Paired Associative Stimulation Research Articles

Repetitive Transcranial Magnetic Stimulation (rTMS) for Higher Brain Function Deficits

The management of higher brain dysfunctions such as stroke-induced unilateral spatial neglect (USN) or aphasia is crucial because these dysfunctions have devastating neurological repercussions on the patients' daily life and quality of life. Impairment of the physiological interhemispheric rivalry is often the result of brain insults such as strokes or traumatic injuries, and it may lead to USN or aphasia. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation method, is a promising tool for restoring the pathological imbalance in interhemispheric rivalry by either suppressing the hyperactivity of the unaffected hemisphere or facilitating hypoactivity in the affected hemisphere. The concept of paradoxical functional facilitation (Kapur, 1996) has important clinical implications when coupled with rTMS applications. In addition to conventional rTMS (c-rTMS), other clinically relevant protocols of patterned rTMS (p-rTMS) have been developed: the theta burst stimulation (TBS), the paired associative stimulation (PAS), and the quadripulse stimulation (QPS). TBS is commonly used in the rehabilitation of patients with post-stroke USN and those with non-fluent aphasia because of its prolonged beneficial effects and the short duration of stimulation. TBS may be considered an effective and safe protocol of rTMS. We foresee broader clinical applications of p-rTMS (TBS) and c-rTMS in the treatment of various neurological deficits.

67. Impact of Riluzole on the effects of paired associative stimulation (PAS) on cortical excitability in ALS patients

Amyotrophic lateral sclerosis (ALS) is a degenerative disease involving upper and lower motor neurons. Paired associative stimulation (PAS) is an experimental method to investigate synaptic plasticity through LTP-like changes. Purpose of this study is to evaluate PAS effects on M1 excitability in ALS patients before and after two weeks of Riluzole intake. Eighteen ALS patients (nine pseudobulbar, nine spinal) have been recruited; we evaluated average amplitude of ten MEPs (120% of resting motor threshold -RMT-) before PAS protocol, right after (T0) and after 10 (T10), 20 (T20), 30 (T30) and 60 (T60) minutes. PAS protocol consisted in 200 electrical stimulus at 0.3 Hz, delivered on median nerve of non-dominant hand (300% sensitive threshold, 500 mcs), associated to a magnetic stimulus at 100% of RMT upon contralateral motor cortex. Interstimulus interval was decided according to latency of the component N20 of SEP, delayed by 2 ms. Repeated measures ANOVA showed a trend to significance in MEP amplitude increase in T20 and T30 (p = 0.066 and 0.057 respectively) and a significant increase in T60 (p = 0.047) in patients without Riluzole. In patients assuming Riluzole, no significant change in MEP amplitude was found. Riluzole could impair sensory-motor integrative circuits, as evaluated by PAS protocol.

Normal sensorimotor plasticity in complex regional pain syndrome with fixed posture of the hand.

Movement disorders associated with complex regional pain syndrome type I have been a subject of controversy over the last 10 years regarding their nature and pathophysiology, with an intense debate about the functional (psychogenic) nature of this disorder. The aim of this study was to test sensorimotor plasticity and cortical excitability in patients with complex regional pain syndrome type I who developed a fixed posture of the hand. Ten patients with complex regional pain syndrome type I in the right upper limb and a fixed posture of the hand (disease duration less than 24 months) and 10 age-matched healthy subjects were enrolled. The following parameters of corticospinal excitability were recorded from the abductor pollicis brevis muscle of both hands by transcranial magnetic stimulation: resting and active motor thresholds, short-interval intracortical inhibition and facilitation, cortical silent period, and short- and long-latency afferent inhibition. Sensorimotor plasticity was tested using the paired associative stimulation protocol. Short-interval intracortical inhibition and long-latency afferent inhibition were reduced only in the affected right hand of patients compared with control subjects. Sensorimotor plasticity was comparable to normal subjects, with a preserved topographic specificity. Our data support the view that motor disorder in complex regional pain syndrome type I is not associated with abnormal sensorimotor plasticity, and it shares pathophysiological abnormalities with functional (psychogenic) dystonia rather than with idiopathic dystonia. © 2016 International Parkinson and Movement Disorder Society.

Increase in PAS-induced neuroplasticity after a treatment course of intranasal ketamine for depression. Report of three cases from a placebo-controlled trial

BackgroundAnimal studies suggest that neural plasticity may play a role in the antidepressant effects of a single ketamine dose. However, the potential effects of repeated ketamine treatments on human neuroplasticity are unknown. MethodsThis pilot RCT study measured plasticity-induced changes before and after a ketamine course, in three treatment-resistant depressed subjects, who were randomized to receive 8 intranasal treatments of 100mg ketamine or 4.5mg midazolam. Mood ratings were performed by a trained blinded rater at baseline and 24h–48h after the ketamine course, using the Montgomery Asberg Depression Rating Scale (MADRS). Neuroplasticity was assessed in the motor cortex using a paired associative stimulation (PAS) paradigm at baseline and 24h–48h after the treatment course. No changes in current psychotropic medication or dosage were permitted for 4weeks prior to trial entry and throughout the trial. ResultsThe subject receiving ketamine, but not those receiving midazolam, presented a marked increase in neural plasticity after the treatment course. However, mood changes were not associated with changes in neural plasticity. LimitationsPilot study with small sample size. Concomitant antidepressant medications taken. Plasticity was tested in the motor cortex only, thus the generalizability of these findings to other brain areas cannot be assumed. ConclusionsThese results suggest that a course of intranasal ketamine may enhance synaptic plasticity in subjects with depression, but this was not associated with antidepressant effects. Further research on this topic is warranted.

Paired Associative Stimulation with High-Frequency Peripheral Component Leads to Enhancement of Corticospinal Transmission at Wide Range of Interstimulus Intervals.

Background: In spinal paired associative stimulation (PAS), orthodromic and antidromic volleys elicited by transcranial magnetic stimulation (TMS) and peripheral nerve stimulation (PNS) coincide at corticomotoneuronal synapses at the spinal cord. The interstimulus interval (ISI) between TMS and PNS determines whether PAS leads to motor-evoked potential (MEP) potentiation or depression. PAS applied as a long-term treatment for neurological patients might alter conduction of neural fibers over time. Moreover, measurements of motoneuron conductance for determination of ISIs may be challenging in these patients.Results: We sought to design a PAS protocol to induce MEP potentiation at wide range of ISIs. We tested PAS consisting of high-intensity (100% stimulator output, SO) TMS and high-frequency (50 Hz) PNS in five subjects at five different ISIs. Our protocol induced potentiation of MEP amplitudes in all subjects at all tested intervals. TMS and PNS alone did not result in MEP potentiation. The variant of PAS protocol described here does not require exact adjustment of ISIs in order to achieve effective potentiation of MEPs.Conclusions: This variant of PAS might be feasible as a long-term treatment in rehabilitation of neurological patients.

Changes in cortico-spinal excitability following uphill versus downhill treadmill exercise

An acute bout of aerobic exercise induces neuroplasticity in the motor cortex. Moreover, paired associative stimulation (PAS) is known to induce neuroplasticity in M1. However, the possible influence of the type of exercise on the neuroplastic changes remains unknown. The present study investigated the effects of two different modes of muscle contraction produced during locomotor exercise on changes in corticospinal (CS) excitability. Subjects performed two 30-min treadmill exercises at an intensity corresponding to 60% of their maximal heart rate with either a +10% (uphill) or −10% (downhill) slope. These exercises were followed or not by paired associative stimulation method (PAS25) which consisted of 200 paired stimuli (0.25Hz, 15min) of median nerve electrical stimulation followed by transcranial magnetic stimulation of the hand M1 area (ISI 25ms). Motor evoked potentials (MEP), assessed through abductor pollicis brevis (APB) activity were obtained before exercise, at 5min, 15min and 30min after exercise. A significant (P<0.05) increase of the MEP amplitude was observed 30min after both exercises but was not different between the two modes of locomotion. On the contrary, MEP amplitude with PAS25 increased only 30min after downhill exercise. We conclude that sub-maximal treadmill exercise increases CS excitability within a period of 30min. However, the predominant mode of muscle contraction during uphill versus downhill locomotion does not influence CS excitability when assessed using a non-exercised muscle. However, results from PAS25 suggest that specific neuroplastic changes occur likely due to homeostatic mechanisms induced by exercise plus a PAS protocol.

State-Dependent Partial Occlusion of Cortical LTP-Like Plasticity in Major Depression.

The synaptic plasticity hypothesis of major depressive disorder (MDD) posits that alterations in synaptic plasticity represent a final common pathway underlying the clinical symptoms of the disorder. This study tested the hypotheses that patients with MDD show an attenuation of cortical synaptic long-term potentiation (LTP)-like plasticity in comparison with healthy controls, and that this attenuation recovers after remission. Cortical synaptic LTP-like plasticity was measured using a transcranial magnetic stimulation protocol, ie, paired associative stimulation (PAS), in 27 in-patients with MDD according to ICD-10 criteria and 27 sex- and age-matched healthy controls. The amplitude of motor-evoked potentials was measured before and after PAS. Patients were assessed during the acute episode and at follow-up to determine the state- or trait-character of LTP-like changes. LTP-like plasticity, the PAS-induced increase in motor-evoked potential amplitudes, was significantly attenuated in patients with an acute episode of MDD compared with healthy controls. Patients with remission showed a restoration of synaptic plasticity, whereas the deficits persisted in patients without remission, indicative for a state-character of impaired LTP-like plasticity. The results provide first evidence for a state-dependent partial occlusion of cortical LTP-like plasticity in MDD. This further identifies impaired LTP-like plasticity as a potential pathomechanism and treatment target of the disorder.

Investigation of Motor Cortical Plasticity and Corticospinal Tract Diffusion Tensor Imaging in Patients with Parkinsons Disease and Essential Tremor.

Parkinson’s disease (PD) and essential tremor (ET) are characterized with motor dysfunctions. Motor circuit dysfunctions can be complementarily investigated by paired associative stimulation (PAS)-induced long-term potentiation (LTP)-like plasticity and diffusion tensor imaging (DTI) of the corticospinal tract (CST). Three groups of twelve subjects with moderate severity PD, ET with intention tremor and healthy controls (HC) were studied. The primary motor cortex (M1) excitability, measured by motor evoked potential (MEP) amplitude and by short-interval and long-interval intracortical inhibition (SICI and LICI) was compared between the three groups before and after PAS. The DTI measures of fractional anisotropy (FA) and mean diffusivity (MD) were acquired. PAS effects and DTI data were simultaneously examined between groups. PAS increased MEP amplitude in HC but not in PD and ET. SICI and LICI were significantly reduced after PAS irrespective of groups. No significant differences of the mean FA and MD were found between groups. There was no significant correlation between the PAS effects and the DTI measures. Findings suggest that both PD and ET with intention tremor have impairment of the associative LTP-like corticospinal excitability change in M1. The microstructure of the CST is not relevant to the deficiency of M1 associative plasticity in PD and ET.

Effects of varenicline on motor cortical plasticity in non-smokers with schizophrenia

BackgroundNicotinic acetylcholine receptors (nAChR) have been implicated in the pathophysiology of schizophrenia, and deficits in this system may contribute to high rates of cigarette smoking in this population. nAChR stimulation may modulate neuroplasticity, or long-term potentiation (LTP), which is a key mediator of cognitive performance. Varenicline is a nAChR partial agonist that may improve cognitive deficits in both smokers and non-smokers with schizophrenia; however, the mechanism by which varenicline alters cognition in schizophrenia remains unclear. Thus, the aim of this randomized, double-blind, placebo-controlled, crossover study was to determine the effects of varenicline on LTP-like plasticity indexed through transcranial magnetic stimulation (TMS) in non-smokers with schizophrenia. MethodsVarenicline (0.5mg BID × 5 doses) or placebo was administered to 9 non-smokers with schizophrenia and 10 non-smoker healthy subjects. LTP-like plasticity was induced by TMS and paired associative stimulation (PAS) at 0.1Hz to the left motor cortex and measured every 15min for two hours post-PAS. ResultsThere was a significant diagnosis × medication interaction on peak potentiation (F (3, 34)=6.04, p<0.02) and post-hoc analyses indicated that varenicline significantly increased LTP in schizophrenia and decreased LTP in healthy subjects. ConclusionsThese preliminary findings suggest that varenicline may produce differential effects in non-smoking schizophrenia compared to control subjects. Given the role of LTP in learning and memory, these observations may suggest the potential for varenicline in the treatment of cognitive deficits in patients with schizophrenia.

Spike-timing-dependent plasticity in the human dorso-lateral prefrontal cortex

Changes in the synaptic strength of neural connections are induced by repeated coupling of activity of interconnected neurons with precise timing, a phenomenon known as spike-timing-dependent plasticity (STDP). It is debated if this mechanism exists in large-scale cortical networks in humans. We combined transcranial magnetic stimulation (TMS) with concurrent electroencephalography (EEG) to directly investigate the effects of two paired associative stimulation (PAS) protocols (fronto-parietal and parieto-frontal) of pre and post-synaptic inputs within the human fronto-parietal network. We found evidence that the dorsolateral prefrontal cortex (DLPFC) has the potential to form robust STDP. Long-term potentiation/depression of TMS-evoked cortical activity is prompted after that DLPFC stimulation is followed/preceded by posterior parietal stimulation. Such bidirectional changes are paralleled by sustained increase/decrease of high-frequency oscillatory activity, likely reflecting STDP responsivity. The current findings could be important to drive plasticity of damaged cortical circuits in patients with cognitive or psychiatric disorders.

Modulation of the Direction and Magnitude of Hebbian Plasticity in Human Motor Cortex by Stimulus Intensity and Concurrent Inhibition.

The mechanisms mediating the efficacy and variability of paired associative stimulation (PAS), thought to be mediated by Hebbian plasticity, remain incompletely understood. The magnitude and direction of Hebbian plasticity may be modulated by the level of neural depolarisation, which is influenced by stimulation intensity and interactions with cortical circuits. PAS effects would be influenced by the intensity of transcranial magnetic stimulation (TMS) and interaction with other circuits. In particular, PAS would be inhibited by concurrent inhibitory input following median nerve stimulation, known as short latency afferent inhibition (SAI). PAS was tested at an interstimulus interval (ISI) 2 ms or 6 ms longer than the N20 peak of the median nerve somatosensory-evoked potential (PASN20+2, PASN20+6). PASN20+2 was tested at three different TMS intensities. Short interval intracortical facilitation and inhibition were tested in the presence of SAI (SICFSAI, SICISAI). The propensity for long term potentiation like effects increased with higher PASN20+2 TMS stimulus intensity, whereas long term depression like effects ensued at subthreshold intensity. Stronger SAI correlated with weaker PAS LTP-like effects across individuals. PASN20+2 (maximal SAI) was less effective than PASN20+6 (weak SAI). SICFSAI or SICISAI did not influence PAS response. Inter-individual differences in SAI contribute to the variability in PAS efficacy. The magnitude and direction of PAS effects is modulated by TMS intensity. Together, these findings indicate that the level of neural activity induced by stimulation likely plays a crucial role in determining the direction and magnitude of Hebbian plastic effects evoked by PAS in human cortex.

EPV 7. PAS-induced plasticity relates to symptom severity and benefit from deep brain stimulation in cervical dystonia

Deep brain stimulation (DBS) of the globus pallidus internus (GPi-DBS) is an established treatment for patients with medication-refractory cervical dystonia ( Volkmann et al., 2014 ), but individual response to DBS is highly variable and predictive factors for the clinical outcome have not been identified yet. Cortical plasticity induced by paired associative stimulation is modulated by DBS in patients with generalized dystonia and has been related to the stability of the DBS effect after switching off stimulation ( Ruge et al., 2011 ). Here, we investigated DBS-induced changes in cortical plasticity over time in patients with cervical dystonia and explored whether differences in response to DBS might be explained by individual variability of neurophysiological markers of plasticity. Methods PAS25 was applied using transcranial magnetic stimulation (TMS) to investigate cortical plasticity in 9 patients with cervical dystonia preoperatively and 3 months after activation of pallidal DBS. PAS response was calculated as mean MEP response at timepoints 0, 15 and 30 min after PAS and expressed as percentage of pre-PAS MEP. Clinical changes were assessed using the TWSTRS severity subscore. Spearman’s correlation coefficient was calculated to evaluate the relationship between neurophysiological measures and clinical scores. Three out of 9 patients were lost to neurophysiological follow up due to intra- and postoperative complications or incompatibility of the neurostimulator for TMS. Results Mean TWSTRS pre OP (17.4 ± 2.1) was reduced with pallidal DBS by 49.5% (post OP TWSTRS: 8.8 ± 2.8; Wilcoxon signed rank test: p = 0.0078; n = 9). Mean PAS response post OP (125.0% ±24.7; n = 6) was smaller compared to pre OP (165.1 ± 26.3) but did not reach significance. Individual courses of both clinical and neurophysiological changes were highly variable across subjects. Preoperative TWSTRS correlated significantly with pre-operative PAS-response ( n = 9; R = 0.78; p = 0.018). In the 6 patients that could be followed up by TMS, the decrease in PAS-response correlated with the decrease in TWSTRS score absolute values at timepoint 6 months after DBS ( n = 6; p = 0.028; R = 0.89). Conclusions Maladaptive plasticity has been discussed to play a major role in the pathophysiology of dystonia ( Quartarone et al., 2003 ). On the other hand, increased cortical plasticity might also imply a greater capability for neuromodulation ( Ruge et al., 2011 ). We found a significant correlation between symptom severity and PAS-induced cortical plasticity as well as a relation of both clinical benefit and neurophysiological change during DBS in patients with cervical dystonia. The individual susceptibility for plastic changes may partially explain the broad range of clinical benefit from DBS in dystonia. Furthermore, the correlation of plasticity with clinical benefit might indicate PAS-induced plasticity as a potential predictive factor for DBS outcome that should be explored in larger studies.

Empowering Reentrant Projections from V5 to V1 Boosts Sensitivity to Motion

Evidence from macaques [1] and humans [2, 3] has shown that back projections from extrastriate areas to the primary visual area (V1) determine whether visual awareness will arise. For example, reentrant projections from the visual motion area (V5) to V1 are considered to be critical for awareness of motion [2, 3]. If these projections are also instrumental to functional processing of moving stimuli [4-8], then increasing synaptic efficacy in V5-V1 connections should induce functionally relevant short-term plastic changes, resulting in enhanced perception of visual motion. Using transcranial magnetic stimulation (TMS), we applied a novel cortico-cortical paired associative stimulation (ccPAS) protocol to transiently enhance visual motion sensitivity and demonstrate both the functional relevance of V5-V1 reentrant projections to motion perception and their plasticity. Specifically, we found that ccPAS aimed at strengthening reentrant connectivity from V5 to V1 (but not in the opposite direction) enhanced the human ability to perceive coherent visual motion. This perceptual enhancement followed the temporal profile of Hebbian plasticity [9-18] and was observed only when an optimal timing of 20ms between TMS pulses [2, 3, 5, 6] was used, not when TMS pulses were delivered synchronously. Thus, plastic change is critically dependent on both the direction and timing of connectivity; if either of these requirements was not met, perceptual enhancement did not take place. We therefore provide novel causal evidence that V5-V1 back projections, instrumental to motion perception, are functionally malleable. These findings have implications for theoretical models of visual awareness and for the rehabilitation of visual deficits.

Attention-related changes in short-term cortical plasticity help to explain fatigue in multiple sclerosis

Background: In multiple sclerosis (MS), pathophysiology of fatigue is only partially known. Objective: The aim of this study was to investigate whether the attention-induced modulation on short- and long-term cortical plasticity mechanisms in primary motor area (M1) is abnormal in patients with MS-related fatigue. Methods: All participants underwent 5-Hz repetitive transcranial magnetic stimulation (rTMS), reflecting short-term plasticity, and paired associative stimulation (PAS), reflecting long-term plasticity, and were asked to focus their attention on the hand contralateral to the M1 stimulated. A group of age-matched healthy subjects acted as control. Results: In patients with MS, 5-Hz rTMS and PAS failed to induce the normal increase in motor-evoked potential (MEP). During the attention-demanding condition, 5-Hz rTMS- and PAS-induced responses differed in patients with MS with and without fatigue. Whereas in patients with fatigue neither technique induced the attention-induced MEP increase, in patients without fatigue they both increased the MEP response, although they did so less efficiently than in healthy subjects. Attention-induced changes in short-term cortical plasticity inversely correlated with fatigue severity. Conclusion: Short-term and long-term plasticity mechanisms are abnormal in MS possibly owing to widespread changes in ion-channel expression. Fatigue in MS reflects disrupted cortical attentional networks related to movement control.

Long-term paired associative stimulation can restore voluntary control over paralyzed muscles in incomplete chronic spinal cord injury patients.

Emerging therapeutic strategies for spinal cord injury aim at sparing or restoring at least part of the corticospinal tract at the acute stage. Hence, approaches that strengthen the weak connections that are spared or restored are crucial. Transient plastic changes in the human corticospinal tract can be induced through paired associative stimulation, a noninvasive technique in which transcranial magnetic brain stimulation is synchronized with electrical peripheral nerve stimulation. A single paired associative stimulation session can induce transient plasticity in spinal cord injury patients. It is not known whether paired associative stimulation can strengthen neuronal connections persistently and have therapeutic effects that are clinically relevant. We recruited two patients with motor-incomplete chronic (one para- and one tetraplegic) spinal cord injuries. The patients received paired associative stimulation for 20-24 weeks. The paraplegic patient, previously paralyzed below the knee level, regained plantarflexion and dorsiflexion of the ankles of both legs. The tetraplegic patient regained grasping ability. The newly acquired voluntary movements could be performed by the patients in the absence of stimulation and for at least 1 month after the last stimulation session. In this unblinded proof-of-principle demonstration in two subjects, long-term paired associative stimulation induced persistent and clinically relevant strengthening of neural connections and restored voluntary movement in previously paralyzed muscles. Further study is needed to confirm whether long-term paired associative stimulation can be used in rehabilitation after spinal cord injury by itself and, possibly, in combination with other therapeutic strategies.

Differential Regulation of Human Paired Associative Stimulation-Induced and Theta-Burst Stimulation-Induced Plasticity by L-type and T-type Ca2+ Channels.

Activity-dependent changes of postsynaptic Ca2+-concentration are influenced by a variety of different Ca2+-channels and play an important role in synaptic plasticity. Paired associative stimulation (PAS) and theta-burst stimulation (TBS) are noninvasive magnetic stimulation protocols used in human subjects to induce lasting corticospinal excitability changes that have been likened to synaptic long-term potentiation and long-term depression. To better characterize the Ca2+-related physiological mechanisms underlying PAS- and TBS-induced plasticity, we examined the impact of different Ca2+-sources. PAS-induced facilitation of corticospinal excitability was blocked by NMDA-receptor blocker dextromethorphan (DXM) and L-type voltage gated Ca2+ channels (VGCC) blocker nimodipine (NDP), but turned into depression by T-type VGCC blocker ethosuximide (ESM). Although, surprisingly, static corticospinal excitability was increased by the combination of DXM and NDP, PAS-induced facilitation was blocked. TBS-induced facilitation of corticospinal excitability, which has previously been shown to be turned into depression by L-type VGCC blocker NDP (Wankerl K, Weise D, Gentner R, Rumpf J, Classen J. 2010. L-type voltage-gated Ca2+ channels: a single molecular switch for long-term potentiation/long-term depression-like plasticity and activity-dependent metaplasticity in humans. J Neurosci. 30(18):6197-6204.), was blocked, but not reverted, by T-type VGCC blocker ESM. The different patterns of Ca2+-channel modulation of PAS- and TBS-induced plasticity may point to an important role of backpropagating action potentials in PAS-induced plasticity, similar as in spike-timing dependent synaptic plasticity, and to a requirement of dendritic Ca2+-dependent spikes in TBS-induced plasticity.

Timing Analysis of Robotic Neuromodulatory Rehabilitation System for Paired Associative Stimulation

In this paper, the timing accuracy of a tapping motion is analyzed for a robotic neuromodulatory rehabilitation system (RNRS). Paired associative stimulation (PAS) refers to repetitive application of conditioned transcranial magnetic stimulation (TMS) with peripheral stimulation at appropriate interstimulus intervals. When overlapped properly, this pairing can be used for rehabilitation through the rebuilding of neural pathways. Therefore in PAS, providing peripheral stimulation at the right time is crucial. The common procedure of PAS in the literature is to use electrical stimulation as peripheral stimulation. However, inspired by the repetitive facilitation exercise (RFE), mechanical stimulation is adopted in this RNRS experiment. Experiments show that RNRS can give mechanical stimulation accurately within a standard deviation of 5 ms. This stimulation is accurate enough when considering a 50 ms overlapping time window, the effective time range over which the overlap happens. The overlapping time window of mechanical stimulation is longer than that of electrical stimulation and it is expected to relax timing requirements in PAS by using RNRS. In addition, fMRI-compatible RNRS will allow further research on how mechanical stimulation itself affects on brain by observing brain activity through fMRI, where a general electrical stimulation device and TMS are not allowed. These results will help to get a consistent neural plasticity effect with RNRS for individuals with stroke and allow performing further research on brain plasticity in fMRI, contributing to the neuromodulation research.

Abnormal cortical synaptic plasticity in minimal hepatic encephalopathy.

Minimal hepatic encephalopathy (MHE) represents the earliest stage of hepatic encephalopathy (HE). MHE is characterized by cognitive function impairment in the domains of attention, vigilance and integrative function, while obvious clinical manifestations are lacking. In the present study, we aimed at assessing whether subjects with MHE showed alterations in synaptic plasticity within the motor cortex. Previous findings suggest that learning in human motor cortex occurs through long-term potentiation (LTP)-like mechanisms. We employed therefore the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in the motor cortex of normal subjects. Fifteen patients with MHE and 15 age- and sex-matched cirrhotic patients without MHE were recruited. PAS consisted of 180 electrical stimuli of the right median nerve paired with a single TMS over the hotspot of right abductor pollicis brevis (APB) at an ISI of 25ms (PAS25). We measured motor evoked potentials (MEPs) before and after each intervention for up to 30min. In healthy subjects the PAS25 protocol was followed by a significant increase of the MEP amplitude. On the contrary, in patients with MHE the MEP amplitude was slightly reduced after PAS. These findings demonstrated that associative sensorimotor plasticity, an indirect probe for motor learning, is impaired in MHE patients.

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.

A meta-analysis of the effects of aging on motor cortex neurophysiology assessed by transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a non-invasive tool used for studying cortical excitability and plasticity in the human brain. This review aims to quantitatively synthesize the literature on age-related differences in cortical excitability and plasticity, examined by TMS. A literature search was conducted using MEDLINE, Embase, and PsycINFO from 1980 to December 2015. We extracted studies with healthy old (50-89years) versus young (16-49years) individuals that utilized the following TMS measures: resting motor threshold (RMT), short-interval cortical inhibition (SICI), short-latency afferent inhibition (SAI), cortical silent period (CSP), intracortical facilitation (ICF), and paired associative stimulation (PAS). We found a significant increase in RMT (g=0.414, 95% confidence interval (CI) [0.284, 0.544], p<0.001), a significant decrease in SAI (g=0.778, 95% CI [0.478, 1.078], p<0.001), and a trending decrease in LTP-like plasticity (g=-0.528, 95% CI [-1.157, 0.100] p<0.1) with age. Our findings suggest an age-dependent reduction in cortical excitability and sensorimotor integration within the human motor cortex. Alterations in the ability to regulate cortical excitability, sensorimotor integration and plasticity may underlie several age-related motor deficits.