Background. Abnormal brain excitability influences recovery after stroke at which time a prolonged transcranial magnetic stimulation (TMS)-induced electromyographic silent period is thought to reflect abnormal inhibitory interneuron excitability. Cortical excitability can be probed directly during the silent period using concurrent electroencephalography (EEG) of TMS-evoked responses. Objective. The primary study objectives were to characterize TMS-evoked cortical potentials (TEPs) using EEG and to investigate associations with persistent hand and arm motor dysfunction in individuals with chronic stroke. Methods. Thirteen participants with chronic stroke-related mild-moderate arm motor impairment and 12 matched controls completed a single TMS-EEG cortical excitability assessment. TEPs recorded from the vertex during cortical silent period (CSP) assessment and while at rest were used to evaluate differences in cortical excitability between stroke and control participants. Associations between TEPs and CSP duration with measures of upper extremity motor behavior were investigated. Results. Significantly increased TEP component peak amplitudes and delayed latencies were observed for stroke participants compared with controls during CSP assessment and while at rest. Delayed early TEP component (P30) peak latencies during CSP assessment were associated with less manual dexterity. CSP duration was prolonged in stroke participants, and correlated with P30 peak latency and paretic arm dysfunction. Conclusions. Abnormal cortical excitability directly measured by early TMS-evoked EEG responses during CSP assessment suggests abnormal cortical inhibition is associated with hand dysfunction in chronic stroke. Further investigation of abnormal cortical inhibition in specific brain networks is necessary to characterize the salient neurophysiologic mechanisms contributing to persistent motor dysfunction after stroke.
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.
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.
Background: Research imaging costs limit lesion-based analyses in already expensive large stroke rehabilitation trials. Despite the belief that lesion characteristics influence recovery and treatment response, prior studies have not sufficiently addressed whether lesion features are an important consideration in motor rehabilitation trial design. Objective: Using clinically-obtained neuroimaging, evaluate how lesion characteristics relate to upper extremity (UE) recovery and response to therapy in a large UE rehabilitation trial. Methods: We reviewed lesions from 297 participants with mild-moderate motor impairment in the Interdisciplinary Comprehensive Arm Rehabilitation Evaluation (ICARE) study and their association with motor recovery, measured by the UE Fugl-Meyer (UE-FM). Significant lesion features identified on correlational and bivariate analysis were further analyzed for associations with recovery and therapy response using longitudinal mixed models. Results: Prior radiographic stroke was associated with less recovery on UE-FM in participants with motor impairment from subsequent subcortical stroke (-5.8 points) and in the overall sample (-3.6 points), but not in participants with cortical or mixed lesions. Lesion volume was also associated with less recovery, particularly after subcortical stroke. Every decade increase in age was associated with 1 less point of recovery on UE-FM. Response to specific treatment regimens varied based on lesion characteristics. Subcortical stroke patients experienced slightly less recovery with higher doses of upper extremity task-oriented training. Participants with cortical or mixed lesions experienced more recovery with higher doses of usual and customary therapy. Other imaging features (leukoaraiosis, ischemic vs. hemorrhagic stroke) were not significant. Conclusions: ICARE clinical imaging revealed information useful for UE motor trial design: stratification of persons with and without prior radiographic stroke may be required in participants with subcortical stroke, the majority of motor rehabilitation trial participants. Most of the prior radiographic strokes were small and cortically-based, suggesting even minor prior brain injury remote to the acute stroke lesion may limit spontaneous and therapy-related recovery. Lesion location may be associated with response to different therapy regimens, but the effects are variable and of unclear significance.
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.
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.
BACKGROUND: The use of transcranial magnetic stimulation (TMS) to evaluate corticomotor excitability of lower limb (LL) muscles can provide insights about neuroplasticity mechanisms underlying LL rehabilitation. However, to date, a majority of TMS studies have focused on upper limb muscles. Posture-related activation is an important under-investigated factor influencing corticomotor excitability of LL muscles. OBJECTIVE: The purpose of this study was to evaluate effects of posture and background activation on corticomotor excitability of ankle muscles. METHODS: Fourteen young neurologically-unimpaired participants (26.1±4.1 years) completed the study. TMS-evoked motor evoked potentials (MEPs) were recorded from the tibialis anterior (TA) and soleus during 4 conditions - standing, standing coactivation, sitting, and sitting coactivation. TA and soleus MEP amplitudes were compared during: (1) standing versus sitting;(2) standing coactivation (standing while activating both TA and soleus) versus sitting coactivation; and (3) standing coactivation versus standing. For each comparison, background EMG for TA and soleus were matched. Trial-to-trial coefficient of variation of MEP amplitude and coil-positioning errors were additional dependent variables. RESULTS: No differences were observed in TA or soleus MEP amplitudes during standing versus sitting. Compared to sitting coactivation, larger MEPs were observed during standing coactivation for soleus but not TA. Compared to standing, the standing coactivation task demonstrated larger MEPs and reduced trial-to-trial MEP variability. CONCLUSION: Our findings suggest that incorporation of measurements in standing in future TMS studies may provide novel insights into neural circuits controlling LL muscles. Standing and standing coactivation tasks may be beneficial for obtaining functionally-relevant neuroplasticity assessments of LL musculature.
OBJECTIVE: Constraint-induced movement therapy (CIMT) has been shown to improve upper extremity voluntary movement and change cortical movement representation after stroke. Direct comparison of the differential degree of cortical reorganization according to chronicity in stroke subjects receiving CIMT has not been performed and was the purpose of this study. We hypothesized that a higher degree of cortical reorganization would occur in the early (less than 9 months post-stroke) compared to the late group (more than 12 months post-stroke).
METHODS: 17 early and 9 late subjects were enrolled. Each subject was evaluated using transcranial magnetic stimulation (TMS) and the Wolf Motor Function Test (WMFT) and received CIMT for 2 weeks.
RESULTS: The early group showed greater improvement in WMFT compared with the late group. TMS motor maps showed persistent enlargement in both groups but the late group trended toward more enlargement. The map shifted posteriorly in the late stroke group. The main limitation was the small number of TMS measures that could be acquired due to high motor thresholds, particularly in the late group.
CONCLUSION: CIMT appears to lead to greater improvement in motor function in the early phase after stroke. Greater cortical reorganization in map size and position occurred in the late group in comparison.
SIGNIFICANCE: The contrast between larger functional gains in the early group vs larger map changes in the late group may indicate that mechanisms of recovery change over the several months following stroke or that map changes are a time-dependent epiphenomenon.
Oscillatory interactions within functionally specialized but distributed brain regions are believed to be central to perceptual and cognitive functions. Here, using human scalp electroencephalography (EEG) recordings combined with source reconstruction techniques, we study how oscillatory activity functionally organizes different neocortical regions during a tactile discrimination task near the limit of spatial acuity. While undergoing EEG recordings, blindfolded participants felt a linear three-dot array presented electromechanically, under computer control, and reported whether the central dot was offset to the left or right. The average brain response differed significantly for trials with correct and incorrect perceptual responses in the timeframe approximately between 130 and 175. ms. During trials with correct responses, source-level peak activity appeared in the left primary somatosensory cortex (SI) at around 45. ms, in the right lateral occipital complex (LOC) at 130. ms, in the right posterior intraparietal sulcus (pIPS) at 160. ms, and finally in the left dorsolateral prefrontal cortex (dlPFC) at 175. ms. Spectral interdependency analysis of activity in these nodes showed two distinct distributed networks, a dominantly feedforward network in the beta band (12-30. Hz) that included all four nodes and a recurrent network in the gamma band (30-100. Hz) that linked SI, pIPS and dlPFC. Measures of network activity in both bands were correlated with the accuracy of task performance. These findings suggest that beta and gamma band oscillatory networks coordinate activity between neocortical regions mediating sensory and cognitive processing to arrive at tactile perceptual decisions.
Background: Despite intensive rehabilitation efforts, most stroke survivors have persistent functional disability of the paretic arm and hand. These motor impairments may be due in part to maladaptive changes in structural and functional connections between brain regions. The following early stage clinical trial study protocol describes a noninvasive brain stimulation approach to target transcallosally mediated interhemispheric connections between the ipsi- and contralesional motor cortices (iM1 and cM1) using corticocortical paired associative stimulation (ihPAS). This clinical trial aims to characterize ihPAS-induced modulation of interhemispheric connectivity and the effect on motor skill performance and learning in chronic stroke survivors. Methods/Design: A repeated-measures, cross-over design study will recruit 20 individuals post-stroke with chronic mild-moderate paretic arm impairment. Each participant will complete an active ihPAS and control ihPAS session. Assessments of cortical excitability and motor skill performance will be conducted prior to and at four time points following the ihPAS intervention. The primary outcome measures will be: TMS-evoked interhemispheric motor connectivity, corticomotor excitability, and response time on a modified serial reaction time task. Discussion/Conclusion: The findings from this single-site early stage clinical trial will provide foundational results to inform the design of larger-scale, multisite clinical trials to evaluate the therapeutic potential of ihPAS-based neuromodulation for upper limb recovery after stroke. This trial is registered with NCT02465034.