M1 Excitability Research Articles

P 229. Transcranial Laser Stimulation-A New Method for Non-Invasive Modulation of Cortical Excitability

Near infrared low-level laser (nirLLL) irradiation penetrates scalp and skull. It was shown to be able to reduce damage from experimentally induced stroke in animals and to improve memory in middle-aged mice. It was also reported to improve the outcome in human cases of acute stroke. In this study we evaluated whether transcranial application of the nirLLL (transcranial laser stimulation-TLS) can modulate the excitability of the motor cortex (M1) as measured by transcranial magnetic stimulation (TMS). In the 1st part of the study, motor evoked potentials (MEPs) from the right abductor pollicis brevis (APB) muscle, elicited by single-pulse TMS applied to the left M1 (intensity 120% of the resting motor threshold, rMT) were measured at baseline and every 5 min (up to 30 min) after the TLS, in 18 healthy subjects. For TLS, the nirLLL (wavelength 905 nm, pulse frequency 3 kHz, power density of 50 mW/cm 2 , single dose of 3 J/cm 2 ) was applied for 60 s over a circular area 3 cm in diameter cantered at left M1 APB hot-spot. In the 2 nd part of the study, the MEPs were recorded in the same way in 6 subjects who were found to have very high rMT and poor response to TLS in the Exp1. The TLS parameters were the same except pulse frequency that was increased to 5 kHz which increased total nirLLL delivered (single dose of 4.5 J/cm 2 ). All applied dosed were within the recommended safety limits for human application of nirLLL in physical medicine. The study was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee. In the 1st part, the most prominent MEP suppression was within time-window 10–25 min following TLS ( Fig. 1 A). Total of 12 subjects (66.7%) had MEP sizes below baseline level in at least 4 out of 7 (i.e. >50%) post-TLS time points-Responders. ANOVA and post hoc pair-wise analyses showed significant reduction of post-TLS MEP sizes related to baseline in Responders ( Fig. 1 B). The only difference between Responders and Non-Responders was in rMT (54.9 ± 5.8, and 63.2 ± 8.7, respectively; t (16) = 2.41, p = 0.029). For all subjects together, average post-TLS MEP size correlated significantly with rMT (Spearman R = 0.499, p = 0.035). In the 2nd part, with higher intensity of TLS, 5 subjects were Responders, 4 of them who were Non-Responders in the 1st part, and 1 who was Responder from the beginning but had much larger MEP suppression in the 2nd part. Average post-TLS MEP sizes in these 5 Responders dropped significantly(t (4) = 5.105, p = 007) in comparison to the 1st part. The M1 excitability was found to be reduced after TLS in dose dependent manner. These findings may give insight into the mechanisms of nirLLL effects in the human cerebral cortex, also suggesting more suitable applications of TLS in clinical settings.

P 43. Functional connectivity between the dorsolateral prefrontal cortex and the ipsilateral primary motor cortex

The prefrontal cortex has a crucial role in higher cognitive functions and various line of evidence point to a tight connectivity network between the dorsolateral prefrontal cortex (DFLPC, BA46) and the ipsilateral primary motor cortex (M1). The main objective of this study was to determine the precise timing and the spatial specificity of this functional connectivity during the performance of a choice-reaction task. Twin coil, neuronavigated transcranial magnetic stimulation (TMS) was used during the performance of a choice-reaction task. By varying the time of stimulation (ISI 6, 8, 12 ms) after a cue (stimulus-onset asynchronies 75, 100, 125 ms) which signalled either a free selection or specified finger movement, the interactions between BA46 and M1 could be investigated. Furthermore, we tested whether the influence of a BA46 stimulation is specific to muscles involved in the task or not by investigating task involved and not-involved muscles. Our results indicate that in unselected muscles during trials with externally specified responses, stimulation of BA46 increases excitability of M1 at a SOA of 75 ms. In freely selected trials, stimulation of BA46 at a SOA of 100 ms facilitates M1 excitability. Our data suggested that the main effects occured at a ISI of 12 ms pointing to an indirect connectivity. In selected muscles this differences disappeared and the M1 output to these muscles was influenced by whether or not the muscle was selected or not. No effects could be observed when BA9 was stimulated. The present results suggest that there is anatomically specific functional connectivity between left BA46 and left M1 during free and specified selection of a movement. This is the first study allowing to draw conclusions about the precise timing of this important functional connectivity.

P 88. Unilateral and bilateral tDCS of the human motor cortex does not differentially modulate motor function in healthy adults

Introduction Transcranial direct current stimulation (tDCS) is a non-invasive technique that modulates the excitability of neurons within the primary motor cortex (M1). Neuronal excitability is modified by the application of direct currents in a polarity specific manner, with anodal-tDCS increasing excitability and cathodal decreasing excitability. Recently it has been shown that bilateral tDCS significantly modulates cortical excitability when compared to unilateral anodal stimulation. However, the effects of different tDCS montages on modulating motor performance are unclear. Further, it remains unclear if changes in motor performance following tDCS outlast the period of stimulation. Objective To determine whether unilateral or bilateral tDCS differentially modulates motor performance of the non-dominant hand in healthy participants. A secondary objective was to further elucidate the mechanisms underlying any potential aftereffects on motor performance following unilateral and bilateral tDCS. Methods Using a randomized, counter-balanced, cross-over design, with a one-week wash-out period, 9 participants (5 female and 4 male, age range 22–45 years) were exposed to 13 min of sham, unilateral or bilateral tDCS applied at 1.0 mA. In all tDCS conditions, the anode was placed over the “hot spot” of the non-dominant extensor carpi radialis longus muscle (ECRL) as determined by transcranial magnetic stimulation (TMS). The applied current was induced by a saline-soaked pair of surface sponge electrodes (25 cm2) delivered by a NeuroConn DC stimulator. TMS was used to measure M1 excitability and short-interval intracortical inhibition (SICI) of the non-dominant contralateral ECRL at baseline, immediately post, 30 and at 60 min following cessation of tDCS. We evaluated motor function at each of these time points in all conditions by having participants complete a Purdue peg board test. Results Both unilateral and bilateral tDCS facilitated motor performance immediately following tDCS (7 & 4% respectively), 30 min (13 & 6%) and 60 min post (21 & 9%)(all p Conclusion Our findings show that both unilateral and bilateral tDCS modulated motor performance for up to 60 min following the removal of tDCS, but the different types of tDCS electrode montages did not differentially modulate motor task performance of the non-dominant hand or indices of cortical plasticity. We have also shown that tDCS (unilateral and bilateral) modulates both cortical excitability and inhibition that outlasts the period of stimulation. Together, these results indicate that tDCS induces behavioral changes in the non-dominant hand as a consequence of mechanisms associated with long-term potentiation.

P 147. Impaired modulation of intracortical inhibition during Go–Stop task in schizophrenia

Background Impaired inhibition has been reported in patients with schizophrenia in a variety of cognitive and motor tasks. Recent transcranial magnetic stimulation studies performed during rest show reduced cortical inhibition in primary motor cortex (M1) at rest in schizophrenia patients, supporting the hypothesis of impaired GABA-ergic inhibition as an underlying mechanism. However, cortical excitability and intracortical inhibition in M1 are highly task-dependent, for example, inhibiting a planned motor response leads to reduced excitability and enhanced intracortical inhibition. Studies on task-dependent cortical excitability and inhibition are lacking in schizophrenia. The aim of this study was therefore to investigate cortical excitability and intracortical inhibition during voluntary motor inhibition in patients with schizophrenia. Methods 25 stabilized patients with schizophrenia (DSMIV) and a group of 23 age-comparable healthy volunteers were included. We used a modified version of the Go–Stop task to study voluntary motor inhibition. This task consisted of moving the index finger in response to Go and Stop signals. In 30% of trials the subject received a visual cue to inhibit the prepared finger lift. Paired-pulse transcranial magnetic stimulation (TMS) was used to measure M1 excitability and short-latency intracortical inhibition (SICI%) during three phases of the task: (i) early without movement preparation (Early); (ii) late with preparation of finger lift (Late prep ); and (iii) late with inhibition of finger lift (Late inhib ). Motor evoked potentials (MEPs) were recorded from the first dorsal interosseous muscle. Results Patients and control subjects performed equally on the voluntary inhibition task, with similar stop signal reaction times (mean SSRT controls 189 ± 21 ms and patients 186 ± 31 ms, P = 0.6). TMS at rest revealed similar resting and active motor thresholds in patients and controls (P > 0.9). The cortical silent period was shorter in the patients but did not differ significantly (mean controls 162 ± 30 ms and patients 147 ± 61 ms, P = 0.36). During the Go–Stop task, cortical excitability was similar in patients and controls with a task-dependent modulation of MEPs (mean RMS MEPs: Early = 477 μV, Late prep = 854 μV, and Late inhib = 531 μV; effect of Phase, P F = 4.5, P = 0.02) with posthoc comparisons revealing a significant reduction in the Late inhib phase in patients compared to controls ( P = 0.02). In patients the SICI% during Late inhib correlated negatively with SSRT ( R = − 0.72, P inhib had longer SSRT. Conclusions To our knowledge this is the first study on task-dependent modulation of cortical excitability and intracortical inhibition in patients with schizophrenia. We show that patients with schizophrenia have reduced SICI during voluntary inhibition of a prepared finger lift. Surprisingly, there were no differences found in task performance or in MEP amplitudes during the task. These findings show that schizophrenia patients are capable of inhibiting motor tasks despite having reduced intracortical inhibition. This suggests the use of compensatory mechanisms in voluntary motor inhibition in stabilized schizophrenia patients.

IS 7. News about short interval intracortical inhibition (SICI)

Conditioned transcranial magnetic stimulation (TMS) techniques have been proposed to reflex many intracortical inhibition or facilitation mechanisms of the primary motor cotex (M1). Conditioning stimuli (CS) at intensity below threshold over M1 suppressed MEP to test stimuli given through the same coil at interstimulus intervals (ISIs) of 1–5 ms (Kujirai methods). The inhibition is called as short interval intracortical inhibition (SICI) and has been considered as one of basic tool to evaluate cortical excitability changes. 1. Physiological features of SICI: SICI was reported to be a cortical inhibition, because neither H-waves nor MEPs to transcranial electrical stimulation were affected. Only later I-waves, probably induced though several synapses in M1, are suppressed by CS, but I1-waves are not. Pharmacological studies showed that GABAA mediated mechanisms could contribute to SICI. The GABAergic inhibition, however, lasts longer than 5 ms even though SICI lasts 5 ms. The GABAergic inhibition may not explain SICI at all 1–5 ms intervals. Inhibition at 1 ms interval mainly reflects the refractory period. Those at 2–5 ms intervals may be produced mainly by GABAergic inhibition. Another point to mind is the mask of inhibition by some facilitation mechanisms. The intracortical facilitation overlaps GABAergic inhibition at later intervals, which must mask the longer part of inhibition. Even at short intervals, short intervals intracortical facilitation (SICF) overlaps it when the CS intensity is too high. When the amount of SICI is reduced in the experiment, we should not simply conclude that the GABAergic inhibition is reduced and consider contamination of these cofounding mechanisms. We should consider the possibility that the MEP could are composed mainly by D-waves or I1-waves and the possibility that the some enhanced intracortical facilitation mask normal inhibition. I will present some example. SICI test showed inhibition reduction in Parkinson’s disease (PD) with usual Kujirai methods. However, when CS was set at 80% RMT, the amount of SICI at an ISI of 3 ms in PD was similar to that in healthy volunteers. Moreover, when using TMS pulse with AP directed currents, normal inhibition was induced and it continued longer than 5 ms probably because AP directed currents produces mainly I3-waves. These findings suggested that M1 GABAergic inhibition is not affected in PD, but some confounding factors may affect the results of SICI experiment. 2. SICI and cortical plasticity: Repetitive TMS (rTMS) noninvasively induces long lasting effects on M1. The lasting effects are considered to be a kind of synaptic plasticity induction in cortical neurons. SICI is used to evaluate the M1 excitability state after these inductions. Conventional rTMS at 5 Hz enhances MEP size and reduces the amount of SICI. However, prolonged 5 Hz rTMS with 1800 pulses does not affect SICI, even though MEP is still enlarged. On the other hand, continuous theta burst stimulation (TBS) decreases both MEP and SICI. Another intervention method of paired associative stimulation (PAS) at interval of 25 ms induces MEP size enlargement without any changes in SICI. Quadri-pulse stimulation (QPS) does not affect SICI in either LTP or LTD like effect inductions. These results indicate that MEP changes by rTMS occur independently of changes in GABAergic inhibition. Those interventions could also induce synaptic plasticity in the cortical GABAergic inter-neuronal networks. However, neuro-plastic characters of M1 GABAergic inter-neuronal networks may be different from that of M1 excitatory neuronal networks. SICI could give us some more information about mechanisms for synaptic plasticity in M1.

P 105. Efficacy of Anodal transcranial direct current stimulation in rehabilitation of motor hand function in chronic incomplete spinal cord injury may depend on sensory impairment: A pilot study

Impairment of motor function in Spinal cord injury (SCI) is associated with reduction in the excitability of motor cortical (M1) representations to muscles ( Freund et al., 2011 ), while recovery is associated with representational plasticity ( Jurkiewicz et al., 2010 ). Noninvasive brain stimulation (NBS) such as anodal transcranial direct current stimulation (atDCS) increases M1 excitability, and has beneficial effects on retention of motor skill training in both the healthy and chronic stroke survivor ( Bastani and Jaberzadeh, 2012 ). However, sensory impairment may independently predict limits of recovery of functional independence ( Kirshblum and O’Connor, 1998 ). This pilot study included incomplete tetraplegic spinal cord injured patients to examine whether the covariate of sensory impairment might account for the possible after effects of atDCS applied during simulated rehabilitation. 8 consenting right-handed outpatients at the London Spinal Cord Injury Centre, with partial impairment of non-dominant hand function (American Spinal Injury Association Impairment Scale (AIS) motor level C5-C7, C-D) were randomly allocated to ACTIVE or SHAM groups in a single-blinded RCT pilot study. Pre-assessment included standardised AIS scoring of upper limb sensory sparing (PINPRICK scoring). Subjects carried out practise of a novel, inclusive manual upper limb motor skill rehabilitation task (MSRT) developed to deliver the novel Task Productivity Rate (TPR) univariate skill measure derived from direct sampling of movement time and target accuracy. 45 min continuous, repetitive MSRT training was applied from naïve baseline state on 3 consecutive days, with follow-up measures 7 days afterwards, during the first 20 min of which received either 20 min ACTIVE anodal tDCS (1 mA, 0.029 mA/cm 2 ) or a SHAM dosage to the non-dominant M1. TPR was obtained from the first 15 min of practise in each session. Repeated measures ANOVA with covariate of PINPRICK scoring as measure of sensory impairment (ANCOVA) were applied to normalised data, with independent t -tests at the follow-up session. The ACTIVE group retained a mean TPR improvement of 42% compared to 7% by SHAM which showed a non-significant trend to benefit of ACTIVE stimulation at follow-up t (6) = 2.24, p = 0.066. ANCOVA revealed significant ( p < 0.05) main effect of ACTIVE stimulation F (1,5) = 12.9, interaction with practise time ( F (3,15) = 3.4, and between-groups effect at follow-up t (6) = 3.16, p = 0.025, r = 0.625. PINPRICK was a significant independent factor F (1,5) = 6.9, which remained stable over time F (3,15) = 0.97, p = 0.43. The independent factors did not interact (confirmatory ANCOVA F (1,4) = 0.52, p = 0.5). Adjunctive application of atDCS to M1 during rehabilitation may have imparted a lasting benefit compared to rehabilitation activity alone. But the covariate of sensory impairment (Pinprick score) independently modulated skill learning and retention scores. Because atDCS did not mitigate the negative effects of sensory impairment on skill acquisition, it is possible that atDCS boosts recovery of motor activation via un-masking of existing M1 connections rather than enhancing motor memory formation necessary for skills uptake (Reis and Fritsch, 2011) .

P 81. Effects of motor cortical quadripulse transcranial magnetic stimulation (QPS) on the contralateral primary motor cortex

Corpus callosum connects the bilateral primary motor cortices (M1s) and plays an important role in motor control. Repetitive transcranial magnetic stimulation (rTMS) is known to induce long-term potentiation (LTP) and long-term depression (LTD) like effect on the stimulated M1. Reported effects of rTMS on the contralateral non-stimultaed M1 are variable between the rTMS techniques and their mechanisms are not fully understood. Quadripulse transcranial magnetic stimulation (QPS) over M1 is known to induce LTP/LTD like plasticity in the stimulated M1. We tested whether QPS over M1 would induce plasticity on the contralateral non-stimulated M1 by measuring motor evoked potentials (MEPs). We also measured several parameters for intracortical and interhemispheric excitability changes in the contralateral M1. Subjects were twelve normal volunteers. We applied QPS over the left M1. The QPS protocol consisted of trains of 4 monophasic TMS pulses separated by inter-stimulus intervals (ISIs) of 5 ms (QPS-5) or 50 ms (QPS-50) with an inter-train interval of 5 s for 30 min. We recorded MEPs to single pulse TMS over the left or right M1 from the relaxed first dorsal interosseous muscles on both sides, before, 0 min and 30 min after QPS. We also measured the resting and active motor thresholds (RMT and AMT), short-and long-interval intracortical inhibition (SICI and LICI), intracortical facilitation (ICF), short-interval intracortical facilitation (SICF), interhemispheric inhibition (IHI), and interhemispheric facilitation (IHF) before and after QPS. After QPS-5, MEPs from the left FDI significantly increased as well as the right FDI. After QPS-50, MEPs from the left FDI did not change significantly, whereas the right FDI decreased significantly. Neither RMT nor AMT changed from the baseline after any conditions. Intracortical inhibition (SICI and LICI) and facilitation (ICF and SICF) did not change after QPS-5 or QPS-50. Both of IHI at an ISI of 10 ms and IHF at an ISI of 4 ms from the left to right hemisphere significantly increased after QPS-5 over the left M1. The QPS-5 over left M1 could also induce LTP in non-stimulated right M1. Increase in the interhemispheric connections (IHI and IHF), without any intrinsic excitability changes in the M1, suggests that the contralateral M1 excitability increment after QPS-5 is associated with the functional potentiation of transcallosal connection from the stimulated to the non-stimulated hemisphere.

Induction of Motor Associative Plasticity in the Posterior Parietal Cortex-Primary Motor Network

There is anatomical and functional connectivity between the primary motor cortex (M1) and posterior parietal cortex (PPC) that plays a role in sensorimotor integration. In this study, we applied corticocortical paired-associative stimuli to ipsilateral PPC and M1 (parietal ccPAS) in healthy right-handed subjects to test if this procedure could modulate M1 excitability and PPC-M1 connectivity. One hundred and eighty paired transcranial magnetic stimuli to the PPC and M1 at an interstimulus interval (ISI) of 8 ms were delivered at 0.2 Hz. We found that parietal ccPAS in the left hemisphere increased the excitability of conditioned left M1 assessed by motor evoked potentials (MEPs) and the input-output curve. Motor behavior assessed by the Purdue pegboard task was unchanged compared with controls. At baseline, conditioning stimuli over the left PPC potentiated MEPs from left M1 when ISI was 8 ms. This interaction significantly attenuated at 60 min after left parietal ccPAS. Additional experiments showed that parietal ccPAS induced plasticity was timing-dependent, was absent if ISI was 100 ms, and could also be seen in the right hemisphere. Our results suggest that parietal ccPAS can modulate M1 excitability and PPC-M1 connectivity and is a new approach to modify motor excitability and sensorimotor interaction.

Two types of exercise‐induced neuroplasticity in congenital hemiparesis: a transcranial magnetic stimulation, functional MRI, and magnetoencephalography study

Early unilateral brain lesions can lead to a persistence of ipsilateral corticospinal projections from the contralesional hemisphere, which can enable the contralesional hemisphere to exert motor control over the paretic hand. In contrast to the primary motor representation (M1), the primary somatosensory representation (S1) of the paretic hand always remains in the lesioned hemisphere. Here, we report on differences in exercise-induced neuroplasticity between individuals with such ipsilateral motor projections (ipsi) and individuals with early unilateral lesions but 'healthy' contralateral motor projections (contra). Sixteen children and young adults with congenital hemiparesis participated in the study (contralateral [Contra] group: n=7, four females, three males; age range 10-30y, median age 16y; ipsilateral [Ipsi] group: n=9, four females, five males; age range 11-31y, median age 12y; Manual Ability Classification System levels I to II in all individuals in both groups). The participants underwent a 12-day intervention of constraint-induced movement therapy (CIMT), consisting of individual training (2h/d) and group training (8h/d). Before and after CIMT, hand function was tested using the Wolf Motor Function Test (WMFT) and diverging neuroplastic effects were observed by transcranial magnetic stimulation (TMS), functional magnetic resonance imaging (fMRI), and magnetoencephalography (MEG). Statistical analysis of TMS data was performed using the non-parametric Wilcoxon signed-rank test for pair-wise comparison; for fMRI standard statistical parametric and non-parametric mapping (SPM5, SnPM3) procedures (first level/second level) were carried out. Statistical analyses of MEG data involved analyses of variance (ANOVA) and t-tests. While MEG demonstrated a significant increase in S1 activation in both groups (p=0.012), TMS showed a decrease in M1 excitability in the Ipsi group (p=0.036), but an increase in M1 excitability in the Contra group (p=0.043). Similarly, fMRI showed a decrease in M1 activation in the Ipsi group, but an increase in activation in the M1-S1 region in the Contra group (for both groups p<0.001 [SnPM3] within the search volume). Different patterns of sensorimotor (re)organization in individuals with early unilateral lesions show, on a cortical level, different patterns of exercise-induced neuroplasticity. The findings help to improve the understanding of the general principles of sensorimotor learning and will help to develop more specific therapies for different pathologies in congenital hemiparesis.

Effect of transient vascular occlusion of the upper arm on motor evoked potentials during force exertion

We previously observed that transient vascular occlusion in volunteers increased the estimation of force exertion with no change in peripheral nerves or muscles. We hypothesized that the primary factor responsible for the overestimation of force exertion during occlusion was the centrally generated motor command, as hypothesized by McCloskey et al. (1974) and McCloskey (1978, 1981). In the present study, we tested the hypothesis that transient vascular occlusion increases the excitability of the primary motor cortex (M1) during force exertion. Healthy human volunteers lay on a bed and squeezed a dynamometer in their right hand. Repetitive gripping forces were exerted at 20%, 40%, or 60% of maximum force, with or without transient (20s) vascular occlusion of the proximal portion of the right upper arm. During the task, single-pulse transcranial magnetic stimulation was applied to the contralateral M1 to induce motor evoked potentials (MEPs) in the flexor carpi ulnaris (FCU) muscle. The MEP amplitudes were enhanced with occlusion under all conditions, with the exception of 60% contraction. In contrast, no significant difference was observed between the MEP amplitudes obtained from the occluded or non-occluded, relaxed FCU muscle. These results suggest that transient vascular occlusion increases the excitability of M1 only during force exertion.

Reflecting on Mirror Mechanisms: Motor Resonance Effects during Action Observation Only Present with Low-Intensity Transcranial Magnetic Stimulation

Transcranial magnetic stimulation (TMS) studies indicate that the observation of other people's actions influences the excitability of the observer's motor system. Motor evoked potential (MEP) amplitudes typically increase in muscles which would be active during the execution of the observed action. This ‘motor resonance’ effect is thought to result from activity in mirror neuron regions, which enhance the excitability of the primary motor cortex (M1) via cortico-cortical pathways. The importance of TMS intensity has not yet been recognised in this area of research. Low-intensity TMS predominately activates corticospinal neurons indirectly, whereas high-intensity TMS can directly activate corticospinal axons. This indicates that motor resonance effects should be more prominent when using low-intensity TMS. A related issue is that TMS is typically applied over a single optimal scalp position (OSP) to simultaneously elicit MEPs from several muscles. Whether this confounds results, due to differences in the manner that TMS activates spatially separate cortical representations, has not yet been explored. In the current study, MEP amplitudes, resulting from single-pulse TMS applied over M1, were recorded from the first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles during the observation of simple finger abductions. We tested if the TMS intensity (110% vs. 130% resting motor threshold) or stimulating position (FDI-OSP vs. ADM-OSP) influenced the magnitude of the motor resonance effects. Results showed that the MEP facilitation recorded in the FDI muscle during the observation of index-finger abductions was only detected using low-intensity TMS. In contrast, changes in the OSP had a negligible effect on the presence of motor resonance effects in either the FDI or ADM muscles. These findings support the hypothesis that MN activity enhances M1 excitability via cortico-cortical pathways and highlight a methodological framework by which the neural underpinnings of action observation can be further explored.

Shaping Motor Cortex Plasticity Through Proprioception

Short-term upper limb disuse induces a hemispheric unbalance between the primary motor cortices (M1s). However, it is still unclear whether these changes are mainly attributable to the absence of voluntary movements or to the reduction of proprioceptive information. The goal of this work was to investigate the role of proprioception in modulating hemispheric balance during a short-term right arm immobilization. We evaluated the 2 M1s excitability and the interhemispheric inhibition (IHI) between M1s in 3 groups of healthy subjects. Two groups received during the immobilization a proprioceptive (P-VIB, 80 Hz) and tactile (T-VIB, 30 Hz) vibration to the right hand, respectively. Another group did not receive any conditioning sensory inputs (No-VIB). We found that in the No-VIB and in the T-VIB groups immobilization induced a decrease of left M1 excitability and IHI from left to right hemisphere and an increase of right M1 excitability and IHI from right to left hemisphere. Differently, only a partial decrease in left M1 excitability, no change in right M1 excitability and in IHI was observed in the P-VIB group. Our findings demonstrate that the maintenance of dynamic proprioceptive inputs in an immobilized arm through muscle vibration can prevent the hemispheric unbalance induced by short-term limb disuse.

Muscle and Timing-specific Functional Connectivity between the Dorsolateral Prefrontal Cortex and the Primary Motor Cortex

The pFC has a crucial role in cognitive control, executive function, and sensory processing. Functional imaging, neurophysiological, and animal studies provide evidence for a functional connectivity between the dorsolateral pFC (DLPFC) and the primary motor cortex (M1) during free choice but not instructed choice selection tasks. In this study, twin coil, neuronavigated TMS was used to examine the precise timing of the functional interaction between human left DLPFC and ipsilateral M1 during the execution of a free/specified choice selection task involving the digits of the right hand. In a thumb muscle that was not involved in the task, a conditioning pulse to the left DLPFC enhanced the excitability of the ipsilateral M1 during free selection more than specified selection 100 msec after presentation of the cue; the opposite effect was seen at 75 msec. However, the difference between free and externally specified conditions disappeared when a task-specific muscle was investigated. In this case, the influence from DLPFC was dominated by task involvement rather than mode of selection, suggesting that other processes related to movement execution were also operating. Finally, we show that the effects were spatially specific because they were absent when an adjacent area of DLPFC was stimulated. These results reveal temporally and spatially selective interactions between BA 46 and M1 that are both task and muscle specific.

Evolution of Premotor Cortical Excitability after Cathodal Inhibition of the Primary Motor Cortex: A Sham-Controlled Serial Navigated TMS Study

BackgroundPremotor cortical regions (PMC) play an important role in the orchestration of motor function, yet their role in compensatory mechanisms in a disturbed motor system is largely unclear. Previous studies are consistent in describing pronounced anatomical and functional connectivity between the PMC and the primary motor cortex (M1). Lesion studies consistently show compensatory adaptive changes in PMC neural activity following an M1 lesion. Non-invasive brain modification of PMC neural activity has shown compensatory neurophysiological aftereffects in M1. These studies have contributed to our understanding of how M1 responds to changes in PMC neural activity. Yet, the way in which the PMC responds to artificial inhibition of M1 neural activity is unclear. Here we investigate the neurophysiological consequences in the PMC and the behavioral consequences for motor performance of stimulation mediated M1 inhibition by cathodal transcranial direct current stimulation (tDCS).PurposeThe primary goal was to determine how electrophysiological measures of PMC excitability change in order to compensate for inhibited M1 neural excitability and attenuated motor performance.HypothesisCathodal inhibition of M1 excitability leads to a compensatory increase of ipsilateral PMC excitability.MethodsWe enrolled 16 healthy participants in this randomized, double-blind, sham-controlled, crossover design study. All participants underwent navigated transcranial magnetic stimulation (nTMS) to identify PMC and M1 corticospinal projections as well as to evaluate electrophysiological measures of cortical, intracortical and interhemispheric excitability. Cortical M1 excitability was inhibited using cathodal tDCS. Finger-tapping speeds were used to examine motor function.ResultsCathodal tDCS successfully reduced M1 excitability and motor performance speed. PMC excitability was increased for longer and was the only significant predictor of motor performance.ConclusionThe PMC compensates for attenuated M1 excitability and contributes to motor performance maintenance.

Network Connectivity and Individual Responses to Brain Stimulation in the Human Motor System

The mechanisms driving cortical plasticity in response to brain stimulation are still incompletely understood. We here explored whether neural activity and connectivity in the motor system relate to the magnitude of cortical plasticity induced by repetitive transcranial magnetic stimulation (rTMS). Twelve right-handed volunteers underwent functional magnetic resonance imaging during rest and while performing a simple hand motor task. Resting-state functional connectivity, task-induced activation, and task-related effective connectivity were assessed for a network of key motor areas. We then investigated the effects of intermittent theta-burst stimulation (iTBS) on motor-evoked potentials (MEP) for up to 25 min after stimulation over left primary motor cortex (M1) or parieto-occipital vertex (for control). ITBS-induced increases in MEP amplitudes correlated negatively with movement-related fMRI activity in left M1. Control iTBS had no effect on M1 excitability. Subjects with better response to M1-iTBS featured stronger preinterventional effective connectivity between left premotor areas and left M1. In contrast, resting-state connectivity did not predict iTBS aftereffects. Plasticity-related changes in M1 following brain stimulation seem to depend not only on local factors but also on interconnected brain regions. Predominantly activity-dependent properties of the cortical motor system are indicative of excitability changes following induction of cortical plasticity with rTMS.

A new temporal window for inducing depressant associative plasticity in human primary motor cortex

ObjectiveSpike-timing dependent plasticity (STDP) usually refers to synaptic plasticity induced by near-synchronous activation of neuronal input and neuronal firing. However, some models of STDP predict effects that deviate from this tight temporal synchrony. We aimed to characterise the induction of STDP using paired associative stimulation (PAS) when the pre-synaptic input arrives in primary motor cortex (M1) at (i) intermediate intervals (50–80ms; PAS50,..PAS80) before the post-synaptic neuron is activated and (ii) long intervals (100–450ms; PAS−100,..PAS−450) after the post-synaptic neuron is activated. PAS at near-synchronicity (PAS25) was applied for comparison. MethodsTo characterise the physiological effects of the different PAS protocols, we examined short- and long-interval intra-cortical inhibition; intra-cortical facilitation and short- and long-latency afferent inhibition, in addition to recording MEPs in 45 healthy individuals. ResultsMEP amplitude was reduced at PAS intervals between −250 and −450ms, increased with PAS25, and unaltered at the remaining intervals. There was no change in intra-cortical inhibitory or facilitatory circuits following any PAS protocol. ConclusionsThese findings provide evidence of a previously unreported temporal window in which PAS induces a depression of corticospinal excitability in human M1. SignificanceEstablishing new temporal rules for STDP broadens its applicability for therapeutic usage in future.

Temporal association between changes in primary sensory cortex and corticomotor output during muscle pain

BackgroundIntegration of information between multiple cortical regions is thought to underpin the experience of pain. Yet studies tend to focus on pain related changes in discrete cortical regions. Although altered processing in the primary motor (M1) and sensory cortex (S1) is implicated in pain, the temporal relationship between these regions is unknown and may provide insight into the interaction between them. MethodsWe used recordings of somatosensory-evoked potentials (SEPs) and transcranial magnetic stimulation to investigate the temporal relationship between altered excitability of the primary sensory cortex and corticomotor output during and after muscle pain induced by hypertonic saline infusion into the right first dorsal interosseous. SEPs and motor-evoked potentials (MEPs) were recorded in 12 healthy individuals. ResultsParticipants reported an average pain intensity of 5.4 (0.5) on a 10-cm visual analogue scale. The area of the N20–P25–N33 complex of the SEP was reduced during and after pain, but MEP amplitudes were suppressed only after pain had resolved. ConclusionsOur data show that pain reduces sensory processing before motor output is altered. This temporal dispersion, coupled with the lack of correlation between pain-induced changes in S1 and M1 excitability, imply either that independent processes are involved, or that reduced excitability of S1 during acute experimental muscle pain mediates latent reductions in motor output via processes that are non-linear and potentially involve activation of a wider brain network.

Different Current Intensities of Anodal Transcranial Direct Current Stimulation Do Not Differentially Modulate Motor Cortex Plasticity

Transcranial direct current stimulation (tDCS) is a noninvasive technique that modulates the excitability of neurons within the motor cortex (M1). Although the aftereffects of anodal tDCS on modulating cortical excitability have been described, there is limited data describing the outcomes of different tDCS intensities on intracortical circuits. To further elucidate the mechanisms underlying the aftereffects of M1 excitability following anodal tDCS, we used transcranial magnetic stimulation (TMS) to examine the effect of different intensities on cortical excitability and short-interval intracortical inhibition (SICI). Using a randomized, counterbalanced, crossover design, with a one-week wash-out period, 14 participants (6 females and 8 males, 22–45 years) were exposed to 10 minutes of anodal tDCS at 0.8, 1.0, and 1.2 mA. TMS was used to measure M1 excitability and SICI of the contralateral wrist extensor muscle at baseline, immediately after and 15 and 30 minutes following cessation of anodal tDCS. Cortical excitability increased, whilst SICI was reduced at all time points following anodal tDCS. Interestingly, there were no differences between the three intensities of anodal tDCS on modulating cortical excitability or SICI. These results suggest that the aftereffect of anodal tDCS on facilitating cortical excitability is due to the modulation of synaptic mechanisms associated with long-term potentiation and is not influenced by different tDCS intensities.

Paired-pulse transcranial magnetic stimulation reveals probability-dependent changes in functional connectivity between right inferior frontal cortex and primary motor cortex during go/no-go performance

The functional role of the right inferior frontal cortex (rIFC) in mediating human behavior is the subject of ongoing debate. Activation of the rIFC has been associated with both response inhibition and with signaling action adaptation demands resulting from unpredicted events. The goal of this study is to investigate the role of rIFC by combining a go/no-go paradigm with paired-pulse transcranial magnetic stimulation (ppTMS) over rIFC and the primary motor cortex (M1) to probe the functional connectivity between these brain areas. Participants performed a go/no-go task with 20% or 80% of the trials requiring response inhibition (no-go trials) in a classic and a reversed version of the task, respectively. Responses were slower to infrequent compared to frequent go trials, while commission errors were more prevalent to infrequent compared to frequent no-go trials. We hypothesized that if rIFC is involved primarily in response inhibition, then rIFC should exert an inhibitory influence over M1 on no-go (inhibition) trials regardless of no-go probability. If, by contrast, rIFC has a role on unexpected trials other than just response inhibition then rIFC should influence M1 on infrequent trials regardless of response demands. We observed that rIFC suppressed M1 excitability during frequent no-go trials, but not during infrequent no-go trials, suggesting that the role of rIFC in response inhibition is context dependent rather than generic. Importantly, rIFC was found to facilitate M1 excitability on all low frequent trials, irrespective of whether the infrequent event involved response inhibition, a finding more in line with a predictive coding framework of cognitive control.

Impairments of Motor-Cortex Responses to Unilateral and Bilateral Direct Current Stimulation in Schizophrenia

Transcranial direct current stimulation (tDCS) is a non-invasive stimulation technique that can be applied to modulate cortical activity through induction of cortical plasticity. Since various neuropsychiatric disorders are characterized by fluctuations in cortical activity levels (e.g., schizophrenia), tDCS is increasingly investigated as a treatment tool. Several studies have shown that the induction of cortical plasticity following classical, unilateral tDCS is reduced or impaired in the stimulated and non-stimulated primary motor cortices (M1) of patients with schizophrenia. Moreover, an alternative, bilateral tDCS setup has recently been shown to modulate cortical plasticity in both hemispheres in healthy subjects, highlighting another potential treatment approach. Here we present the first study comparing the efficacy of unilateral tDCS (cathode left M1, anode right supraorbital) with simultaneous bilateral tDCS (cathode left M1, anode right M1) in patients with schizophrenia. tDCS-induced cortical plasticity was monitored by investigating motor-evoked potentials induced by single-pulse transcranial magnetic stimulation applied to both hemispheres. Healthy subjects showed a reduction of left M1 excitability following unilateral tDCS on the stimulated left hemisphere and an increase in right M1 excitability following bilateral tDCS. In schizophrenia, no plasticity was induced following both stimulation paradigms. The pattern of these results indicates a complex interplay between plasticity and connectivity that is impaired in patients with schizophrenia. Further studies are needed to clarify the biological underpinnings and clinical impact of these findings.