The effects of five sessions of continuous theta burst stimulation over contralesional sensorimotor cortex paired with paretic skilled motor practice in people with chronic stroke.

BACKGROUND: In individuals with chronic stroke, impairment of the paretic arm may be exacerbated by increased contralesional transcallosal inhibition (TCI). Continuous theta burst stimulation (cTBS) can decrease primary motor cortex (M1) excitability and TCI. However, contralesional cTBS shows inconsistent effects after stroke. Variable effects of cTBS could stem from failure to pair stimulation with skilled motor practice or a focus of applying cTBS over M1. OBJECTIVE: Here, we investigated the effects of pairing cTBS with skilled practice on motor learning and arm function. We considered the differential effects of stimulation over two different brain regions: contralesional M1 (M1c) or contralesional primary somatosensory cortex (S1c). METHODS: 37 individuals with chronic stroke participated in five sessions of cTBS and paretic arm skilled practice of a serial targeting task (STT); participants received either cTBS over M1c or S1c or sham before STT practice. Changes in STT performance and Wolf Motor Function Test (WMFT) were assessed as primary outcomes. Assessment of bilateral corticospinal, intracortical excitability and TCI were secondary outcomes. RESULTS: cTBS over sensorimotor cortex did not improve STT performance and paretic WMFT-rate beyond sham cTBS. TCI was reduced bi-directionally following the intervention, regardless of stimulation group. In addition, we observed an association between STT performance change and paretic WMFT-rate change in the M1c stimulation group only. CONCLUSIONS: Multiple sessions of STT practice can improve paretic arm function and decrease TCI bilaterally, with no additional benefit of prior cTBS. Our results suggest that improvement in STT practice following M1c cTBS scaled with change in paretic arm function in some individuals. Our results highlight the need for a better understanding of the mechanisms of cTBS to effectively identify who may benefit from this form of brain stimulation.

White Matter Biomarkers Associated with Motor Change in Individuals with Stroke: A Continuous Theta Burst Stimulation Study.

Continuous theta burst stimulation (cTBS) is a form of noninvasive repetitive brain stimulation that, when delivered over the contralesional hemisphere, can influence the excitability of the ipsilesional hemisphere in individuals with stroke. cTBS applied prior to skilled motor practice interventions may augment motor learning; however, there is a high degree of variability in individual response to this intervention. The main objective of the present study was to assess white matter biomarkers of response to cTBS paired with skilled motor practice in individuals with chronic stroke. We tested the effects of stimulation of the contralesional hemisphere at the site of the primary motor cortex (M1c) or primary somatosensory cortex (S1c) and a third group who received sham stimulation. Within each stimulation group, individuals were categorized into responders or nonresponders based on their capacity for motor skill change. Baseline diffusion tensor imaging (DTI) indexed the underlying white matter microstructure of a previously known motor learning network, named the constrained motor connectome (CMC), as well as the corticospinal tract (CST) of lesioned and nonlesioned hemispheres. Across practice, there were no differential group effects. However, when categorized as responders vs. nonresponders using change in motor behaviour, we demonstrated a significant difference in CMC microstructural properties (as measured by fractional anisotropy (FA)) for individuals in M1c and S1c groups. There were no significant differences between responders and nonresponders in clinical baseline measures or microstructural properties (FA) in the CST. The present study identifies a white matter biomarker, which extends beyond the CST, advancing our understanding of the importance of white matter networks for motor after stroke.

An acute bout of exercise modulates both intracortical and interhemispheric excitability.

Primary motor cortex (M1) excitability is modulated following a single session of cycling exercise. Specifically, short-interval intracortical inhibition and intracortical facilitation are altered following a session of cycling, suggesting that exercise affects the excitability of varied cortical circuits. Yet we do not know whether a session of exercise also impacts the excitability of interhemispheric circuits between, and other intracortical circuits within, M1. Here we present two experiments designed to address this gap in knowledge. In experiment 1, single and paired pulse transcranial magnetic stimulation (TMS) were used to measure intracortical circuits including, short-interval intracortical facilitation (SICF) tested at 1.1, 1.5, 2.7, 3.1 and 4.5 ms interstimulus intervals (ISIs), contralateral silent period (CSP) and interhemispheric interactions by measuring transcallosal inhibition (TCI) recorded from the abductor pollicus brevis muscles. All circuits were assessed bilaterally pre and two time points post (immediately, 30 min) moderate intensity lower limb cycling. SICF was enhanced in the left hemisphere after exercise at the 1.5 ms ISI. Also, CSP was shortened and TCI decreased bilaterally after exercise. In Experiment 2, corticospinal and spinal excitability were tested before and after exercise to investigate the locus of the effects found in Experiment 1. Exercise did not impact motor-evoked potential recruitment curves, Hoffman reflex or V-wave amplitudes. These results suggest that a session of exercise decreases intracortical and interhemispheric inhibition and increases facilitation in multiple circuits within M1, without concurrently altering spinal excitability. These findings have implications for developing exercise strategies designed to potentiate M1 plasticity and skill learning in healthy and clinical populations.

Multiple measures of corticospinal excitability are associated with clinical features of multiple sclerosis.

In individuals with multiple sclerosis (MS), transcranial magnetic stimulation (TMS) may be employed to assess the integrity of corticospinal system and provides a potential surrogate biomarker of disability. The purpose of this study was to provide a comprehensive examination of the relationship between multiple measures corticospinal excitability and clinical disability in MS (expanded disability status scale (EDSS)). Bilateral corticospinal excitability was assessed using motor evoked potential (MEP) input-output (IO) curves, cortical silent period (CSP), short-interval intracortical inhibition (SICI), intracortical facilitation (ICF) and transcallosal inhibition (TCI) in 26 individuals with MS and 11 healthy controls. Measures of corticospinal excitability were compared between individuals with MS and controls. We evaluated the relationship(s) between age and clinical demographics such as age at MS onset (AO), disease duration (DD) and clinical disability (EDSS) with measures of corticospinal excitability. Corticospinal excitability thresholds were higher, MEP latency and CSP onset delayed and MEP durations prolonged in individuals with MS compared to controls. Age, DD and EDSS correlated with corticospinal excitability thresholds. Also, TCI duration and the linear slope of the MEP amplitude IO curve correlated with EDSS. Hierarchical regression modeling demonstrated that combining multiple TMS-based measures of corticospinal excitability accounted for unique variance in clinical disability (EDSS) beyond that of clinical demographics (AO, DD). Our results indicate that multiple TMS-based measures of corticospinal and interhemispheric excitability provide insights into the potential neural mechanisms associated with clinical disability in MS. These findings may aid in the clinical evaluation, disease monitoring and prediction of disability in MS.

Loss of short-latency afferent inhibition and emergence of afferent facilitation following neuromuscular electrical stimulation.

Neuromuscular electrical stimulation (NMES) increases the excitability of corticospinal (CS) pathways by altering circuits in motor cortex (M1). How NMES affects circuits interposed between the ascending afferent volley and descending CS pathways is not known. Presently, we hypothesized that short-latency afferent inhibition (SAI) would be reduced and afferent facilitation (AF) enhanced when NMES increased CS excitability. NMES was delivered for 40 min over the ulnar nerve. To assess CS excitability, motor evoked potentials (MEPs) were evoked using transcranial magnetic stimulation (TMS) delivered at 120% resting threshold for first dorsal interosseus muscle. These MEPs increased by ∼1.7-fold following NMES, demonstrating enhanced CS excitability. SAI and AF were tested by delivering a "conditioning" electrical stimulus to the ulnar nerve 18-25 ms and 28-35 ms before a "test" TMS pulse, respectively. Conditioned MEPs were compared to unconditioned MEPs evoked in the same trials. TMS was adjusted so unconditioned MEPs were not different before and after NMES. At the SAI interval, conditioned MEPs were 25% smaller than unconditioned MEPs before NMES but conditioned and unconditioned MEPs were not different following NMES. At the AF interval, conditioned MEPs were not different from unconditioned MEPs before NMES, but were facilitated by 33% following NMES. Thus, when NMES increases CS excitability there are concurrent changes in the effect of afferent input on M1 excitability, resulting in a net increase in the excitatory effect of the ascending afferent volley on CS circuits. Maximising this excitatory effect on M1 circuits may help strengthen CS pathways and improve functional outcomes of NMES-based rehabilitation programs.

Neuromuscular electrical stimulation: implications of the electrically evoked sensory volley.

Neuromuscular electrical stimulation (NMES) generates contractions by depolarising axons beneath the stimulating electrodes. The depolarisation of motor axons produces contractions by signals travelling from the stimulation location to the muscle (peripheral pathway), with no involvement of the central nervous system (CNS). The concomitant depolarisation of sensory axons sends a large volley into the CNS and this can contribute to contractions by signals travelling through the spinal cord (central pathway) which may have advantages when NMES is used to restore movement or reduce muscle atrophy. In addition, the electrically evoked sensory volley increases activity in CNS circuits that control movement and this can also enhance neuromuscular function after CNS damage. The first part of this review provides an overview of how peripheral and central pathways contribute to contractions evoked by NMES and describes how differences in NMES parameters affect the balance between transmission along these two pathways. The second part of this review describes how NMES location (i.e. over the nerve trunk or muscle belly) affects transmission along peripheral and central pathways and describes some implications for motor unit recruitment during NMES. The third part of this review summarises some of the effects that the electrically evoked sensory volley has on CNS circuits, and highlights the need to identify optimal stimulation parameters for eliciting plasticity in the CNS. A goal of this work is to identify the best way to utilize the electrically evoked sensory volley generated during NMES to exploit mechanisms inherent to the neuromuscular system and enhance neuromuscular function for rehabilitation.

Neuromuscular electrical stimulation has a global effect on corticospinal excitability for leg muscles and a focused effect for hand muscles.

The afferent volley generated during neuromuscular electrical stimulation (NMES) can increase the excitability of human corticospinal (CS) pathways to muscles of the leg and hand. Over time, such increases can strengthen CS pathways damaged by injury or disease and result in enduring improvements in function. There is some evidence that NMES affects CS excitability differently for muscles of the leg and hand, although a direct comparison has not been conducted. Thus, the present experiments were designed to compare the strength and specificity of NMES-induced changes in CS excitability for muscles of the leg and hand. Two hypotheses were tested: (1) For muscles innervated by the stimulated nerve (target muscles), CS excitability will increase more for the hand than for the leg. (2) For muscles not innervated by the stimulated nerve (non-target muscles), CS excitability will increase for muscles of the leg but not muscles of the hand. NMES was delivered over the common peroneal (CP) nerve in the leg or the median nerve at the wrist using a 1-ms pulse width in a 20 s on, 20 s off cycle for 40 min. The intensity was set to evoke an M-wave that was ~15% of the maximal M-wave in the target muscle: tibialis anterior (TA) in the leg and abductor pollicis brevis (APB) in the hand. Ten motor-evoked potentials (MEPs) were recorded from the target muscles and from 2 non-target muscles of each limb using transcranial magnetic stimulation delivered over the "hotspot" for each muscle before and after the NMES. MEP amplitude increased significantly for TA (by 45 ± 6%) and for APB (56 ± 8%), but the amplitude of these increases was not different. In non-target muscles, MEPs increased significantly for muscles of the leg (42 ± 4%), but not the hand. Although NMES increased CS excitability for target muscles to the same extent in the leg and hand, the differences in the effect on non-target muscles suggest that NMES has a "global" effect on CS excitability for the leg and a "focused" effect for the hand. These differences may reflect differences in the specificity of afferent projections to the cortex. Global increases in CS excitability for the leg could be advantageous for rehabilitation as NMES applied to one muscle could strengthen CS pathways and enhance function for multiple muscles.

Changes in corticospinal excitability evoked by common peroneal nerve stimulation depend on stimulation frequency.

The afferent volley generated during neuromuscular electrical stimulation (NMES) can increase the excitability of the human corticospinal (CS) pathway. This study was designed to determine the effect of different frequencies of NMES applied over the common peroneal nerve on changes in CS excitability for the tibialis anterior (TA) muscle. We hypothesized that higher frequencies of stimulation would produce larger increases in CS excitability than lower frequencies. NMES was applied at 10, 50, 100, or 200 Hz during separate sessions held at least 48 h apart. The stimulation was delivered in a 20 s on, 20 s off cycle for 40 min using a 1 ms pulse width. The intensity of stimulation was set to evoke an M-wave in response to a single pulse that was 15% of the maximal M-wave. CS excitability was evaluated by the amplitude of motor-evoked potentials (MEPs) in TA evoked by transcranial magnetic stimulation. MEPs were recorded immediately before and after the 40 min of NMES and in each 20 s "off" period. For each subject, MEPs recorded during three successive "off" periods were averaged together (n = 9 MEPs), providing a temporal resolution of 2 min for assessing changes in CS excitability. When delivering NMES at 100 Hz, MEPs became significantly elevated from those evoked before the stimulation at the 24th min, and there was a twofold increase in MEP amplitude after 40 min. NMES delivered at 10, 50, and 200 Hz did not significantly alter MEP amplitude. The amplitude of MEPs evoked in soleus and vastus medialis followed similar patterns as those evoked simultaneously in TA, but these changes were mostly not of statistical significance. There were no changes in the ratio of maximal H-reflex to maximal M-wave in TA or soleus. These experiments demonstrate a frequency-dependent effect of NMES on CS excitability for TA and show that, under the conditions of the present study, 100-Hz stimulation was more effective than 10, 50, and 200 Hz. This effect of NMES on CS excitability was strongest in the stimulated muscle and may be mediated primarily at a supraspinal level. These results contribute to a growing body of knowledge about how the afferent volley generated during NMES influences the CNS and have implications for identifying optimal NMES parameters to augment CS excitability for rehabilitation of dorsiflexion after CNS injury.