded with electroencephalography. Transcranial magnetic stimulation with a conditioning test paired-pulse paradigm was used to investigate the effect of GPi DBS on the primary motor cortex. How GPi DBS might modulate the motor cortical plasticity was tested using a paired associative stimulation paradigm with repetitive pairs of GPi DBS and motor cortical stimulation at specific time intervals. GPi stimulation produced 2 peaks of cortical evoked potentials with latencies of ∼10 and ∼25 milliseconds in the motor cortical area. Cortical facilitation was observed at ∼10 milliseconds after single-pulse GPi DBS, and cortical inhibition was observed after a ∼25-millisecond interval. Repetitive pairs of GPi stimulation with cortical stimulation at these 2 time intervals produced long-term potentiation-like effects in the motor cortex. Single-pulse DBS modulates cortical excitability and plasticity at specific time intervals. These effects may be related to the mechanism of action of DBS. Combination of DBS with cortical stimulation with appropriate timing has therapeutic potential and could be explored in the future as a method to enhance the effects of neuromodulation for neurological and psychiatric diseases. Ann Neurol 2018;83:352-362.

Reduced neuroplasticity in the dorsolateral prefrontal cortex in patients with depression as indexed by paired associative stimulation paradigm combined with EEG

Reduced neuroplasticity in the dorsolateral prefrontal cortex in patients with depression as indexed by paired associative stimulation paradigm combined with EEG

Paired associative transspinal and transcortical stimulation produces plasticity in human cortical and spinal neuronal circuits.

Anatomical, physiological, and functional connectivity exists between the neurons of the primary motor cortex (M1) and spinal cord. Paired associative stimulation (PAS) produces enduring changes in M1, based on the Hebbian principle of associative plasticity. The present study aimed to establish neurophysiological changes in human cortical and spinal neuronal circuits by pairing noninvasive transspinal stimulation with transcortical stimulation via transcranial magnetic stimulation (TMS). We delivered paired transspinal and transcortical stimulation for 40 min at precise interstimulus intervals, with TMS being delivered after (transspinal-transcortical PAS) or before (transcortical-transspinal PAS) transspinal stimulation. Transspinal-transcortical PAS markedly decreased intracortical inhibition, increased intracortical facilitation and M1 excitability with concomitant decreases of motor threshold, and reduced the soleus Hoffmann's reflex (H-reflex) low frequency-mediated homosynaptic depression. Transcortical-transspinal PAS did not affect intracortical circuits, decreased M1 excitability, and reduced the soleus H-reflex-paired stimulation pulses' mediated postactivation depression. Both protocols affected the excitation threshold of group Ia afferents and motor axons. These findings clearly indicate that the pairing of transspinal with transcortical stimulation produces cortical and spinal excitability changes based on the timing interval and functional network interactions between the two associated inputs. This new PAS paradigm may constitute a significant neuromodulation method with physiological impact, because it can be used to alter concomitantly excitability of intracortical circuits, corticospinal neurons, and spinal inhibition in humans.

Who May Benefit From Armeo Power Treatment? A Neurophysiological Approach to Predict Neurorehabilitation Outcomes

BackgroundThe Armeo Power, a rehabilitation exoskeleton that allows early treatment of motor disabilities, provides intelligent arm support in a large 3-dimensional work space, thus enabling patients to perform intensive, repetitive, and goal-oriented exercises. This device could efficiently induce new connections and facilitate plasticity phenomena potentiation. Knowledge of the potential brain plasticity reservoir after brain damage constitutes a prerequisite for an optimal rehabilitation strategy. ObjectiveTo identify potential neurophysiologic markers predicting the responsiveness of stroke patients to upper limb robotic treatment. DesignProspective cohort study. SettingBehavioral and Robotic Neurorehabilitation Laboratory of IRCCS Centro Neurolesi Bonino-Pulejo, Messina, Italy. PatientsWe enrolled 35 patients who had sustained a first-ever ischemic supratentorial stroke at least 2 months before enrollment and had unilateral hemiplegia. MethodsAll patients underwent 40 Armeo Power training sessions that lasted 1 hour each (ie, 5 times a week for 8 weeks). Main Outcome MeasurementsWe assessed the spasticity and motor function of the upper limb by means of the Modified Ashworth scale and Fugl-Meyer assessment, respectively. Moreover, we evaluated the cortical excitability and plasticity potential of the bilateral primary motor areas in response to the repetitive paired associative stimulation paradigm using transcranial magnetic stimulation and Armeo Power kinematic parameters. ResultsThe patients who showed significant repetitive paired associative stimulation aftereffects at baseline exhibited an evident increase of cortical plasticity in the affected hemisphere (motor evoked potential amplitude increase, P = .03), a decrease of interhemispheric inhibition (affected hemisphere cortical silent period duration decrease, P = .01; unaffected hemisphere cortical silent period duration increase, P = .004; repetitive paired associative stimulation aftereffect increase, P = .008). Such findings were paralleled by clinical improvements (Fugl-Meyer, P = .04) and Armeo Power kinematic improvements (elbow flexion/extension, P = .02; shoulder range of movement, P = .002). ConclusionsOur data suggest that use of Armeo Power may improve upper limb motor function recovery as predicted by reshaping of cortical and transcallosal plasticity, according to the baseline cortical excitability. Level of EvidenceIV

Stimulus uncertainty enhances motor cortical plasticity induced with a paired associative stimulation paradigm

Event Abstract Back to Event Stimulus uncertainty enhances motor cortical plasticity induced with a paired associative stimulation paradigm Martin Sale1*, Abbey Nydam2, Marc Kamke1 and Jason Mattingley1, 2 1 The University of Queensland, Queensland Brain Institute, Australia 2 The University of Queensland, School of Psychology, Australia Neuroplasticity manifests as a change in structure and function of the central nervous system, and is important for memory formation, skill acquisition and recovery following injury. A factor known to influence plasticity mechanisms is stimulus uncertainty. An uncertain stimulus can be more conducive to learning than a predictable one. In humans, neuroplasticity can be induced non-invasively in primary motor cortex with paradigms that employ transcranial magnetic stimulation (TMS). These paradigms show some promise in promoting functional recovery after stroke, but their effectiveness in the clinical domain is hampered by substantial effect variability. One such paradigm, paired associative stimulation (PAS), induces plasticity by repeatedly pairing an electrical stimulus delivered to the median nerve in the wrist, with TMS of the contralateral motor cortex 25 ms later. This study aimed to investigate whether stimulus uncertainty influences the effectiveness of PAS-induced plasticity. Participants (n = 28) attended two sessions during which a modified PAS protocol was used to introduce stimulus uncertainty by randomly including unpaired (TMS-only) stimulation throughout PAS. Prior to each paired or unpaired trial, an auditory stimulus was delivered at a contingency that was either predictive (no uncertainty) or random (maximum uncertainty) regarding the subsequent paired or unpaired stimulation. Based on evidence that probabilistic encoding of uncertainty modulates learning in low-level sensory areas, it was predicted that PAS-induced plasticity would be greater in the maximum uncertainty condition. The results demonstrated PAS-induced plasticity effects, but only for the random contingency condition. The findings have implications for research aimed at optimising plasticity paradigms for therapeutic application, and suggest that manipulating stimulus uncertainty can boost plasticity induction. Keywords: Learning, Motor Cortex, Transcranial Magnetic Stimulation, plasticity, predictive coding, entropy Conference: XII International Conference on Cognitive Neuroscience (ICON-XII), Brisbane, Queensland, Australia, 27 Jul - 31 Jul, 2014. Presentation Type: Poster Topic: Memory and Learning Citation: Sale M, Nydam A, Kamke M and Mattingley J (2015). Stimulus uncertainty enhances motor cortical plasticity induced with a paired associative stimulation paradigm. Conference Abstract: XII International Conference on Cognitive Neuroscience (ICON-XII). doi: 10.3389/conf.fnhum.2015.217.00336 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 19 Feb 2015; Published Online: 24 Apr 2015. * Correspondence: Dr. Martin Sale, The University of Queensland, Queensland Brain Institute, Brisbane, Australia, m.sale@uq.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Martin Sale Abbey Nydam Marc Kamke Jason Mattingley Google Martin Sale Abbey Nydam Marc Kamke Jason Mattingley Google Scholar Martin Sale Abbey Nydam Marc Kamke Jason Mattingley PubMed Martin Sale Abbey Nydam Marc Kamke Jason Mattingley Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

P 174. Effects of paired associative stimulation on developmental motor plasticity in children

Transcranial magnetic stimulation (TMS) offers increasingly sophisticated means of assessing neurophysiology and neuroplasticity mechanisms but applications in children have been limited. Paired associative stimulation (PAS) is an advanced TMS method that pairs peripheral sensory stimulation with TMS primary motor cortex (M1) stimulation. PAS induces rapid, reversible and topographically specific increases in adult motor cortex excitability consistent with NMDAR-dependent long-term potentiation. PAS has not been studied in the more plastic brains of children. Our aim wasto define the developmental profile of PAS in children. We hypothesized that rates of PAS MEP enhancement would be higher in children compared to adults. Healthy, right-handed children aged 6–18 years were recruited from the Alberta Perinatal Stroke Project (APSP) healthy control cohort and general population. Median nerve stimulation (300% sensory threshold) was delivered 25 ms prior to suprathreshold (1 mV) left M1 stimulation (90 pairings, 7 min).Difference in mean peak-to-peak amplitude of right APB motor evoked potentials (MEP) was the primary outcome. Forty single pulse TMS measures were obtained at baseline, immediately after, and 15, 30, 45, and 75 min post-PAS. PAS effects were categorized as definitive (significantly elevated post-MEP at multiple timepoints), possible (single timepoint only) or no effect. Secondary outcomes included change in slope of stimulus response curve (SRC) post-PAS and standard safety and tolerability evaluations. Of 15 children (9 male, mean age 12 years), 8 (53%) showed definitive positive PAS effects, 2 were possible, and 5 showed no MEP change following PAS (none showed a decrease). Despite this, mean SRC slope increased across the entire group (pre 5.43 ± 1.09, post 6.50 ± 1.14, p = 0.05). Of the 8 children with definite PAS, maximal mean MEP increase was immediately post-PAS in 5 and at 15 min in 3. PAS effect was not clearly associated with age ( p = 0.24). PAS procedures were well tolerated with no serious adverse events. Recorded tolerability scores were favorable, scoring better than “a long car ride” on average. Wrist pain was common (20%) but became quickly tolerated. Other side effects (headache, neck pain, tingling, nausea, presyncope) were infrequent (<7%) and mild. PAS paradigms appear safe and well tolerated in children. Frequency of positive PAS effects may be higher in children (>50%) than in adults. SRC curves may be more sensitive than mean MEP amplitude changes to PAS effects. PAS may provide new insights into mechanisms of developmental motor plasticity and inform therapeutic interventions in cerebral palsy and motor disorders of childhood.

P 123. CIPASS: Trial of a daily program of cerebral stimulation by TMS using a PAS paradigm in the recovery phase of stroke patients

Introduction Paired Associative Stimulation (PAS) is a non-invasive brain stimulation technique allowing to modulate precisely brain plasticity. Effects on plasticity have been demonstrated in healthy subjects and stroke patients ( Stefan et al., 2000 , Castel-Lacanal et al., 2007 , Castel-Lacanal et al., 2009 ), translated by a motor-evoked potentiel (MEP) facilitation of the targeted muscle that was persistent (1 h), reversible and topographically specific. CIPASS (Chronic IPAS in Stroke) is a new neuromodulation protocol where a PAS session is performed during 5 days to hemiparetic patients with a stroke (less than 6 months). Objectives Our goals is to demonstrate a lasting increase (3 days) of motor cortical plasticity for extensor wrist muscles (Extensor Carpi Radialis, ECR), and an improvement of upper limb function. Our judgment criteria are electrophysiological and motors parameters. Materials and methods The intervention consists of a combination of two stimulations: an electrical and a magnetic stimulation (using TMS) with a frequency at 0,1 Hz over 30 min. This is a randomized, double-blind and placebo-controlled trial. 18 patients (13 men and 5 women, mean age: 47.3 ± 12.7 years) have been included (Fugl-Meyer Motor Scale: FMMS, upper limb section: 24.2/66 ± 13.1) divided into two groups (PAS: n = 10 and Placebo: n = 8). One session of PAS stimulation was applied to the ECR muscle on a daily basis during 5 days. The MEP surface of ECR muscle and FMMS variations have been analysed. Results Our trial will end in December 2012. Our first results have demonstrated, 3 days after the end of the last PAS session (J8), an important increase of MEP surfaces for group PAS (+168 ± 268%) compared to group Placebo (+0.1 ± 48%); with no significant difference between the 2 groups. Individual results show more important facilitation effects for patients of group PAS (5/10 patients: MEP facilitation > +100%) than group B (8/8 patients: MEP facilitation Fig. 1 ). FMMS improvement was slightly higher for group PAS (+6.1 ± 4.5 pts) than group Placebo (+4.6 ± 4.1 pts) at J8, also due to spontaneous recovery and rehabilitation. Individuals results show a more important improvement of FMMS for patients of group PAS (6/10 patients: ΔJ1–J8 > +4 pts) than group B (2/8 patients: Δ J1–J8 > +4 pts) ( Fig. 2 ). Conclusion A daily program of PAS session seems to induce long-term changes in the excitability of corticospinal projection to wrist muscles in group PAS up to 3 days following the end of the stimulation program; motor effects seem however less conclusive. These results have to be confirmed with a larger sample to allow us to draw reliable conclusions. This trial will help us to better understand brain plasticity processes and to prove the relevance of CIPASS use as a therapeutic adjunct in stroke rehabilitation.

Short-interval intracortical inhibition blocks long-term potentiation induced by paired associative stimulation

Paired associative stimulation (PAS) of the motor cortex leads to increased motor evoked potential (MEP) amplitudes in the stimulated hand muscles. We hypothesized that evoking GABA(A) receptor-mediated short-interval intracortical inhibition (SICI) simultaneously with excitatory PAS would depress long-term potentiation plasticity in motor cortex. Four different PAS paradigms were tested, standard PAS (PAS25) and three conditioned PAS protocols (CS2-PAS25, CS2-PAS25adj, and CS10-PAS25adj). A subthreshold conditioning stimulus 2 ms (CS2) or 10 ms (CS10) before the test stimuli was added to the conditioned PAS protocols. Since CS2 has inhibitory and CS10 has facilitatory effect on cortical excitability, in the CS2-PAS25adj and CS10-PAS25adj protocols, TS intensity was adjusted to produce a 1-mV MEP in the presence of CS2 or CS10 to control for the degree of corticospinal excitation. As expected, MEP amplitudes after PAS25 were higher compared with that at baseline, but importantly, MEP amplitudes did not change after PAS was induced in the presence of SICI in either the CS2-PAS25 or CS2-PAS25adj condition. Furthermore, the CS10-PAS25adj protocol showed significantly increased MEP amplitude at 60 min after PAS compared with baseline. These results show that SICI blocked the induction of long-term potentiation-like plasticity in the motor cortex, indicating that GABAergic circuits play an important role in the regulation of cortical plasticity. The study demonstrates a noninvasive and nonpharmacological way to achieve focal modulation of plasticity.

10. Sensorimotor interaction and motor learning in facial muscles

Background and aim : Integration of sensory information with motor output is thought to be important in motor learning. In limb muscles, this is studied using the short afferent inhibition (SAI) paradigm, to assess sensorimotor interaction, and paired associative stimulation (PAS), to evaluate LTP-like plasticity. As far as we know, SAI and PAS paradigms have never been used in the territory of the cranial nerves. The present study was aimed at testing in normal subjects whether sensorimotor interaction and LTP-like plasticity can be observed in facial muscles as well as in limb muscles. Methods : Motor evoked potentials (MEPs) were evoked in the depressor angulis oris (DAO) muscle of 7 subjects. MEPs were recorded from the contralateral DAO at rest and during 10% maximal voluntary contraction (active condition). SAI was tested in 5 subjects, by pairing electrical stimulation (ES, intensity 3 times the perceptual threshold) of the facial nerve, with magnetic stimulation (TMS, 120% of motor threshold intensity) of the facial motor cortex. Intervals between ES and TMS were 5, 10, 15, 20, 25 and 30 ms. The LTP-like plasticity protocol (200 pairs of ES and TMS, 20 ms ISI, at 0.25 Hz) was tested in X subjects by evoking twenty MEPs in both resting and active conditions, before and at 0, 20 and 30 min after paired stimulation. Results : Facial nerve stimulation in the SAI paradigm had no significant affect on MEP amplitude, either in the active or in the relaxed DAO muscle. By contrast MEP amplitude at rest showed a trend of facilitation (p < 0,072) after the PAS protocol administration. When tested at rest this effect was observed at baseline and after 10 min. On the contrary MEP amplitude recorded during activity was significantly enhanced at 10 (p < 0,026) and 30 (p < 0,014) minutes after PAS. There was a significant difference between the time course in resting and active conditions (p < 0,019). Conclusions : These data show that there is no short latency afferent inhibition in the facial motor cortex, yet despite this, there is evidence for maintained LTP-like plasticity. Further studies are needed to understand how and why PAS works in facial muscles despite the absence of SAI. A larger sample is also required to confirm the PAS effect on resting DAO MEPs. A second point to be clarified is why the PAS time course at rest is different from that operating during active condition.

Effect of Consecutive Application of Paired Associative Stimulation on Motor Recovery in a Rat Stroke Model: A Preliminary Study

This study investigated the changes in motor evoked potential (MEP) amplitude and motor behavior index when paired associative stimulation (PAS), a conjoint stimulation of a peripheral nerve and the motor cortex, was applied in a rat stroke model. The PAS was applied to 19 rats and sham stimulation was applied to 15 rats. One part of PAS consisted of peripheral electrical stimulation of the soleus muscle and the other part was transcranial magnetic stimulation of the motor cortex. The stimulation was repeated for 30 min with a frequency of 0.05 Hz. Five sessions of PAS were applied over 5 consecutive days. The motor behavior index was higher in the PAS group than in the sham stimulation group at 7 d after ischemic brain injury. There was no lasting difference between the PAS animals and the sham stimulation group in MEP amplitude although MEP amplitude was increased immediately after PAS. MEP amplitude can be increased by the PAS paradigm in rats as well as in humans and PAS has potential therapeutic value for motor recovery after brain injury.

Changes in somatosensory-evoked potentials and high-frequency oscillations after paired-associative stimulation

Paired-associative stimulation (PAS), combining electrical median nerve stimulation with transcranial magnetic stimulation (TMS) with a variable delay, causes long-term potentiation or depression (LTP/LTD)-like cortical plasticity. In the present study, we examined how PAS over the motor cortex affected a distant site, the somatosensory cortex. Furthermore, the influences of PAS on high-frequency oscillations (HFOs) were investigated to clarify the origin of HFOs. Interstimulus intervals between median nerve stimulation and TMS were 25 ms (PAS(25)) and 10 ms (PAS(10)). PAS was performed over the motor and somatosensory cortices. SEPs following median nerve stimulation were recorded before and after PAS. HFOs were isolated by 400-800 Hz band-pass filtering. PAS(25) over the motor cortex increased the N20-P25 and P25-N33 amplitudes and the HFOs significantly. The enhancement of the P25-N33 amplitude and the late HFOs lasted more than 60 min. After PAS(10) over the motor cortex, the N20-P25 and P25-N33 amplitudes decreased for 40 min, and the HFOs decreased for 60 min. Frontal SEPs were not affected after PAS over the motor cortex. PAS(25/10) over the somatosensory cortex did not affect SEPs and HFOs. PAS(25/10) over the motor cortex caused the LTP/LTD-like phenomena in a distant site, the somatosensory cortex. The PAS paradigms over the motor cortex can modify both the neural generators of SEPs and HFOs. HFOs may reflect the activation of GABAergic inhibitory interneurons regulating pyramidal neurons in the somatosensory cortex.

Factors influencing the magnitude and reproducibility of corticomotor excitability changes induced by paired associative stimulation

Several paired-associative stimulation (PAS) protocols induce neuroplastic changes in human motor cortex (M1). To understand better the inherent variability of responses to PAS, we investigated the effectiveness and reproducibility of two PAS paradigms, and neurophysiological and experimental variables that may influence this. Motor evoked potentials (MEPs) were elicited by transcranial magnetic stimulation (TMS) of right M1, and recorded from surface EMG of left abductor pollicis brevis (APB) and first dorsal interosseous before and after PAS. PAS consisted of electrical stimulation of left median nerve paired with TMS over right M1 25 ms later. Twenty subjects were given one of two PAS protocols: short (132 paired stimuli at 0.2 Hz) or long (90 paired stimuli at 0.05 Hz), and were re-tested with the same protocol on 3 separate occasions, with 11 subjects tested in the morning and 9 in the afternoon. Neurophysiological variables assessed included MEP amplitude, resting and active motor threshold, short-interval intracortical inhibition, intracortical facilitation and cortical silent period duration. The short PAS protocol produced greater APB MEP facilitation (51%) than the long protocol (11%), and this did not differ between sessions. The neurophysiological variables did not consistently predict responses to PAS. Both PAS protocols induced more APB MEP facilitation, and greater reproducibility between sessions, in experiments conducted in the afternoon. The mechanism for this is unclear, but circadian rhythms in hormones and neuromodulators known to influence neuroplasticity warrant investigation. Future studies involving PAS should be conducted at a fixed time of day, preferably in the afternoon, to maximise neuroplasticity and reduce variability.