Augmenting Plasticity Induction in Human Motor Cortex by Disinhibition Stimulation.

Cellular studies showed that disinhibition, evoked pharmacologically or by a suitably timed priming stimulus, can augment long-term plasticity (LTP) induction. We demonstrated previously that transcranial magnetic stimulation evokes a period of presumably GABA(B)ergic late cortical disinhibition (LCD) in human primary motor cortex (M1). Here, we hypothesized that, in keeping with cellular studies, LCD can augment LTP-like plasticity in humans. In Experiment 1, patterned repetitive TMS was applied to left M1, consisting of 6 trains (intertrain interval, 8 s) of 4 doublets (interpulse interval equal to individual peak I-wave facilitation, 1.3-1.5 ms) spaced by the individual peak LCD (interdoublet interval (IDI), 200-250 ms). This intervention (total of 48 pulses applied over ∼45 s) increased motor-evoked potential amplitude, a marker of corticospinal excitability, in a right hand muscle by 147% ± 4%. Control experiments showed that IDIs shorter or longer than LCD did not result in LTP-like plasticity. Experiment 2 indicated topographic specificity to the M1 hand region stimulated by TMS and duration of the LTP-like plasticity of 60 min. In conclusion, GABA(B)ergic LCD offers a powerful new approach for augmenting LTP-like plasticity induction in human cortex. We refer to this protocol as disinhibition stimulation (DIS).

Movement-generated afference paired with transcranial magnetic stimulation: an associative stimulation paradigm.

BACKGROUND: A peripheral nerve stimulus can enhance or suppress the evoked response to transcranial magnetic stimulation (TMS) depending on the latency of the preceding peripheral nerve stimulation (PNS) pulse. Similarly, somatosensory afference from the passively moving limb can transiently alter corticomotor excitability, in a phase-dependent manner. The repeated association of PNS with TMS is known to modulate corticomotor excitability; however, it is unknown whether repeated passive-movement associative stimulation (MAS) has similar effects. METHODS: In a proof-of-principal study, using a cross-over design, seven healthy subjects received in separate sessions: (1) TMS (120% of the resting motor threshold-RMT, optimal site for Flexor Carpi Radialis) with muscle at rest; (2) TMS paired with cyclic passive movement during extension cyclic passive movement (400 pairs, 1 Hz), with the intervention order randomly assigned. Normality was tested using the Kolmogorov-Smirnov test, then compared to pre-intervention baseline using repeated measures ANOVA with a Dunnet multiple comparisons test. RESULTS: MAS led to a progressive and significant decrease in the motor evoked potential (MEP) amplitude over the intervention (R(2) = 0.6665, P < 0.0001), which was not evident with TMS alone (R(2) = 0.0068, P = 0.641). Post-intervention excitability reduction, only present with MAS intervention, remained for 20 min (0-10 min = 68.2 ± 4.9%, P < 0.05; 10-20 min = 73.3 ± 9.7%, P < 0.05). CONCLUSION: The association of somatosensory afference from the moving limb with TMS over primary motor cortex in healthy subjects can be used to modulate corticomotor excitability, and may have therapeutic implications.

Reversal of TMS-induced motor twitch by training is associated with a reduction in excitability of the antagonist muscle.

BACKGROUND: A single session of isolated repetitive movements of the thumb can alter the response to transcranial magnetic stimulation (TMS), such that the related muscle twitch measured post-training occurs in the trained direction. This response is attributed to transient excitability changes in primary motor cortex (M1) that form the early part of learning. We investigated; (1) whether this phenomenon might occur for movements at the wrist, and (2) how specific TMS activation patterns of opposing muscles underlie the practice-induced change in direction. METHODS: We used single-pulse suprathreshold TMS over the M1 forearm area, to evoke wrist movements in 20 healthy subjects. We measured the preferential direction of the TMS-induced twitch in both the sagittal and coronal plane using an optical goniometer fixed to the dorsum of the wrist, and recorded electromyographic (EMG) activity from the flexor carpi radialis (FCR) and extensor carpi radialis (ECR) muscles. Subjects performed gentle voluntary movements, in the direction opposite to the initial twitch for 5 minutes at 0.2 Hz. We collected motor evoked potentials (MEPs) elicited by TMS at baseline and for 10 minutes after training. RESULTS: Repetitive motor training was sufficient for TMS to evoke movements in the practiced direction opposite to the original twitch. For most subjects the effect of the newly-acquired direction was retained for at least 10 minutes before reverting to the original. Importantly, the direction change of the movement was associated with a significant decrease in MEP amplitude of the antagonist to the trained muscle, rather than an increase in MEP amplitude of the trained muscle. CONCLUSIONS: These results demonstrate for the first time that a TMS-twitch direction change following a simple practice paradigm may result from reduced corticospinal drive to muscles antagonizing the trained direction. Such findings may have implications for training paradigms in neurorehabilitation.

Rapid slowing of maximal finger movement rate: fatigue of central motor control?

Exploring the limits of the motor system can provide insights into the mechanisms underlying performance deterioration, such as force loss during fatiguing isometric muscle contraction, which has been shown to be due to both peripheral and central factors. However, the role of central factors in performance deterioration during dynamic tasks has received little attention. We studied index finger flexion/extension movement performed at maximum voluntary rate (MVR) in ten healthy subjects, measuring movement rate and amplitude over time, and performed measures of peripheral fatigue. During 20 s finger movements at MVR, there was a decline in movement rate beginning at 7-9 s and continuing until the end of the task, reaching 73% of baseline (P < 0.001), while amplitude remained unchanged. Isometric maximum voluntary contraction force and speed of single ballistic flexion and extension finger movements remained unchanged after the task, indicating a lack of peripheral fatigue. The timing of finger flexor and extensor EMG burst activity changed during the task from an alternating flexion/extension pattern to a less effective co-contraction pattern. Overall, these findings suggest a breakdown of motor control rather than failure of muscle force generation during an MVR task, and therefore that the mechanisms underlying the early decline in movement rate are central in origin.

Plasticity in neurological disorders and challenges for noninvasive brain stimulation (NBS).

There has been considerable interest in trialing NBS in a range of neurological conditions, and in parallel the range of NBS techniques available continues to expand. Underpinning this is the idea that NBS modulates neuroplasticity and that plasticity is an important contributor to functional recovery after brain injury and to the pathophysiology of neurological disorders. However while the evidence for neuroplasticity and its varied mechanisms is strong, the relationship to functional outcome is less clear and the clinical indications remain to be determined. To be maximally effective, the application of NBS techniques will need to be refined to take into account the diversity of neurological symptoms, the fundamental differences between acute, longstanding and chronic progressive disease processes, and the differential part played by functional and dysfunctional plasticity in diseases of the brain and spinal cord.

NeuroMeasure: A Software Package for Quantification of Cortical Motor Maps Using Frameless Stereotaxic Transcranial Magnetic Stimulation.

The recent enhanced sophistication of non-invasive mapping of the human motor cortex using MRI-guided Transcranial Magnetic Stimulation (TMS) techniques, has not been matched by refinement of methods for generating maps from motor evoked potential (MEP) data, or in quantifying map features. This is despite continued interest in understanding cortical reorganization for natural adaptive processes such as skill learning, or in the case of motor recovery, such as after lesion affecting the corticospinal system. With the observation that TMS-MEP map calculation and quantification methods vary, and that no readily available commercial or free software exists, we sought to establish and make freely available a comprehensive software package that advances existing methods, and could be helpful to scientists and clinician-researchers. Therefore, we developed NeuroMeasure, an open source interactive software application for the analysis of TMS motor cortex mapping data collected from Nexstim® and BrainSight®, two commonly used neuronavigation platforms. NeuroMeasure features four key innovations designed to improve motor mapping analysis: de-dimensionalization of the mapping data, fitting a predictive model, reporting measurements to characterize the motor map, and comparing those measurements between datasets. This software provides a powerful and easy to use workflow for characterizing and comparing motor maps generated with neuronavigated TMS. The software can be downloaded on our github page: https://github.com/EdwardsLabNeuroSci/NeuroMeasure. AIM: This paper aims to describe a software platform for quantifying and comparing maps of the human primary motor cortex, using neuronavigated transcranial magnetic stimulation, for the purpose of studying brain plasticity in health and disease.

Enhanced corticomotor excitability with dynamic fatiguing exercise of the lower limb in multiple sclerosis.

OBJECTIVE: To determine if task performance and fatigability during rapid repetitive exercise of the lower limb differ in a group of MS subjects compared to a control group, and what central changes accompany the development of fatigue and the period of recovery. METHODS: Transcranial magnetic stimulation (TMS) was used to compare motor evoked potential (MEP) responses between 10 clinically definite MS subjects (7F, 33-64 years of age; EDSS or= 4/5) and 13 control subjects during and after 5 bouts of a 15-second maximum rate foot-tapping task performed at 1 minute intervals. RESULTS: Maximum voluntary contraction (MVC) force of ankle dorsiflexion was lower (15 %) in the MS group compared to controls; however there were no differences in the rate of foot tapping. The rate of foot tapping decreased during each bout of exercise to a comparable degree in both groups, but there was no overall deterioration in performance across the 5 repeat bouts in either group. MS subjects showed a greater decline in strength than controls after exercise (20.7+/-7.7% vs. 6+/-3.6%; p<0.05). MEP amplitude increased significantly for the exercised limb in both groups, but the increase was greater in MS subjects (65.9+/-27% vs. 31+/-19.6%; MS vs. control; p<0.05). MEP amplitude also increased for the non-exercised limb in controls (40.6+/-15.6%, p<0.01) but not in MS subjects. CONCLUSIONS: Mild to moderately affected MS subjects can perform a fatiguing exercise requiring a high level of central motor control but this is associated with a greater strength loss and increase in corticomotor excitability compared to unaffected individuals. SIGNIFICANCE: Central adaptive processes are likely to have a significant role in maintaining task performance in MS.

Spike-timing-related plasticity is preserved in Parkinson's disease and is enhanced by dopamine: evidence from transcranial magnetic stimulation.

We sought to investigate the effects of dopamine on motor cortical plasticity in Parkinson's disease (PD) using a novel interventional transcranial magnetic stimulation protocol that targets spike-timing-dependent plasticity (iTMS). Six patients (3F, mean age 62 years) with mild-moderate PD (mean disease duration 6 years, UPDRS-off 13, UPDRS-on 3, H&Y stage 2, daily levodopa dosage 450 mg) were studied off and on levodopa on separate days. Paired TMS pulses at resting motor threshold with an inter-stimulus interval of 1.5 ms were given over the hand area of the motor cortex for 20 min at 0.2 Hz. Single-pulse motor evoked potential (MEP) amplitude and visually cued simple reaction time (SRT) were measured before and after iTMS. When on levodopa, MEP amplitude increased to 278+/-36% of baseline (p<0.01), and when off levodopa to 157+/-13% of baseline (p=0.02). All patients showed a significantly greater increase in MEP amplitude when on levodopa than off levodopa (p=0.01). SRT was reduced to 95% baseline after iTMS off levodopa (p=0.02), but did not change on levodopa. These findings indicate that motor cortex plasticity to iTMS is preserved in mild-moderate PD. The effects of this spike-timing-related TMS protocol on cortical excitability were consistent and were enhanced by levodopa. The results support the important role of dopamine in regulating synaptic plasticity and justify a larger crossover study to assess the therapeutic effects of iTMS in PD.

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS).

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS.

Central motor drive and perception of effort during fatigue in multiple sclerosis.

OBJECTIVE: To determine if task performance and fatiguability during repeated low-level contractions of an intrinsic hand muscle differ in a group of MS subjects compared with a control group, and what central changes accompany the development of fatigue and the period of recovery, whether these measures are related to subjective ratings of fatigue or perception of effort. METHODS: Force of index finger abduction, rating of perceived effort, and motor evoked potential amplitude and silent period duration were measured during and after a 20-min. intermittent submaximal (40%) contraction of the first dorsal interosseous muscle in 23 clinically definite MS subjects with mild-moderate symptoms, and 15 controls. RESULTS: Rating of perceived effort increased at a greater rate in the MS group than in control subjects during exercise, and this was associated with larger increases in both MEP amplitude and silent period duration. CONCLUSIONS: Submaximal fatiguing exercise is associated with an enhanced central motor drive and increased perception of effort in MS. SIGNIFICANCE: MS subjects can increase central drive during fatiguing exercise to a greater degree than controls, but this is associated with greater perceived exertion. These factors may underlie the more general complaint of fatigue experienced by people with MS.

Repetitive paired-pulse TMS at I-wave periodicity markedly increases corticospinal excitability: a new technique for modulating synaptic plasticity.

OBJECTIVE: We hypothesised that facilitatory I-wave interaction set up by paired-pulse transcranial magnetic stimulation delivered with I-wave periodicity (iTMS) may reinforce trans-synaptic events and provide a means for modulating synaptic plasticity and cortical excitability. Our objective was to determine whether prolonged iTMS can increase corticospinal excitability, and whether this form of stimulation can have lasting aftereffects. METHODS: Paired stimuli of equal strength with a 1.5 ms inter-stimulus interval were delivered for 30 min at a rate of 0.2 Hz. Motor threshold and motor evoked potential (MEP) amplitude to single-pulse TMS was compared before and after intervention. RESULTS: Paired-pulse MEP amplitude increased linearly throughout the period of iTMS, and had increased five-fold by the end of the stimulation period. Single-pulse MEP amplitude was increased a mean of four-fold for 10 min after stimulation. Motor threshold was unaffected. CONCLUSIONS: iTMS is an effective method for increasing excitability of the human motor cortex, and probably acts by increasing synaptic efficacy. SIGNIFICANCE: Reinforcement of trans-synaptic events by iTMS may provide a means to investigate and modulate synaptic plasticity in the brain.

Differential activation of frontal lobe areas by lexical and semantic language tasks: a functional magnetic resonance imaging study.

To determine whether frontal lobe regions, including Broca's area, dorsolateral prefrontal cortex (DLPFC) and supplementary motor area (SMA), are differentially activated during lexical and semantic language tasks, we used functional magnetic resonance imaging in eight healthy right-handed subjects silently performing two semantic tasks (adjective and verb generation) and a lexical retrieval task (noun recall). Activation was observed in Broca's area, DLPFC and SMA for all tasks. Broca's area activation was approximately doubled during the semantic tasks compared with the lexical task (verbs vs nouns: 19.1+/-4.5 vs 8.9+/-1.6 voxels, p=0.02; adjectives vs nouns 24.4+/-7.5 vs 10.1+/-2.8 voxels, p=0.04); however, there were no significant differences in the DLFPC or SMA across tasks. We conclude that Broca's area is more active during tasks that have a semantic content, whereas areas involved in preparatory processing (SMA) and memory retrieval (DLPFC) are engaged equally during both types of task.

Motor cortex reorganisation in Parkinson's disease.

Transcranial magnetic stimulation mapping of the motor cortical projection to the hand was performed in a group of patients with Parkinson's disease (PD) of variable duration to determine whether there is evidence of cortical reorganisation. Map shifts were found in the majority of PD cases (12/15), in untreated early cases as well as treated cases of longer duration, and there was a correlation between inter-side difference in the severity of PD symptoms (Unified Parkinson's Disease Rating Scale) and interhemispheric map displacement (r=0.60; P=0.018). These findings indicate that there is reorganisation of the corticomotor representation of the hand in PD, even at a relatively early stage of the disease, and suggest a dynamic process of reorganisation in the motor cortex due to an increase in the pallidal inhibitory inputs to the thalamo-cortical projections.

Corticomotor organisation and motor function in multiple sclerosis.

Our objective was to determine whether there are changes in the corticomotor map for the hand in multiple sclerosis, and whether these changes correlate with indices of motor function and measures of corticomotor conduction or excitability. Transcranial magnetic stimulation (TMS) maps, motor evoked potential (MEP) latency and amplitude, motor threshold and EDSS and Purdue-pegboard measurements were made in 26 subjects with relapsing-remitting multiple sclerosis. Correlations were sought between these measurements using the Pearson product-moment correlation with a level of significance of p = 0.05 (two-tailed). Map displacement was positively correlated with MEP latency (p = 3 x 10(-4)) and EDSS (p = 0.007), and negatively correlated with Purdue score (p = 4 x 10(-4)). Purdue scores correlated with all MEP parameters (latency, p = 4 x 10(-10); threshold, p = 4 x 10(-6); amplitude, p = 0.003). We conclude that motor reorganisation is associated with impaired corticomotor conduction and may reflect a process of neural plasticity associated with axonal demyelination in MS. An understanding of motor function in MS should incorporate models of both axonal demyelination and conduction deficits as well as neural plasticity.

Primary writing tremor: motor cortex reorganisation and disinhibition.

BACKGROUND: Primary writing tremor (PWT) is a task-specific tremor of uncertain origin. There has been debate as to whether PWT represents a variant of essential tremor or a tremulous form of focal dystonia related to writer's cramp. In writer's cramp there is evidence of changes in intracortical inhibition (ICI), as well as cortical motor reorganisation. OBJECTIVE: To study corticomotor organisation and short-latency ICI in a patient with typical task-specific PWT. METHODS: Transcranial magnetic stimulation mapping of the corticomotor representation of the hand and studies of ICI using paired-pulse stimulation were performed in a 47-year-old right-handed woman with a pure task-specific writing tremor. RESULTS: The motor maps for the hand were displaced posteriorly on both sides and reverted to a normal position after treatment with botulinum toxin. Short-latency ICI was reduced for the dominant hand. CONCLUSION: The findings indicate reorganisation and disinhibition of the corticomotor projection to the hand and point to the participation of cortical centres in the origin of PWT.

Stroke subtype and motor impairment influence contralesional excitability.

OBJECTIVE: The nonlesioned motor cortex (M1NL) is thought to be hyperexcitable in patients with subacute or chronic stroke and offers a promising therapeutic target. However, whether M1NL excitability behaves the same for subcortical and cortical strokes is unknown. The aim of the present study was to determine whether cortical, or purely subcortical, strokes have a different effect on M1NL excitability. METHODS: We looked for correlations between the Fugl-Meyer (FM) score and M1NL resting motor threshold (RMTNL) in 34 stroke survivors classified according to lesion location (cortico-subcortical or purely subcortical). In addition to the FM, the Wolf Motor Score and motor power were measured. RESULTS: FM correlated with RMTNL for subcortical (r = 0.82; p = 0.001) but not for cortical strokes (r = 0.11; p = 0.62). Likewise, Wolf Motor Score (r = -0.62; p = 0.03) and motor power (r = 0.64; p = 0.023) were correlated with RMTNL for the subcortical group, but not for the cortical group. CONCLUSION: We show that the impact on M1NL depends on lesion location and conclude that protocols aimed at reducing M1NL cortical excitability may be worth exploring for subcortical but not for cortical stroke.

Evidence for an excitatory GABAA response in human motor cortex in idiopathic generalised epilepsy.

PURPOSE: Impaired GABAergic inhibition has been implicated in the pathophysiology of epilepsy. The possibility of a paradoxical excitatory effect of GABA in epilepsy has been suggested, but has not been investigated in vivo. We investigated pre- and post-synaptic GABAergic mechanisms in patients with idiopathic generalised epilepsy (IGE). METHOD: In 10 patients and 12 control subjects we explored short- and long-interval intracortical inhibition (SICI, LICI; post-synaptic GABAA and GABAB-mediated respectively) and long-interval intracortical facilitation (LICF; pre-synaptic disinhibition) using transcranial magnetic stimulation. RESULTS: While post-synaptic GABAB-mediated inhibition was unchanged in IGE (p=0.09), LICF was reduced compared to controls (controls: 141±17% of baseline; untreated patients: 107±12%, p=0.2; treated patients: 79±10%, p=0.003). GABAA-mediated inhibition was reduced in untreated patients (response amplitude 56±4% of baseline vs. 26±6% in controls, p=0.004) and normalised with treatment (37±12%, p=0.5 vs. controls). When measured during LICI, GABAA-mediated inhibition became excitatory in untreated IGE (response amplitude 120±10% of baseline, p=0.017), but not in treated patients. CONCLUSION: Pre- and post-synaptic GABA-mediated inhibitory mechanisms are altered in IGE. The findings lend in vivo support to evidence from experimental models and in vitro studies of human epileptic brain tissue that GABA may have a paradoxical excitatory role in ictogenesis.

Motor outcome after subcortical stroke correlates with the degree of cortical reorganization.

OBJECTIVE: The contribution of cortical reorganization to motor recovery after a subcortical stroke is uncertain. The purpose of the study was to investigate the relationship between changes in motor cortex organization, and the degree of motor function after a subcortical stroke. METHODS: Transcranial magnetic stimulation mapping of the corticomotor projection to the hand was performed in 27 patients who had suffered a subcortical ischemic stroke resulting in an upper limb motor deficit up to 23 years previously. Corticospinal conduction was assessed by measurements of motor evoked potential latency, amplitude and threshold. Motor function in the upper limb was assessed using the Motor Assessment Scale for Stroke and measurements of grip strength. RESULTS: Motor maps for the hand were displaced on the affected side relative to the unaffected side in 17 patients. In 10 of these patients in whom corticospinal conduction had normalized, there was a strong positive correlation between the magnitude of the map shift and grip strength in the affected hand (r=0.79; P=0.006). In the other seven patients with a map shift, in whom corticospinal conduction was still impaired, there was a tendency for a larger map area to be associated with better motor function, and in the group as a whole there was a correlation between map area and grip strength (r=0.52; P=0.005). CONCLUSIONS: The present findings provide evidence that the cortical plasticity and reorganization that occurs after a subcortical stroke is functionally significant and contributes to motor outcome.

Motor outcome after subcortical stroke: MEPs correlate with hand strength but not dexterity.

OBJECTIVE: Motor evoked potential (MEP) amplitude and threshold are predictors of functional outcome in the early stages after stroke, and improvement in these parameters usually accompanies motor recovery. The aim of this study in patients with subcortical stroke was to determine whether there is a correlation between MEP amplitude and threshold and the degree of recovery of strength and dexterity in the affected hand. METHODS: MEP amplitude and threshold were measured on the affected and unaffected sides in 23 patients who had suffered a subcortical ischaemic stroke up to 23 years previously. Grip strength was measured using a hand-held dynamometer and dexterity was assessed using a modification of the McCarron test battery. RESULTS: Grip strength correlated with both MEP amplitude and threshold (r=0.49 and r=-0.54, respectively, P<0.05), whereas the McCarron score for motor dexterity did not correlate significantly with either of these MEP parameters. CONCLUSIONS: Grip strength and dexterity correlate differentially with MEP parameters of excitability and conduction in the corticospinal pathway after recovery in patients with subcortical stroke. Grip strength is dependent on restoration of corticospinal excitability and conduction whereas additional factors such as cortical reorganization may underlie recovery of motor dexterity.