Modulation of motor cortex excitability by paired peripheral and transcranial magnetic stimulation

Objective

Repetitive application of peripheral electrical stimuli paired with transcranial magnetic stimulation (rTMS) of M1 cortex at low frequency, known as paired associative stimulation (PAS), is an effective method to induce motor cortex plasticity in humans. Here we investigated the effects of repetitive peripheral magnetic stimulation (rPMS) combined with low frequency rTMS (‘magnetic-PAS’) on intracortical and corticospinal excitability and whether those changes were widespread or circumscribed to the cortical area controlling the stimulated muscle.

Modulation of motor cortex excitability by different levels of whole-hand afferent electrical stimulation

Objective

In a previous transcranial magnetic stimulation (TMS) study we demonstrated that suprathreshold mesh-glove (MG) whole-hand stimulation elicits lasting changes in motor cortical excitability. Currently, there is no consensus with regard to the optimal parameters for the induction of sensorimotor cortical plasticity using peripheral electrical stimulation. Thus, in the present study we explore the modulatory effects of MG stimulation at different stimulus intensities and different frequencies in order to identify an optimal stimulation protocol.

Methods

MG stimulation was performed on 12 healthy subjects in separate sessions at different stimulation levels: sub-sensory at 50 Hz, sensory at 50 Hz and motor at 2 Hz. To verify if stimulation at lower frequencies is less effective, an additional experiment at sensory level with 2 Hz was performed. TMS was used to assess motor threshold (MT), motor evoked potentials (MEPs) recruitment curve (RC), short latency intracortical inhibition (SICI) and intracortical facilitation (ICF) to paired-pulse TMS at baseline (T0), immediately after (T1) and 1 h (T2) after 30 min of MG stimulation. F-wave studies were performed to assess spinal motoneuron excitability.

Results

MG stimulation at sub-sensory/50 Hz and sensory/2 Hz level determines no significant cortical excitability changes; at sensory/50 Hz level and at motor/2 Hz level we found decreased MT, increased MEP RC as well as reduced SICI and increased ICF at T1 and T2.

Conclusions

MG stimulation at sensory/50 Hz and motor/2 Hz level induces similar long-lasting modulatory effects on motor cortical excitability. Both the strength of the corticospinal projections and the intracortical networks are influenced to the same extend.

Significance

The study provides further evidence that stimulation intensity and frequency can independently modulate motor cortical plasticity. The selection of optimal stimulation parameters has potentially important implications for the neurorehabilitation of patients after brain damage (e.g. stroke, traumatic brain injury) with hand motor deficits.     

Effects of paired associated stimulation with different stimulation position on motor cortex excitability and upper limb motor function in patients with cerebral infarction

ObjectiveTo investigate the effects of paired associated stimulation (PAS) with different stimulation position on motor cortex excitability and upper limb motor function in patients with cerebral infarction.MethodA total of 120 volunteers with cerebral infarction were randomly divided into four groups. Based on conventional rehabilitation treatment, the PAS stimulation group was given the corresponding position of PAS treatment once a day for 28 consecutive days. The MEP amplitude and RMT of both hemispheres were assessed before and after treatment, and a simple upper limb Function Examination Scale (STEF) score, simplified upper limb Fugl–Meyer score (FMA), and improved Barthel Index (MBI) were used to assess upper limb motor function in the four groups.ResultsFollowing PAS, the MEP amplitude decreased, and the RMT of abductor pollicis brevis (APB) increased on the contralesional side, while the MEP amplitude increased and the RMT of APB decreased on the ipsilesional side. After 28 consecutive days the scores of STEF, FMA, and MBI in the bilateral stimulation group were significantly better than those in the ipsilesional stimulation group and the contralesional stimulation group, but there was no significant difference in the scores of STEF, FMA, and MBI between the ipsilesional stimulation group and the contralesional stimulation group.ConclusionThe excitability of the motor cortex can be changed when the contralesional side or the ipsilesional side was given the corresponding PAS stimulation, while the bilateral PAS stimulation can more easily cause a change of excitability of the motor cortex, resulting in better recovery of the upper limb function.     

Paired-associative stimulation can modulate muscle fatigue induced motor cortex excitability changes

The aim of this study was to examine whether the changes of the motor cortex excitability induced by muscle fatigue could be affected by prior or subsequent intervention protocol supposed to induce opposing excitability changes. For this purpose we used paired associative stimulation (PAS) method, where peripheral nerve stimuli were associated with transcranial magnetic stimulation (TMS) of the motor cortex at a fixed interstimulus interval of 25 ms. The PAS protocol used is known to produce a long lasting, long-term potentiation (LTP) like change of cortical plasticity manifested by significant increase in motor evoked potentials (MEPs) amplitude. In this study, we confirmed significant MEP size reduction following fatigue, which had been already reported in the literature. When PAS was applied either immediately before or after muscle fatigue protocol, the excitability changes were largely occluded and MEP sizes remained close to baseline levels. However, in spite of the effects on cortical excitability, conditioning with PAS did not cause any change in target fatigue measure, the endurance point, which remained the same as when fatiguing protocol was applied alone. The present results demonstrate that fatigue-related changes in cortical excitability can be modulated by either prior or subsequent excitability promoting activity. They also suggest that muscle fatigue associated changes in motor cortical excitability probably represent non-specific activity-related plasticity, rather than a direct expression of the so-called central fatigue.     

Suppression of motor cortical excitability by magnetic stimulation of the cerebellum

EMG responses of the relaxed right thenar muscle evoked by magnetic stimulation over the sensorimotor cortex were suppressed by magnetic conditioning stimulation over the occiput. The optimal interstimulus interval for reduction of the EMG amplitude was 4–6 ms. The optimal conditioning position and induced current direction were 3–4 cm below the inion when the induced current in the center of the figure-8 coil flowed from right to left horizontally. It differed from that for activating the descending motor pathway. We consider this suppression to be due to the inhibition of motor cortex excitability caused by stimulation of the dentato-thalamo-cortical pathway at the dentate nuclei or superior cerebellar peduncle.     

Modulation of motor cortex excitability induced by pinch grip repetition

Summary. We examined the influence of right handed pinch grips and the effect of a motor training on motor cortex excitability of the left first dorsal interosseus muscle (FDI). TMS single and paired pulses were applied over the right human motor cortex (M1) during and after right handed pinch grips with low force. In another experiment, these stimulations were performed before and after a 30-minute right handed pinch grip training. Results: MEP amplitudes in left FDI were reduced when TMS single pulses were applied during the pinch grip. Simultaneously, motor cortex excitability was enhanced but returned to baseline after the training period. Conclusion: Phasic pinch grips of the right hand exert an inhibiting effect on the corticospinal excitability of the ipsilateral motor cortex and lead to an increase of intracortical excitability. These changes are distinct and independent of each other. Motor training has an interhemispheric effect on intracortical excitability.     

Use of theta-burst stimulation in changing excitability of motor cortex: A systematic review and meta-analysis

Noninvasive brain stimulation has been demonstrated to modulate cortical activity in humans. In particular, theta burst stimulation (TBS) has gained notable attention due to its ability to induce lasting physiological changes after short stimulation durations. The present study aimed to provide a comprehensive meta-analytic review of the efficacy of two TBS paradigms; intermittent (iTBS) and continuous (cTBS), on corticospinal excitability in healthy individuals. Literature searches yielded a total of 87 studies adhering to the inclusion criteria. iTBS yielded moderately large MEP increases lasting up to 30 min with a pooled SMD of 0.71 (p < 0.00001). cTBS produced a reduction in MEP amplitudes lasting up to 60 min, with the largest effect size seen at 5 min post stimulation (SMD = −0.9, P < 0.00001). The collected studies were of heterogeneous nature, and a series of tests conducted indicated a degree of publication bias. No significant change in SICI and ICF was observed, with exception to decrease in SICI with cTBS at the early time point (SMD = 0.42, P = 0.00036). The results also highlight several factors contributing to TBS efficacy, including the number of pulses, frequency of stimulation and BDNF polymorphisms. Further research investigating optimal TBS stimulation parameters, particularly for iTBS, is needed in order for these paradigms to be successfully translated into clinical settings.     

Acute effects of lithium on excitability of human motor cortex

ObjectiveLithium has been widely used to treat bipolar affective disorder for over 60 years. Still, its acute effects in human cerebral cortex are poorly understood. This study aimed at investigating the acute effects of lithium on motor cortex excitability as measured by transcranial magnetic stimulation (TMS).MethodsTen healthy young adults participated in a double-blind placebo-controlled randomized crossover study with four sessions, where a single oral dose of lithium carbonate (450 mg, 900 mg, or 1350 mg) or placebo was tested. Focal TMS of the hand area of left motor cortex was used to test resting and active motor thresholds, motor evoked potential input–output curve (MEP IO-curve), slope of the MEP IO-curve and paired-pulse measures of intracortical inhibition and facilitation before, and two and four hours after drug administration.ResultsTwo hours post drug administration, 450 mg of lithium carbonate increased the slope of the MEP IO-curve while 1350 mg tended to decrease it. Lithium had no effect on motor thresholds, or intracortical inhibition or facilitation.ConclusionsThe acute effects of lithium on MEP IO-curve, a marker of corticospinal excitability, are consistent with an inverted U-shaped dose–response relationship.SignificanceFindings are important for our understanding of the therapeutic and toxic effects of lithium on the human central nervous system.     

Focal enhancement of motor cortex excitability during motor imagery: a transcranial magnetic stimulation study

OBJECTIVES: In order to learn more about the physiology of the motor cortex during motor imagery, we evaluated the changes in excitability of two different hand muscle representations in the primary motor cortex (M1) of both hemispheres during two imagery conditions. MATERIALS AND METHODS: We applied focal transcranial magnetic stimulation (TMS) over each M1, recording motor evoked potentials (MEPs) from the contralateral abductor pollicis brevis (APB) and first dorsal interosseus (FDI) muscles during rest, imagery of contralateral thumb abduction (C-APB), and imagery of ipsilateral thumb abduction (I-APB). We obtained measures of motor threshold (MT), MEP recruitment curve (MEP-rc) and F waves. RESULTS: Motor imagery compared with rest significantly decreased the MT and increased MEPs amplitude at stimulation intensities clearly above MT in condition C-APB, but not in condition I-APB. These effects were not significantly different between right and left hemisphere. MEPs simultaneously recorded from the FDI, which was not involved in the task, did not show facilitatory effects. There were no significant changes in F wave amplitude during motor imagery compared with rest. CONCLUSIONS: Imagery of unilateral simple movements is associated with increased excitability only of a highly specific representation in the contralateral M1 and does not differ between hemispheres.     

Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson's disease.

OBJECTIVE: To assess the effects of focal motor cortex stimulation on motor performance and cortical excitability in patients with Parkinson's disease (PD). METHODS: Repetitive transcranial magnetic stimulation (rTMS) was performed on the left motor cortical area corresponding to the right hand in 12 'off-drug' patients with PD. The effects of subthreshold rTMS applied at 0.5 Hz (600 pulses) or at 10 Hz (2000 pulses) using a 'real' or a 'sham' coil were compared to those obtained by a single dose of l-dopa. The assessment included a clinical evaluation by the Unified Parkinson's Disease Rating Scale and timed motor tasks, and a neurophysiological evaluation of cortical excitability by single- and paired-pulse TMS techniques. RESULTS: 'Real' rTMS at 10 or 0.5 Hz, but not 'sham' stimulation, improved motor performance. High-frequency rTMS decreased rigidity and bradykinesia in the upper limb contralateral to the stimulation, while low-frequency rTMS reduced upper limb rigidity bilaterally and improved walking. Concomitantly, 10 Hz rTMS increased intracortical facilitation, while 0.5 Hz rTMS restored intracortical inhibition. CONCLUSIONS: Low- and high-frequency rTMS of the primary motor cortex lead to significant but differential changes in patients with PD both on clinical and electrophysiological grounds. The effects on cortical excitability were opposite to previous observations made in healthy subjects, suggesting a reversed balance of cortical excitability in patients with PD compared to normals. However, the underlying mechanisms of these changes remain to determine, as well as the relationship with clinical presentation and response to l-dopa therapy. SIGNIFICANCE: The present study gives some clues to appraise the role of the primary motor cortex in PD. Clinical improvement induced by rTMS was too short-lasting to consider therapeutic application, but these results support the perspective of the primary motor cortex as a possible target for neuromodulation in PD.     

Repetitive transcranial magnetic stimulation of the dorsolateral prefrontal cortex and cortical excitability in patients with major depressive disorder

Repetitive transcranial magnetic stimulation (rTMS) of the dorsolateral prefrontal cortex is a relatively non-invasive technique with putative therapeutic effects in major depression. However, the exact neurophysiological basis of these effects needs further clarification. Therefore, we studied the impact of ten daily sessions of left, dorsolateral prefrontal rTMS on motor cortical excitability, as revealed by transcranial magnetic stimulation-elicited motor-evoked potentials in 30 patients. As compared to the non-responders, responders (33%) showed changes in parameters pointing towards a reduced cortical excitability. These results suggest that repetitive transcranial magnetic stimulation of the dorsolateral, prefrontal cortex may have inhibitory effects on motor cortical neuronal excitability in patients with major depressive disorder. Furthermore, measurement of motor cortical excitability may be a useful tool for investigating and monitoring inhibitory brain effects of antidepressant stimulation techniques like rTMS.     

Intracellularly studied excitability changes in coronal-pericruciate neurons following low frequency stimulation of the corticobulbar tract

Direct intracellular measurements of excitability changes to injected current were made in 116 cortical neurons of awake cats following antidromic or orthodromic activation by repetitive, 1–6 Hz stimulation of the pes pedunculi. The predominant effect seen in antidromically activated cells was a transient decrease in excitability and input resistance. The predominant effect seen in orthodromically (transsynaptically) activated cells was a transient increase in excitability and input resistance. In the absence of accompanying change in rates of spontaneous spike activity, the above results suggest that adaptations supporting the changes in excitability and resistance occur locally to these cells.     

Effect of afferent input on motor cortex excitability during stroke recovery

Objective

Afferent input is proposed to mediate its effect on motor functions by modulating the excitability of the motor cortex. We aimed to clarify – in a longitudinal study – how afferent input affects motor cortex excitability after stroke and how it is associated with recovery of hand function.

Methods

The motor cortex excitability was studied by measuring the reactivity of the motor cortex beta rhythm to somatosensory stimulation. We recorded the amplitude of the suppression and subsequent rebound of the beta oscillations during tactile finger stimulation with MEG in 23 first-ever stroke patients within one week and at 1 and 3 months after stroke, with concomitant evaluation of hand function.

Results

The strength of the beta rhythm rebound, suggested to reflect decreased motor cortex excitability, was weak in the affected hemisphere after stroke and it was subsequently increased during recovery. The rebound strength correlated with hand function tests in all recordings.

Conclusion

Motor cortex excitability is modulated by afferent input after stroke. The motor cortex excitability is increased in the AH acutely after stroke and decreases in parallel with recovery of hand function.

Significance

The results implicate the importance of parallel recovery of both sensory and motor systems in functional recovery after stroke.     

Age-related changes of motor evoked potentials in healthy humans: Non-invasive evaluation of central and peripheral motor tracts excitability and conductivity

A comparative analysis of the corticospinal tract nervous propagation and excitability threshold was carried out in young (25 subjects, age range 16-35 years) and in elderly (40 subjects, 51-86 years) populations of healthy volunteers. Motor evoked potentials (MEPs) were recorded from the hand and foot muscles following transcranial magnetic stimulation (TCS) during complete relaxation and active contraction of the target muscles. Threshold intensities corresponded to the stimulator's output eliciting liminal MEPs in about 50% of stimuli during relaxation. It was found that threshold values of magnetic TCS were significantly higher in the elderly (44 +/- 6.4% vs 39 +/- 3.5% for the hand; 66 +/- 10.1% vs 56 +/- 6.7% for the foot; P < 0.001) than in the young subjects. Moreover, this index progressively increased with age (P < 0.001), whilst the propagation time along the central motor tracts did not parallel such an age-related trend.     

Long-lasting potentiation of synaptic potentials in the motor cortex produced by stimulation of the sensory cortex in the cat: a basis of motor learning

A long-lasting increase in the efficiency of synaptic transmission in the central nervous system has been thought to be one of the bases of learning and memory. To explore the possibility that the motor cortex (area 4γ) itself is involved in motor learning, the existence of long-term potentiation (LTP) was examined by recording excitatory postsynaptic potentials (EPSPs) from motor cortical neurons. Short tetanic intracortical microstimulation (ICMS) of the somatic sensory cortex produced a marked potentiation of the EPSPs in a small group of motor cortical neurons. The results raised the possibility that the input from the sensory cortex participates in motor learning and retention of the learned motor skills.     

Modulation of excitability in human primary somatosensory and motor cortex by paired associative stimulation targeting the primary somatosensory cortex

Input from primary somatosensory cortex (S1) to primary motor cortex (M1) is important for high-level motor performance, motor skill learning and motor recovery after brain lesion. This study tested the effects of manipulating S1 excitability with paired associative transcranial stimulation (S1-PAS) on M1 excitability. Given the important role of S1 in sensorimotor integration, we hypothesized that changes in S1 excitability would be directly paralleled by changes in M1 excitability. We applied two established protocols (S1-PAS(LTP) and S1-PAS(LTD) ) to the left S1 to induce long-term potentiation (LTP)-like or long-term depression (LTD)-like plasticity. S1 excitability was assessed by the early cortical components (N20-P25) of the median nerve somatosensory-evoked potential. M1 excitability was assessed by motor-evoked potential amplitude and short-interval intracortical inhibition. Effects of S1-PAS(LTP) were compared with those of a PAS(LTP) protocol targeting the left M1 (M1-PAS(LTP) ). S1-PAS(LTP) and S1-PAS(LTD) did not result in significant modifications of S1 or M1 excitability at the group level due to substantial interindividual variability. The individual S1-PAS-induced changes in S1 and M1 excitability showed no correlation. Furthermore, the individual changes in S1 and M1 excitability induced by S1-PAS(LTP) did not correlate with changes in M1 excitability induced by M1-PAS(LTP) . This demonstrates that the effects of S1-PAS in S1 are variable across individuals and, within a given individual, unrelated to those induced by S1-PAS or M1-PAS in M1. Potentially, this extends the opportunities of therapeutic PAS applications because M1-PAS 'non-responders' may well respond to S1-PAS.     

The relationship between motor cortex excitability and severity of Alzheimer's disease: a transcranial magnetic stimulation study

Introduction

In Alzheimer's disease (AD), transcranial magnetic stimulation (TMS) studies have been limited to test motor cortical excitability. The aim of this study was to investigate the inhibitory circuits of the motor cortex and to relate these to measures of cognitive function in AD patients. Results were compared with those of a control group of healthy subjects matched for age, sex and education.

Patients and methods

Forty-five AD patients and 37 healthy volunteers were included in the study. Each participant received a neurological evaluation, Mini-Mental State Examination (MMSE), and Clinical Dementia Rating (CDR). Neurophysiological evaluations included resting and active motor threshold (rMT and aMT), motor evoked potential (MEP), cortical silent period (CSP), and transcallosal inhibition (TI).

Results

AD patients showed significantly reduced rMT, aMT and shorter MEP onset latency; in addition there was a prolongation of both CSP and TI. There was a significant positive correlation between the MMSE and CDR, on the one hand, and aMT and rMT, on the other hand, whereas the correlation was negative with CSP and TI durations.

Conclusion

AD is associated with hyperexcitability of the motor cortex, which supports the hypothesis that changes in GABAb and glutamate function are important factors in cognitive impairment.     

The effects of peripheral deafferentation on spontaneously bursting neurons in the somatosensory cortex of waking cats

Single neurons (n=356) were studied in the forelimb representation of awake, quietly resting cats. Thirty-five spontaneously bursting neurons in a sample of 206 cells recorded before forelimb deafferentation were compared to 39 spontaneously bursting neurons in a sample of 127 neurons studied 1–3 weeks after deafferentation. The probability of encountering bursting neurons increased significantly following deafferentation from 17% to 31% of the sample (P<0.005). The same 5 classes of bursting cells were observed after deafferentation but there were significant changes in the duration of interspike intervals in some classes, in the probability of observing certain classes, and in the proportion of spikes found in bursts. The probability of encountering class III cells, a class thought to consist primarily of non-inactivating pyramidal burst neurons, nearly doubled and the average interspike interval length within the burst increased from 1.9 to 3.0 ms. The burst structure in the other classes did not change but they were found less frequently. These other classes may include inhibitory interneurons which receive less excitatory drive after deafferentation and therefore provide less inhibition to class III cells. The differential behavior of the different classes of bursting cells may be one reason why the overall level of spontaneous activity does not change after deafferentation and it suggests that there are homeostatic mechanisms in primary somatosensory cortex that maintain a certain level of neural activity.     

Kinesthetic motor imagery and spinal excitability: The effect of contraction intensity and spatial localization

OBJECTIVE: Data on whether motor imagery (MI) modulates spinal excitability are equivocal. The purpose of this study was to determine if imagined muscle contractions of the left plantar flexor (PF) alter spinal excitability, and if so, to determine whether this alteration is intensity dependent and/or localized to the target muscles. Our research questions required two experiments. METHODS: In experiment 1, 16 healthy volunteers performed imagined muscle contractions using a kinesthetic approach with their left PF at 25% and 100% of imagined effort (IE). The soleus H-reflex was evoked during three conditions, which were separated by about 15s: rest (preceding MI), during MI, and recovery (following the cessation of MI). In experiment 2, a subset of subjects from experiment 1 performed MI with their left PF at 100% of IE, while either the soleus or flexor carpi radialis (FCR) H-reflex was measured. RESULTS: In experiment 1, we observed a facilitation of soleus H-wave amplitude during MI compared to the rest and recovery conditions (p<0.05). Furthermore, the soleus H-wave amplitude was greater during 100% than 25% of IE (p<0.05). In experiment 2, soleus and FCR H-wave amplitude increased during imagined muscle contractions of the left PF (p<0.05). These changes were independent of voluntary muscle activity. CONCLUSIONS: These findings suggest MI can increase spinal excitability by the intensity of imagined effort, but this effect is not fully localized to the task specific muscle. SIGNIFICANCE: These data provide evidence that MI can increase spinal excitability in healthy subjects, which suggests future studies are warranted to examine the clinical relevance of this effect. These studies are needed to help establish a therapeutic theory by which to advance motor function rehabilitation using MI.     

Maturation of inhibitory and excitatory motor cortex pathways in children

Objective

To study intracortical inhibition and facilitation with paired-pulse transcranial magnetic stimulation in children, adolescents and adults. Methods: Paired-pulse transcranial magnetic stimulation (interstimulus intervals (ISI): 1, 3, 5, 10 and 20 ms) was applied over the primary motor cortex (M1) in 30 healthy subjects (range 6–30 years, median age 15 years and 8 months, SD 7,9) divided in three groups: adults (? 18 years), adolescents (> 10 and < 18 years) and children (? 10 years). Results: We observed significantly less intracortical inhibition (SICI) in children’s M1 compared to that of adults. Adolescents showed significantly less SICI at the 5 ms interval than did adults. No significant differences were apparent in intracortical facilitation (ICF). Conclusion: We postulate that, as in adults, the maturing M1 possesses horizontal glutamatergic cross-links that represent the neuronal substrate of excitatory intracortical pathways. GABAergic interneurons, the neuronal substrate of inhibitory intracortical pathways, mature between childhood and adulthood. Reduced GABAergic inhibition may facilitate neuronal plasticity and motor learning in children.