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.

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.

Myelin status is associated with change in functional mobility following slope walking in people with multiple sclerosis.

BACKGROUND: The level of myelin disruption in multiple sclerosis patients may impact the capacity for training-induced neuroplasticity and the magnitude of therapeutic response to rehabilitation interventions. Downslope walking has been shown to increase functional mobility in individuals with multiple sclerosis, but it is unclear if myelin status influences therapeutic response. OBJECTIVE: The current study aimed to examine the relationship between baseline myelin status and change in functional mobility after a walking intervention. METHODS: The Timed Up and Go test was used to measure functional mobility before and after completion of a repeated, six-session slope walking intervention in 16 participants with relapsing-remitting multiple sclerosis. Multi-component T2 relaxation imaging was used to index myelin water fraction of overall water content in brain tissue compartments. RESULTS: Results demonstrated that the ratio of the myelin water fraction in lesion to normal-appearing white matter (myelin water fraction ratio) significantly predicted 31% of the variance in change in Timed Up and Go score after the downslope walking intervention, where less myelin disruption was associated with greater intervention response. CONCLUSIONS: Myelin water content fraction ratio may offer a neural biomarker of myelin to identify potential responders to interventions targeting functional impairments in multiple sclerosis.

Establishing between-session reliability of TMS-conditioned soleus H-reflexes.

Transcranial magnetic stimulation (TMS) of the primary motor cortex (M1) can be used to evaluate descending corticomotor influences on spinal reflex excitability through modulation of the Hoffman reflex (H-reflex). The purpose of this study was to characterize between-session reliability of cortical, spinal, and cortical-conditioned spinal excitability measures collected from the soleus muscle. Thirteen able-bodied young adult participants were tested over four sessions. Intraclass correlation coefficients were calculated to quantify between-session reliability of active motor threshold (AMT), unconditioned H-reflexes (expressed as a percentage of Mmax), and conditioned H-reflexes using short-latency facilitation (SLF) and long-latency facilitation (LLF). Pearson correlation coefficients were calculated to assess associations between H-reflex facilitation and unconditioned H-reflex amplitude. Between-session reliability for SLF (ICC=0.71) was higher than for LLF (ICC=0.45), was excellent for AMT (ICC=0.95), and was moderate for unconditioned H-reflexes (ICC=0.63). Our results suggest moderate-to-good reliability of SLF and LLF to evaluate cortical influences on spinal reflex excitability across multiple testing sessions in able-bodied individuals.

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.

Understanding the role of the primary somatosensory cortex: Opportunities for rehabilitation.

Emerging evidence indicates impairments in somatosensory function may be a major contributor to motor dysfunction associated with neurologic injury or disorders. However, the neuroanatomical substrates underlying the connection between aberrant sensory input and ineffective motor output are still under investigation. The primary somatosensory cortex (S1) plays a critical role in processing afferent somatosensory input and contributes to the integration of sensory and motor signals necessary for skilled movement. Neuroimaging and neurostimulation approaches provide unique opportunities to non-invasively study S1 structure and function including connectivity with other cortical regions. These research techniques have begun to illuminate casual contributions of abnormal S1 activity and connectivity to motor dysfunction and poorer recovery of motor function in neurologic patient populations. This review synthesizes recent evidence illustrating the role of S1 in motor control, motor learning and functional recovery with an emphasis on how information from these investigations may be exploited to inform stroke rehabilitation to reduce motor dysfunction and improve therapeutic outcomes.

Comparing a diffusion tensor and non-tensor approach to white matter fiber tractography in chronic stroke.

Diffusion tensor imaging (DTI)-based tractography has been used to demonstrate functionally relevant differences in white matter pathway status after stroke. However, it is now known that the tensor model is insensitive to the complex fiber architectures found in the vast majority of voxels in the human brain. The inability to resolve intra-voxel fiber orientations may have important implications for the utility of standard DTI-based tract reconstruction methods. Intra-voxel fiber orientations can now be identified using novel, tensor-free approaches. Constrained spherical deconvolution (CSD) is one approach to characterize intra-voxel diffusion behavior. In the current study, we performed DTI- and CSD-based tract reconstruction of the corticospinal tract (CST) and corpus callosum (CC) to test the hypothesis that characterization of complex fiber orientations may improve the robustness of fiber tract reconstruction and increase the sensitivity to identify functionally relevant white matter abnormalities in individuals with chronic stroke. Diffusion weighted magnetic resonance imaging was performed in 27 chronic post-stroke participants and 12 healthy controls. Transcallosal pathways and the CST bilaterally were reconstructed using DTI- and CSD-based tractography. Mean fractional anisotropy (FA), apparent diffusion coefficient (ADC), axial diffusivity (AD), and radial diffusivity (RD) were calculated across the tracts of interest. The total number and volume of reconstructed tracts was also determined. Diffusion measures were compared between groups (Stroke, Control) and methods (CSD, DTI). The relationship between post-stroke motor behavior and diffusion measures was evaluated. Overall, CSD methods identified more tracts than the DTI-based approach for both CC and CST pathways. Mean FA, ADC, and RD differed between DTI and CSD for CC-mediated tracts. In these tracts, we discovered a difference in FA for the CC between stroke and healthy control groups using CSD but not DTI. CSD identified ipsilesional CST pathways in 9 stroke participants who did not have tracts identified with DTI. Additionally, CSD differentiated between stroke ipsilesional and healthy control non-dominant CST for several measures (number of tracts, tract volume, FA, ADC, and RD) whereas DTI only detected group differences for number of tracts. In the stroke group, motor behavior correlated with fewer diffusion metrics derived from the DTI as compared to CSD-reconstructed ipsilesional CST and CC. CSD is superior to DTI-based tractography in detecting differences in diffusion characteristics between the nondominant healthy control and ipsilesional CST. CSD measures of microstructure tissue properties related to more motor outcomes than DTI measures did. Our results suggest the potential utility and functional relevance of characterizing complex fiber organization using tensor-free diffusion modeling approaches to investigate white matter pathways in the brain after stroke.

Evaluation of white matter myelin water fraction in chronic stroke.

Multi-component T2 relaxation imaging (MCRI) provides specific in vivo measurement of myelin water content and tissue water environments through myelin water fraction (MWF), intra/extra-cellular water fraction (I/EWF) and intra/extracellular and global geometric mean T2 (GMT2) times. Quantitative MCRI assessment of tissue water environments has provided new insights into the progression and underlying white matter pathology in neural disorders such as multiple sclerosis. It has not previously been applied to investigate changes in white matter in the stroke-affected brain. Thus, the purposes of this study were to 1) use MCRI to index myelin water content and tissue water environments in the brain after stroke 2) evaluate relationships between MWF and diffusion behavior indexed by diffusion tensor imaging-based metrics and 3) examine the relationship between white matter status (MWF and fractional anisotropy) and motor behavior in the chronic phase of stroke recovery. Twenty individuals with ischemic stroke and 12 matched healthy controls participated. Excellent to good test/re-test and inter-rater reliability was observed for region of interest-based voxelwise MWF data. Reduced MWF was observed in whole-cerebrum white matter (p < 0.001) and in the ipsilesional (p = 0.017) and contralesional (p = 0.037) posterior limb of internal capsule (PLIC) after stroke compared to whole-cerebrum and bilateral PLIC MWF in healthy controls. The stroke group also demonstrated increased I/EWF, I/E GMT2 and global GMT2 times for whole-cerebrum white matter. Measures of diffusion behavior were also significantly different in the stroke group across each region investigated (p < 0.001). MWF was not significantly correlated with specific tensor-based measures of diffusion in the PLIC for either group. Fractional anisotropy in the ipsilesional PLIC correlated with motor behavior in chronic stroke. These results provide novel insights into tissue-specific changes within white matter after stroke that may have important applications for the understanding of the neuropathology of stroke.