Homeostatic plasticity in human motor cortex demonstrated by two consecutive sessions of paired associative stimulation

Long-term potentiation (LTP) and long-term depression (LTD) underlie most models of learning and memory, but neural activity would grow or shrink in an uncontrolled manner, if not guarded by stabilizing mechanisms. The Bienenstock-Cooper-Munro (BCM) rule proposes a sliding threshold for LTP/LTD induction: LTP induction becomes more difficult if neural activity was high previously. Here we tested if this form of homeostatic plasticity applies to the human motor cortex (M1) in vivo by examining the interactions between two consecutive sessions of paired associative stimulation (PAS). PAS consisted of repeated pairs of electrical stimulation of the right median nerve followed by transcranial magnetic stimulation of the left M1. The first PAS session employed an interstimulus interval equalling the individual N20-latency of the median nerve somatosensory-evoked cortical potential plus 2 ms, N20-latency minus 5 ms, or a random alternation between these intervals, to induce an LTP-like increase in motor-evoked potential (MEP) amplitudes in the right abductor pollicis brevis muscle (PAS(LTP)), an LTD-like decrease (PAS(LTD)), or no change (PAS(Control)), respectively. The second PAS session 30 min later was always PAS(LTP). It induced an moderate LTP-like effect if conditioned by PAS(Control), which increased if conditioned by PAS(LTD), but decreased if conditioned by PAS(LTP). Effects on MEP amplitude induced by the second PAS session exhibited a negative linear correlation with those in the first PAS session. Because the two PAS sessions activate identical neuronal circuits, we conclude that 'homosynaptic-like' homeostatic mechanisms in accord with the BCM rule contribute to regulating plasticity in human M1.     

Short-term and long-term plasticity interaction in human primary motor cortex

Repetitive transcranial magnetic stimulation (rTMS) over primary motor cortex (M1) elicits changes in motor evoked potential (MEP) size thought to reflect short‐ and long‐term forms of synaptic plasticity, resembling short‐term potentiation (STP) and long‐term potentiation/depression (LTP/LTD) observed in animal experiments. We designed this study in healthy humans to investigate whether STP as elicited by 5‐Hz rTMS interferes with LTP/LTD‐like plasticity induced by intermittent and continuous theta‐burst stimulation (iTBS and cTBS). The effects induced by 5‐Hz rTMS and iTBS/cTBS were indexed as changes in MEP size. We separately evaluated changes induced by 5‐Hz rTMS, iTBS and cTBS applied alone and those induced by iTBS and cTBS delivered after priming 5‐Hz rTMS. Interactions between 5‐Hz rTMS and iTBS/cTBS were investigated under several experimental conditions by delivering 5‐Hz rTMS at suprathreshold and subthreshold intensity, allowing 1 and 5 min intervals to elapse between 5‐Hz rTMS and TBS, and delivering one and ten 5‐Hz rTMS trains. We also investigated whether 5‐Hz rTMS induces changes in intracortical excitability tested with paired‐pulse transcranial magnetic stimulation. When given alone, 5‐Hz rTMS induced short‐lasting and iTBS/cTBS induced long‐lasting changes in MEP amplitudes. When M1 was primed with 10 suprathreshold 5‐Hz rTMS trains at 1 min before iTBS or cTBS, the iTBS/cTBS‐induced after‐effects disappeared. The 5‐Hz rTMS left intracortical excitability unchanged. We suggest that STP elicited by suprathreshold 5‐Hz rTMS abolishes iTBS/cTBS‐induced LTP/LTD‐like plasticity through non‐homeostatic metaplasticity mechanisms. Our study provides new information on interactions between short‐term and long‐term rTMS‐induced plasticity in human M1.     

Action observation with kinesthetic illusion can produce human motor plasticity

After watching sports, people often feel as if their sports skills might have been improved, even without any actual training. On some occasions, this motor skill learning through observation actually occurs. This phenomenon may be due to the fact that both action and action observation (AO) can activate shared cortical areas. However, the neural basis of performance gain through AO has not yet been fully clarified. In the present study, we used transcranial magnetic stimulation to investigate whether primary motor cortex (M1) plasticity is a physiological substrate of AO‐induced performance gain and whether AO itself is sufficient to change motor performance. The excitability of M1, especially that of its intracortical excitatory circuit, was enhanced after and during AO with kinesthetic illusion but not in interventions without this illusion. Moreover, behavioral improvement occurred only after AO with kinesthetic illusion, and a significant correlation existed between the performance gain and the degree of illusion. Our findings indicated that kinesthetic illusion is an essential component of the motor learning and M1 plasticity induced by AO, and this insight may be useful for the strategic rehabilitation of stroke patients.     

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.     

Dynamic functional connectivity states characterize NREM sleep and wakefulness

According to recent neuroimaging studies, temporal fluctuations in functional connectivity patterns can be clustered into dynamic functional connectivity (DFC) states and correspond to fluctuations in vigilance. However, whether there consistently exist DFC states associated with wakefulness and sleep stages and what are the characteristics and electrophysiological origin of these states remain unclear. The aims of the current study were to investigate the properties of DFC in different sleep stages and to explore the relationship between the characteristics of DFC and slow‐wave activity. We collected both eyes‐closed wakefulness and sleep data from 48 healthy young volunteers with simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) recordings. EEG data were employed as the gold standard of sleep stage scoring, and DFC states were estimated based on fMRI data. The results demonstrated that DFC states of the fMRI signals consistently corresponded to wakefulness and nonrapid eye movement sleep stages independent of the number of clusters. Furthermore, the mean dwell time of these states significantly correlated with slow‐wave activity. The inclusion or omission of regression of the global signal and the selection of parcellation schemes exerted minimal effects on the current findings. These results provide strong evidence that DFC states underlying fMRI signals match the fluctuations of vigilance and suggest a possible electrophysiological source of DFC states corresponding to vigilance states.     

Botulinum toxin injections reduce associative plasticity in patients with primary dystonia

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long‐term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation‐evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short‐interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Corticomotor excitability and plasticity following complex visuomotor training in young and old adults

Previous studies with transcranial magnetic stimulation (TMS) have shown that advancing age may influence plasticity induction in human motor cortex (M1), but these changes have been assessed with TMS-induced paradigms or simple motor tasks. The aim of this study was to examine changes in corticospinal excitability and intracortical inhibition as markers of corticomotor plasticity following complex motor training in young and old adults. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 16 young (20-35 years) and 16 older (aged 60-75 years) adults before and after motor skill training. Motor training consisted of three 6-minute blocks of a complex visuomotor task that required matching the metacarpophalangeal (MCP) joint angle of the index finger using abduction-adduction movements. Single- and paired-pulse TMS over the left M1 was used to assess changes in right FDI motor-evoked potentials (MEPs) and short-interval intracortical inhibition (SICI) before and after each training block. Visuomotor tracking performance was diminished in old compared with young adults throughout training. However, improvement in tracking error was similar for young and old adults (7-24% increase in each training block). For young and old adults, motor training increased FDI MEP amplitude (≥ 20%) and reduced the magnitude of SICI (≥ 19%) after each visuomotor training block, reflecting use-dependent plasticity. However, no difference in corticomotor plasticity (change in MEP or SICI) was observed between young and old adults. Further studies are needed to identify the experimental or behavioral factors that might contribute to the maintenance of corticomotor plasticity in older adults.     

Cortical plasticity is preserved in nondemented older individuals with severe ischemic small vessel disease

Ischemic small vessel disease (SVD) is a common finding on routine scans in older people, but cognitive sequelae vary considerably. To improve understanding of mechanisms underlying decline or preservation of cognitive function in this condition, we assessed cognition and cortical plasticity in 20 elderly subjects with severe SVD and 20 age‐matched controls without SVD, as rated on conventional MRI. Cognitive status was determined with a neuropsychological test battery, cortical plasticity induced with a paired associative stimulation protocol. Microstructural white matter changes were further analyzed for fractional anisotrophy using diffusion tensor imaging. We found that cortical plasticity as well as memory functions were preserved in severe SVD, while executive functions showed trendwise or significant decreases. Within the SVD group, lower white matter integrity in parahippocampal regions and posterior parts of the corpus callosum was associated with larger cortical plasticity, an association not seen for prefrontal white matter tracts. Enhanced cortical plasticity in subjects with lower white matter integrity in memory‐relevant areas might thus indicate a compensatory mechanism to counteract memory decline in severe SVD. Hum Brain Mapp, 2013. © 2012 Wiley Periodicals, Inc.     

Amphetamine enhances training-induced motor cortex plasticity

OBJECTIVES: Repetitive synchronized movements lead to short-term plastic changes in the primary motor cortex, which can be assessed by transcranial magnetic stimulation (TMS). Drugs which enhance such plastic changes could be of therapeutical interest, e.g. in patients with cerebral lesions. MATERIAL AND METHODS: We studied the effect of amphetamine on motor performance and plastic changes in the motor cortex as revealed by TMS mapping in healthy humans, who had to train a repetitive synchronized movement over 1 h. RESULTS: Cortical plastic changes observed after 1 h of training were more pronounced with amphetamine, whereas motor performance did not differ between training sessions with and without amphetamine. CONCLUSION: We conclude that amphetamine is able to enhance training-induced motor cortex plasticity. This effect could be due to its known influence on the GABAergic and glutamatergic system, but might also result from its role as an indirect catecholaminergic agonist.     

Involvement of different neuronal components in the induction of cortical plasticity with associative stimulation

Background

Paired associative stimulation (PAS), with stimulus interval of 21.5 or 25?ms, using transcranial magnetic stimulation in the posterior-anterior (PA) current direction, produces a long-term-potentiation-like effect. Stimulation with PA directed current generates both early and late indirect (I)-waves while that in anterior-posterior (AP) current predominantly elicits late I-waves. Short interval intracortical inhibition (SICI) inhibits late I-waves but not early I-waves.

Corticomotor plasticity following unilateral strength training

Introduction: We used transcranial magnetic stimulation (TMS) to investigate 3 weeks of unilateral leg strength training on ipsilateral motor cortex (iM1) excitability, and short-latency intracortical inhibition (SICI). Methods: Right leg dominant participants (n = 14) were randomly divided into either a strength training (ST) or control group. The ST group completed 9 training sessions (4 sets of 6 to 8 repetitions of single right leg squats). Results: We observed a 41% increase in right leg strength, and a 35% increase in strength of the untrained left leg (P < 0.01). There was a significant increase in motor evoked potential (MEP) amplitude recruitment curve for the untrained left leg (P < 0.01). SICI of the iM1 decreased by 21% for the untrained left leg (P < 0.01). Conclusions: The findings provide evidence for corticomotor adaptation for unilateral leg strength training within the iM1 that is modulated by changes in interhemispheric inhibition. Muscle Nerve 46: 384-393, 2012.     

Mechanisms underlying human motor system plasticity

There has been increased interest in the ability of the adult human nervous system to reorganize and adapt to environmental changes throughout life. This ability has been termed "plasticity." Plastic changes in the cerebral cortex have been studied: (a) as modifications of sensory or motor cortical representation of specific body parts (cortical maps, body representation level); and (b) as changes in the efficacy of existing synapses or generation of new synapses (neuronal or synaptic level). In this review, we describe paradigms used to study mechanisms of plasticity in the intact human motor system, the functional relevance of such plasticity, and possible ways to modulate it.     

Differential modulation of motor cortex excitability in BDNF Met allele carriers following experimentally induced and use-dependent plasticity

The purpose of this study was to investigate how healthy young subjects with one of three variants of the brain‐derived neurotrophic factor (BDNF) gene modulate motor cortex excitability following experimentally induced and use‐dependent plasticity interventions. Electromyographic recordings were obtained from the right first dorsal interosseous (FDI) muscle of 12 Val/Val, ten Val/Met and seven Met/Met genotypes (aged 18–39 years). Transcranial magnetic stimulation of the left hemisphere was used to assess changes in FDI motor‐evoked potentials (MEPs) following three separate interventions involving paired associative stimulation, a simple ballistic task and complex visuomotor tracking task using the index finger. Val/Val subjects increased FDI MEPs following all interventions (≥ 25%, P < 0.01), whereas the Met allele carriers only showed increased MEPs after the simple motor task (≥ 26%, P < 0.01). In contrast to the simple motor task, there was no significant change in MEPs for the Val/Met subjects (7%, P = 0.50) and a reduction in MEPs for the Met/Met group (?38%, P < 0.01) following the complex motor task. Despite these differences in use‐dependent plasticity, the performance of both motor tasks was not different between BDNF genotypes. We conclude that modulation of motor cortex excitability is strongly influenced by the BDNF polymorphism, with the greatest differences observed for the complex motor task. We also found unique motor cortex plasticity in the rarest form of the BDNF polymorphism (Met/Met subjects), which may have implications for functional recovery after disease or injury to the nervous system in these individuals.     

Combined effect of repetitive transcranial magnetic stimulation and physical exercise on cortical plasticity

Physical exercise can minimize dysfunction and optimize functional motor recovery after stroke by modulating cortical plasticity. However, the limitation of physical exercise is that large amounts of time and effort are necessary to significantly improve motor function, and even then, substantial exercise may not be sufficient to normalize the observed improvements. Thus, interventions that could be used to strengthen physical exercise-induced neuroplasticity may be valuable in treating hemiplegia after stroke. Repetitive transcranial magnetic stimulation seems to be a viable strategy for enhancing such plasticity. As a non-invasive cortical stimulation technique, repetitive transcranial magnetic stimulation is able to induce longterm plastic changes in the motor system. Recently, repetitive transcranial magnetic stimulation was found to optimize the plastic changes caused by motor training, thereby enhancing the long-term effects of physical exercise in stroke patients. Therefore, it is believed that the combination of repetitive transcranial magnetic stimulation and physical exercise may represent a superior method for restoring motor function after stroke.     

Cerebellar Modulation of Sensorimotor Associative Plasticity Is Impaired in Cervical Dystonia

Background

In recent years, cervical dystonia (CD) has been recognized as a network disorder that involves not only the basal ganglia but other brain regions, such as the primary motor and somatosensory cortex, brainstem, and cerebellum. So far, the role of the cerebellum in the pathophysiology of dystonia is only poorly understood.

Objective

The objective of this study was to investigate the role of the cerebellum on sensorimotor associative plasticity in patients with CD.

Methods

Sixteen patients with CD and 13 healthy subjects received cerebellar transcranial direct current stimulation (ctDCS) followed by a paired associative stimulation (PAS) protocol based on transcranial magnetic stimulation that induces sensorimotor associative plasticity. Across three sessions the participants received excitatory anodal, inhibitory cathodal, and sham ctDCS in a double-blind crossover design. Before and after the intervention, motor cortical excitability and motor symptom severity were assessed.

Results

PAS induced an increase in motor cortical excitability in both healthy control subjects and patients with CD. In healthy subjects this effect was attenuated by both anodal and cathodal ctDCS with a stronger effect of cathodal stimulation. In patients with CD, anodal stimulation suppressed the PAS effect, whereas cathodal stimulation had no influence on PAS. Motor symptom severity was unchanged after the intervention.

Conclusions

Cerebellar modulation with cathodal ctDCS had no effect on sensorimotor associative plasticity in patients with CD, in contrast with the net inhibitory effect in healthy subjects. This is further evidence that the cerebello-thalamo-cortical network plays a role in the pathophysiology of dystonia. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.     

TMS-assisted neurophysiological profiling of the dopamine receptor agonist cabergoline in human motor cortex

Summary. Dopamine plays a broad role in motor control and practice-dependent plasticity. Here we tested, in eight healthy subjects, the effects of the dopamine receptor agonist cabergoline on motor cortical excitability because the state of motor cortex can strongly influence practice-dependent plasticity. Cabergoline enhances practice-dependent plasticity but the mechanisms are unknown. We used transcranial magnetic stimulation for testing of motor cortical excitability. A single dose of 2 mg of cabergoline increased short-interval intracortical inhibition, a measure of excitability of GABA-dependent inhibitory neural circuits, and decreased various excitatory measures (motor evoked potential amplitude and short-interval intracortical facilitation). Other measures of motor cortical (motor threshold, cortical silent period duration), spinal (peripheral silent period duration, F-wave) and neuromuscular excitability (maximum M-wave) remained unchanged. This shift in the balance from excitation to inhibition may assist, by improving the ‘signal-to-noise ratio’ in motor cortex, in the positive modulating effect of cabergoline on practice-dependent plasticity.     

Motor cortical plasticity is impaired in Unverricht–Lundborg disease

Patients with Unverricht–Lundborg disease, also referred to as progressive myoclonus epilepsy type 1, exhibit widespread motor symptoms and signs in addition to epileptic seizures, which suggest abnormal excitability of the primary motor pathways. To explore the plasticity of the sensory–motor cortex, we employed a modern neurophysiological method, the paired associative stimulation protocol, which resembles the concept of long‐term potentiation of experimental studies. Seven patients with genetically verified Unverricht–Lundborg disease and 13 healthy control subjects were enrolled in the study to characterize cortical sensory–motor plasticity. In the study protocol, peripheral electric median nerve stimulation preceded navigated transcranial magnetic stimulation targeted to the representation area of thenar musculature on the contralateral primary motor cortex. The protocol consisted of 132 transcranial magnetic stimulation trials at 0.2 Hz, preceded by peripheral sensory stimulation at 25 ms. Motor‐evoked potential amplitudes were analyzed at baseline and after the paired associative stimulation protocol at an intensity of 130% of the individual motor threshold. The patients with Unverricht–Lundborg disease exhibited an average decrease of 15% in motor‐evoked potential amplitudes 30 minutes after paired associative stimulation, whereas in the control subjects, a significant increase (101%) was observed (P < .05), as expected. The results indicate a lack of normal cortical plasticity in Unverricht–Lundborg disease, which stresses the role of abnormal motor cortical functions or sensorimotor integration as possible pathophysiological contributors to the motor symptoms. The impaired cortical plasticity may be associated with the previously reported structural and physiological abnormalities of the primary motor cortex. © 2011 Movement Disorder Society