Transcranial Magnetic Stimulation Of M1 Research Articles

Insight into motor fatigue mechanisms in natalizumab treated multiple sclerosis patients with wearing off

Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence (‘wearing-off’) before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab’s effect on MS-related fatigue. Forty-five relapsing–remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.

Dissecting the neural underpinnings of the short-latency response to transcranial magnetic stimulation of motor cortex: A computational modeling study

Abstract Objective: Transcranial magnetic stimulation (TMS) over the primary motor cortex (M1) elicits a series of high frequency volleys termed D- and I-waves measured epidurally in the corticospinal tract of awake humans. The D-wave is thought to be caused by direct activation of corticospinal axons, while I-waves are believed to be generated by trans-synaptic activation of corticospinal axons. The cortical circuits and mechanisms involved in the generation of I-waves by TMS of M1 remain unclear. Methods: We implemented a computational model of a cortical column with biophysically-based cortical neurons, following an existing model (Traub 2005). The TMS induced E-field was modeled as intracellular current injections of monophasic TMS pulses into the axon terminals of pyramidal neurons (PN). We constructed dose–response curves of spiking activity averaged across layer 5 (L5) PN as a function of the proportion of activated PN. Results: Model-based responses were compared to I-waves recorded from L5 PN in rodent M1 during TMS (Li 2017), and the network model reproduced I-waves only during the activation of axon terminals of L5 PN in contrast to activation of axon terminals of L2/3 or L6 PN. Inhibitory interneurons in deep layers fired in synchrony during the late phases of I-waves offering a potential explanation for the reduction in magnitude of late I-waves seen in experimental studies after administration of GABA-A agonists. Virtual lesioning of model neurons revealed that recurrent synaptic connections between L5 PN mediated by AMPA receptors play a prominent role in the generation of I-waves. Conclusions: Activation of presynaptic terminal of L5 PN is necessary to generate an I-wave response to TMS. Further, recurrent excitatory synaptic connections between L5 PN play a prominent role in the generation of I-wave response. Significance: Gaining a better understanding of circuit mechanisms of TMS of the M1 could enable optimization of stimulation paradigms. Keywords: Transcranial magnetic stimulation, I-waves, Cortical column model, Motor cortex

The spectral features of EEG responses to transcranial magnetic stimulation of the primary motor cortex depend on the amplitude of the motor evoked potentials.

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can excite both cortico-cortical and cortico-spinal axons resulting in TMS-evoked potentials (TEPs) and motor-evoked potentials (MEPs), respectively. Despite this remarkable difference with other cortical areas, the influence of motor output and its amplitude on TEPs is largely unknown. Here we studied TEPs resulting from M1 stimulation and assessed whether their waveform and spectral features depend on the MEP amplitude. To this aim, we performed two separate experiments. In experiment 1, single-pulse TMS was applied at the same supra-threshold intensity on primary motor, prefrontal, premotor and parietal cortices and the corresponding TEPs were compared by means of local mean field power and time-frequency spectral analysis. In experiment 2 we stimulated M1 at resting motor threshold in order to elicit MEPs characterized by a wide range of amplitudes. TEPs computed from high-MEP and low-MEP trials were then compared using the same methods applied in experiment 1. In line with previous studies, TMS of M1 produced larger TEPs compared to other cortical stimulations. Notably, we found that only TEPs produced by M1 stimulation were accompanied by a late event-related desynchronization (ERD—peaking at ~300 ms after TMS), whose magnitude was strongly dependent on the amplitude of MEPs. Overall, these results suggest that M1 produces peculiar responses to TMS possibly reflecting specific anatomo-functional properties, such as the re-entry of proprioceptive feedback associated with target muscle activation.

P150 Exploiting I-wave rhythmicity to optimize the stimulus-response relationship for TMS of M1

Background Repetitive Transcranial Magnetic Stimulation (TMS) of the primary motor cortex (M1) can modulate corticospinal excitability beyond the time of stimulation, but the after-effects are subject to substantial variability. One determining factor are inter-individual differences in the way TMS stimulates the intracortical circuits that generate the descending volleys (I-waves) in the corticospinal tract. Objective We systematically studied possibilities to utilize individual I-wave rhythmicity to enhance the efficacy of low-intensity TMS of M1 to excite corticospinal output. Methods In healthy individuals, we recorded the motor evoked potential (MEP) evoked by paired, triple and quadruple pulse TMS. The inter-pulse interval (IPI) was adjusted to the individual I1-peak latency or the trough between the I1- and I2-wave. TMS used biphasic pulses with the second phase inducing a posterior-to-anterior current in M1. Results Paired, triple and quadruple pulse TMS at individual I-wave peak latency evoked larger MEP amplitudes than single-pulse TMS or paired, triple and quadruple pulse TMS at the I1-I2 trough. I1-peak latency facilitation was already visible at 70% resting motor threshold and was comparable for paired, triple and quadruple pulse TMS. A control experiment showed significant I1-peak latency facilitation also relative to a control condition in which IPI was shorter than individual I1-latency. Conclusion Our preliminary study results support our hypothesis that I-wave interaction can be utilized to optimize the efficacy of TMS over M1 to excite the corticospinal output neurons. The effects are already maximal when using paired-pulse TMS, as triple pulse or quadruple-pulse TMS did not result in additional MEP facilitation. The use of individually adjusted paired-pulse TMS at I-wave latency might help to reduce inter-individual variability of repetitive TMS over human M1. This work was supported by the Lundbeck Foundation (Grant of Excellence “ContAct” R59 A5399) and the Novo Nordisk Foundation (Interdisciplinary Synergy Programme Grant ”BASICS” NNF14OC0011413).

Influence of paravertebral muscles training on brain plasticity and postural control in chronic low back pain

Background and purposeIsometric activation (ISOM) of deep multifidi muscles (MF) can influence postural adjustments and primary motor cortex (M1) function in chronic low back pain (CLBP). In order to better understand how ISOM impacts on CLBP condition, the present study contrasted ISOM after-effects on M1 function, MF postural activation and pain with another training, the global activation of paravertebral muscles (GLOB, hip extension). The main objective of this study was to compare the effects of ISOM and GLOB (3-week training each) on MF postural activation and M1 function in a CLBP population. MethodsTwenty-four people with CLBP were randomly allocated to ISOM and GLOB groups for a 3-week daily practice. Pre/post-training after-effects were assessed by the onset of superficial MF (MF-S) activation during ballistic limb movements (bilateral shoulder flexion in standing; unilateral hip extension in prine lying), MF-S corticomotor control tested by transcranial magnetic stimulation of M1, and assessment of pain, kinesiophobia and disability by standardized questionnaires. ResultsBoth ISOM and GLOB improved pain and disability. However, only ISOM influenced M1 function (decreased corticospinal excitability and increased intracortical inhibition), fastened MF-S postural activation and decreased kinesiophobia. ConclusionsChanges of corticospinal excitability and of MF-S postural adjustments suggest that ISOM better influenced brain plasticity. Future studies should further test whether our novel findings relate to an influence of the exercises on the lumbopelvic control of different muscles and on cognitive function. Clinically, individual's evaluation remains warranted before prescribing one or the other of these two conventional exercises for reducing pain. ImplicationsThis original study presents how motor control exercises can influence brain plasticity and postural control in chronic low back pain. This knowledge will impact on the decision of clinicians to prescribe specific exercises with a view of improving motor control in this musculoskeletal condition.

Altered function of intracortical networks in chronic lateral epicondylalgia.

Lateral epicondylalgia (LE) is a musculotendinous condition characterized by persistent pain, sensorimotor dysfunction and motor cortex reorganization. Although there is evidence linking cortical reorganization with clinical symptoms in LE, the mechanisms underpinning these changes are unknown. Here we investigated activity in motor cortical (M1) intracortical inhibitory and facilitatory networks in individuals with chronic LE and healthy controls. Surface electromyography was recorded bilaterally from the extensor carpi radialis brevis (ECRB) muscle of 14 LE (4 men, 41.5±9.9years) and 14 control participants (4 men, 42.1±11.1years). Transcranial magnetic stimulation of M1 was used to evaluate resting and active motor threshold, corticomotor output, short- (SICI) and long-latency intracortical inhibition (LICI) and intracortical facilitation (ICF) of both hemispheres. In individuals with LE, SICI (p=0.005), ICF (p=0.026) and LICI (p=0.046) were less in the M1 contralateral to the affected ECRB muscle compared with healthy controls. Motor cortical threshold (rest: p=0.57, active: p=0.97) and corticomotor output (p=0.15) were similar between groups. No differences were observed between individuals with LE and healthy controls for the M1 contralateral to the unaffected ECRB muscle. These data provide evidence of less intracortical inhibition mediated by both GABAA and GABAB receptors, and less intracortical facilitation in the M1 contralateral to the affected ECRB in individuals with LE compared with healthy controls. Similar changes were not present in the M1 contralateral to the unaffected ECRB. These changes may provide the substrate for M1 reorganization in chronic LE and could provide a target for future therapy. Lateral epicondylalgia (LE) is a common musculoskeletal condition characterized by elbow pain and sensorimotor dysfunction. The excitability and organization of the motor cortical representation of the wrist extensor muscles is altered in LE, but the mechanisms that underpin these changes are unknown. evidence of less intracortical inhibition mediated by both GABAA and GABAB receptors, and less intracortical facilitation mediated by NMDA receptors, in the M1 contralateral to the affected extensor carpi radialis brevis muscle in chronic LE compared with healthy controls. Altered activity in intracortical networks may contribute to altered motor cortex organization in LE and could provide a potential target for future treatments.

What Makes the Muscle Twitch: Motor System Connectivity and TMS-Induced Activity

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) evokes several volleys of corticospinal activity. While the earliest wave (D-wave) originates from axonal activation of cortico-spinal neurons (CSN), later waves (I-waves) result from activation of mono- and polysynaptic inputs to CSNs. Different coil orientations preferentially stimulate cortical elements evoking different outputs: latero-medial-induced current (LM) elicits D-waves and short-latency electromyographic responses (MEPs); posterior-anterior current (PA) evokes early I-waves. Anterior-posterior current (AP) is more variable and tends to recruit later I-waves, featuring longer onset latencies compared with PA-TMS. We tested whether the variability in response to AP-TMS was related to functional connectivity of the stimulated M1 in 20 right-handed healthy subjects who underwent functional magnetic resonance imaging while performing an isometric contraction task. The MEP-latency after AP-TMS (relative to LM-TMS) was strongly correlated with functional connectivity between the stimulated M1 and a network involving cortical premotor areas. This indicates that stronger premotor-M1 connectivity increases the probability that AP-TMS recruits shorter latency input to CSNs. In conclusion, our data strongly support the hypothesis that TMS of M1 activates distinct neuronal pathways depending on the orientation of the stimulation coil. Particularly, AP currents seem to recruit short latency cortico-cortical projections from premotor areas.

Functional Topography of Cortical Thumb Movement Representations in Human Primary Motor Cortex

Intracortical microstimulation and single cell recordings in non-human primates showed that both, muscles and movements are represented in primary motor cortex (M1). This was also suggested in humans using electrophysiological and neuroimaging techniques. Transcranial magnetic stimulation (TMS) thus far was used to study motor cortical muscle representations, but data on movement representations in man are scarce. Therefore, we used TMS of M1 to evoke directional (flexion, extension) thumb movements and generated topographic movement maps (TMS-mov-map) in fourteen healthy individuals. TMS-mov-maps were related to the individual voluntary motor output (Vol-mov, directional thumb acceleration). Conventional TMS-motor evoked potentials (TMS-MEP) were simultaneously recorded from the prime movers (flexor and extensor pollicis brevis) and also compared to the voluntary motor output. Remarkably stable topographic maps were generated with both, thumb flexion and extension being multiply represented, overlapped and interspersed. Thumb Flexion was usually more robust than extension. TMS-mov-maps rather than TMS-MEP-maps seemed to better reflect the individual voluntary motor output. The findings emphasize existing models of multiple, overlapping finger movement representations in human M1, and indicate that this model also adapts to antagonistic thumb movements. The results suggest that investigating topographic movement maps may be an interesting adjunct in studying human motor cortical topography and its relevance for motor control.

Changes in corticospinal excitability during reach adaptation in force fields

Both abrupt and gradually imposed perturbations produce adaptive changes in motor output, but the neural basis of adaptation may be distinct. Here, we measured the state of the primary motor cortex (M1) and the corticospinal network during adaptation by measuring motor-evoked potentials (MEPs) before reach onset using transcranial magnetic stimulation of M1. Subjects reached in a force field in a schedule in which the field was introduced either abruptly or gradually over many trials. In both groups, by end of the training, muscles that countered the perturbation in a given direction increased their activity during the reach (labeled as the on direction for each muscle). In the abrupt group, in the period before the reach toward the on direction, MEPs in these muscles also increased, suggesting a direction-specific increase in the excitability of the corticospinal network. However, in the gradual group, these MEP changes were missing. After training, there was a period of washout. The MEPs did not return to baseline. Rather, in the abrupt group, off direction MEPs increased to match on direction MEPs. Therefore, we observed changes in corticospinal excitability in the abrupt but not gradual condition. Abrupt training includes the repetition of motor commands, and repetition may be the key factor that produces this plasticity. Furthermore, washout did not return MEPs to baseline, suggesting that washout engaged a new network that masked but did not erase the effects of previous adaptation. Abrupt but not gradual training appears to induce changes in M1 and/or corticospinal networks.

Corticomotor control of deep abdominal muscles in chronic low back pain and anticipatory postural adjustments

Contralateral transversus abdominis muscle (cTrA) is known to be anticipatory to rapid focal movement. The activation of ipsilateral TrA (iTrA) follows cTrA, but their anticipatory interaction in healthy subjects seems to be delayed in low back pain (LBP) patients. TrA delay in LBP is linked with reorganization of the primary motor cortex (M1), thus supporting that cortical changes underlie the altered postural control. Our study tested whether differences in postural adjustments were present in LBP for TrA onsets and co-activation, and whether these differences were paralleled by cortical motor changes. Thirteen chronic LBP patients and 9 healthy Controls were enrolled. Surface recordings of cTrA/internal oblique (IO) and iTrA/IO were collected during a rapid shoulder flexion task while standing. Transcranial magnetic stimulation of M1 tested TrA/IO corticospinal excitability, active motor threshold and short-interval intracortical inhibition (SICI). In LBP compared to Controls, iTrA/IO activation was delayed, co-activation was absent, timing between TrA/IO onsets was impaired, and SICI was missing. Between-outcomes correlations observed in one group were not significant in the other. Delay of iTrA/IO and the lacking co-activation were not explained by between-group differences of transcranial magnetic stimulation outcomes. TrA/IO co-activation is present during rapid focal movement in healthy subjects only. LBP patients displayed an important alteration of the control of spine stability that can be explained by altered mechanisms of M1 motor programming.

Cerebellar Stimulation in Ataxia

The cerebellum plays an important role in movement execution and motor control by modulation of the primary motor cortex (M1) through cerebello-thalamo-cortical connections. Transcranial magnetic stimulation (TMS) allows direct investigations of neural networks by stimulating neural structures in humans noninvasively. The motor evoked potential to single-pulse TMS of M1 is used to measure the motor cortical excitability. A conditioning stimulus over the cerebellum preceding a test stimulus of the contralateral M1 enables us to study the cerebellar regulatory functions on M1. In this brief review, we describe this cerebellar stimulation method and its usefulness as a diagnostic tool in clinical neurophysiology.

Contributions of the Motor Cortex to Adaptive Control of Reaching Depend on the Perturbation Schedule

During adaptation, motor commands tend to repeat as performance plateaus. It has been hypothesized that this repetition produces plasticity in the motor cortex (M1). Here, we considered a force field reaching paradigm, varied the perturbation schedule to potentially alter the amount of repetition, and quantified the interaction between disruption of M1 using transcranial magnetic stimulation (TMS) and the schedule of perturbations. In the abrupt condition (introduction of the perturbation on a single trial followed by constant perturbation), motor output adapted rapidly and was then followed by significant repetition as performance plateaued. TMS of M1 had no effect on the rapid adaptation phase but reduced adaptation at the plateau. In the intermediate condition (introduction of the perturbation over 45 trials), disruption of M1 had no effect on the phase in which motor output changed but again impaired adaptation when performance had plateaued. Finally, when the perturbation was imposed gradually (over 240 trials), the motor commands continuously changed during adaptation and never repeated, and disruption of M1 had no effect on performance. Therefore, TMS of M1 appeared to reduce adaptation of motor commands during a specific phase of learning: when motor commands tended to repeat.

Reward‐related activity in the human motor cortex

The human primary motor cortex (M1) participates in motor learning and response selection, functions that rely on feedback on the success of behavior (i.e. reward). To investigate the possibility that behavioral contingencies alter M1 activity in humans, we tested intracortical inhibition with single and paired (subthreshold/suprathreshold) transcranial magnetic stimulation during a slot machine simulation that delivered variable money rewards for three-way matches and required no movement. A two-way match before the third barrel had stopped (increased reward expectation) was associated with more paired-pulse inhibition than no match. Receiving a large reward on the preceding trial augmented this effect. A control task that manipulated attention to the same stimuli produced no changes in excitability. The origin of this reward-related activity is not clear, although dopaminergic ventral tegmental area neurons project to M1, where they are thought to inhibit output neurons and could be the source of the finding. Transcranial magnetic stimulation of M1 may be useful as a quantitative measure of reward-related activity.

Modulation of excitability of human motor cortex (M1) by 1 Hz transcranial magnetic stimulation of the contralateral M1.

Previous studies demonstrated that single-pulse transcranial magnetic stimulation (TMS) of one motor cortex (M1) exerts a brief inhibitory effect on the contralateral M1. The purpose of this study was to test the hypothesis that 30min of 1Hz TMS of M1 will result in a lasting increase in excitability in the contralateral M1. Healthy volunteers were tested on 2 separate days, before (baseline) and after one of two interventions: (a) stimulation of M1 with 1Hz TMS for 30min at 115% of resting motor threshold, and (b) sham stimulation. Recruitment curves to TMS, pinch force, and simple reaction time were assessed in the hand contralateral to the unstimulated motor cortex. The main finding of this study was that 30min of 1Hz significantly increased recruitment curves in the contralateral motor cortex in the real stimulation condition relative to sham (P<0.005, factorial analysis of variance (ANOVA)). This change outlasted the stimulation period for at least 15min and occurred in the absence of changes in pinch force or reaction time. These results raise the potential for inducing lasting modulation of excitability in M1 by 1Hz TMS of the other M1, a phenomenon possibly reflecting modulation of interhemispheric interactions. It is conceivable that 1Hz TMS applied to M1 may be used to modulate excitability in the opposite motor cortex for therapeutic purposes.

Role of the human motor cortex in rapid motor learning

Recent studies suggest that the human primary motor cortex (M1) is involved in motor learning, but the nature of that involvement is not clear. Here, learning-related changes in M1 excitability were studied with transcranial magnetic stimulation (TMS) while na subjects practiced either a ballistic or a ramp pinch task to the 0.5-Hz beat of a metronome. Subjects rapidly learned to optimize ballistic contractions as indicated by a significant increase in peak pinch acceleration and peak force after the 60-min practice epoch. The increase in force and acceleration was associated with an increase in motor evoked potential (MEP) amplitude in a muscle involved in the training (flexor policis brevis) but not in a muscle unrelated to the task (abductor digiti minimi). MEPs returned to their baseline amplitude after subjects had acquired the new skill, whereas no practice-induced changes in MEP amplitude were observed after subjects had overlearned the task, or after practicing slow ramp pinches. Since the changes in MEP amplitude were observed only after TMS of M1 but not after direct stimulation of the corticospinal tract, these findings indicate task- and effector-specific involvement of human M1 in rapid motor learning.