Sleep benefits perceptual but not movement-based learning of locomotor sequences.

Practicing complex locomotor skills, such as those involving a step sequence engages distinct perceptual and motor mechanisms that support the recall of learning under new conditions (i.e., skill transfer). While sleep has been shown to enhance learning of sequences of fine movements (i.e., sleep-dependent consolidation), here we examined whether this benefit extends to learning of a locomotor pattern. Specifically, we tested the perceptual and motor learning of a locomotor sequence following sleep compared to wake. We hypothesized that post-practice sleep would increase locomotor sequence learning in the perceptual, but not in the motor domain. In this study, healthy young adult participants (n = 48; 18-33 years) practiced a step length sequence on a treadmill cued by visual stimuli displayed on a screen during training. Participants were then tested in a perceptual condition (backward walking with the same visual stimuli), or a motor condition (forward walking but with an inverted screen). Skill was assessed immediately, and again after a 12-h delay following overnight sleep or daytime wake (n = 12 for each interval/condition). Off-line learning improved following sleep compared to wake, but only for the perceptual condition. Our results suggest that perceptual and motor sequence learning are processed separately after locomotor training, and further points to a benefit of sleep that is rooted in the perceptual as opposed to the motor aspects of motor learning.

Resting state brain network segregation is associated with walking speed and working memory in older adults.

Older adults exhibit larger individual differences in walking ability and cognitive function than young adults. Characterizing intrinsic brain connectivity differences in older adults across a wide walking performance spectrum may provide insight into the mechanisms of functional decline in some older adults and resilience in others. Thus, the objectives of this study were to: (1) determine whether young adults and high- and low-functioning older adults show group differences in brain network segregation, and (2) determine whether network segregation is associated with working memory and walking function in these groups. The analysis included 21 young adults and 81 older adults. Older adults were further categorized according to their physical function using a standardized assessment; 54 older adults had low physical function while 27 were considered high functioning. Structural and functional resting state magnetic resonance images were collected using a Siemens Prisma 3T scanner. Working memory was assessed with the NIH Toolbox list sorting test. Walking speed was assessed with a 400 m-walk test at participants' self-selected speed. We found that network segregation in mobility-related networks (sensorimotor, vestibular, and visual networks) was higher in younger adults compared to older adults. There were no group differences in laterality effects on network segregation. We found multivariate associations between working memory and walking speed with network segregation scores. Higher right anterior cingulate cortex network segregation was associated with higher working memory function. Higher right sensorimotor, right vestibular, right anterior cingulate cortex, and lower left anterior cingulate cortex network segregation was associated with faster walking speed. These results are unique and significant because they demonstrate higher network segregation is largely related to higher physical function and not age alone.

Reduced corticospinal drive and inflexible temporal adaptation during visually guided walking in older adults.

Corticospinal drive during walking is reduced in older adults compared with young adults, but it is not clear how this decrease might compromise one's ability to adjust stepping, particularly during visuomotor adaptation. We hypothesize that age-related changes in corticospinal drive could predict differences in older adults' step length and step time adjustments in response to visual perturbations compared with younger adults. Healthy young (n = 21; age 18-33 yr) and older adults (n = 20; age 68-80 yr) were tested with a treadmill task, incorporating visual feedback of the foot position and stepping targets in real-time. During adaptation, the visuomotor gain was reduced on one side, causing the foot cursor and step targets to move slower on that side of the screen (i.e., split-visuomotor adaptation). Corticospinal drive was quantified by coherence between electromyographic signals in the beta-gamma frequency band (15-45 Hz). The results showed that 1) older adults adapted to visuomotor perturbations during walking, with a similar reduction in error asymmetry compared with younger adults; 2) however, older adults showed reduced adaptation in step time symmetry, despite demonstrating similar adaptation in step length asymmetry compared with younger adults; and 3) smaller overall changes in step time asymmetry was associated with reduced corticospinal drive to the tibialis anterior in the slow leg during split-visuomotor adaptation. These findings suggest that changes in corticospinal drive may affect older adults' control of step timing in response to visual challenges. This could be important for safe navigation when walking in different environments or dealing with unexpected circumstances.NEW & NOTEWORTHY Corticospinal input is essential for visually guided walking, especially when the walking pattern must be modified to accurately step on safe locations. Age-related changes in corticospinal drive are associated with inflexible step time, which necessitates different locomotor adaptation strategies in older adults.

Comparison of the conventional and immersing powdered crude drugs (IPCD) methods for color and extraction of quantitative indicator ingredients in the Kampo formula decoction of daiokanzoto.

AIM: The immersing powdered crude drugs (IPCD) method is a quick and simple method for preparing decoctions. Here, the conventional and IPCD methods were compared for the color and extraction of quantitative indicator ingredients in the daiokanzoto decoction solution, and the suitability of the IPCD method was assessed. METHODS: The color of decoction solutions was visually observed, and the Commission Internationale de L'éclairage (CIE) L*a*b*color parameters were measured using conventional and IPCD methods. The extracted amounts of sennoside A and glycyrrhizic acid, which are quantitative indicator ingredients of rhubarb and glycyrrhiza, respectively, were quantified. RESULTS: Using both methods, the decoction solution colors were strong for rhubarb alone and daiokanzoto but weak for glycyrrhiza alone. The color change of daiokanzoto was thought to be primarily caused by rhubarb alone. The L*a*b* values of the decoction solution determined by the IPCD method were comparable to those determined by the conventional method (60 min). Using the conventional method, sennoside A and glycyrrhizic acid were mostly extracted in 10 and 30 min, respectively. Using the IPCD method, both sennoside A and glycyrrhizic acid were fully extracted in 2 min. The IPCD method yielded significantly more sennoside A and glycyrrhizic acid (2 times and 1.5 times, respectively) than the conventional method (60 min). CONCLUSION: The IPCD method was found to be comparable to the conventional method in terms of the color, and using IPCD method, the same or greater amounts of quantitative indicator ingredients of crude drugs in the decoction of daiokanzoto compared to the conventional method. It was suggested that there are limitations to assessing the equivalence of decoctions from decoction color. The IPCD method may be a useful method although it is prudent to use the IPCD method for Kampo formula decoction in clinical practice with a certain degree of caution.

Asymmetric shoe height induces reactive changes in gait kinematics but not kinetics in healthy young adults.

BACKGROUND: Footwear interventions are a potential avenue to correct walking asymmetry in neurologic populations, such as stroke. However, the motor learning mechanisms that underlie the changes in walking imposed by asymmetric footwear are unclear. RESEARCH QUESTION: The objectives of this study were to examine symmetry changes during and after an asymmetric shoe height intervention in (1) vertical impulse and (2) spatiotemporal gait parameters and (3) joint kinematics, in healthy young adults METHODS: Eleven healthy young adults (3 males, 8 females; 21.2 ± 3.1 years old) participated in this study. Participants walked on an instrumented treadmill at 1.3 m/s for four conditions: (1) a 5-minute familiarization with equal shoe height, (2) a 5-minute baseline with equal shoe height, (3) a 10-minute intervention, where participants walked with asymmetric shoe height with a 10 mm shoe insert in one shoe, and (4) a 10-minute post-intervention, where participants walked with equal shoe height. Asymmetry in kinetics and kinematics were used to identify changes during intervention and aftereffects, a hallmark of feedforward adaptation RESULTS: Participants did not alter vertical impulse asymmetry (p = 0.667) nor stance time asymmetry (p = 0.228). During the intervention, step time asymmetry (p = 0.003) and double support asymmetry (p < 0.001) were greater compared to baseline. Leg joint asymmetry during stance (Ankle plantarflexion: p < 0.001; Knee flexion: p < 0.001; Hip extension: p = 0.011) was greater during the intervention compared to baseline. However, changes in spatiotemporal gait variables and joint mechanics did not demonstrate aftereffects. SIGNIFICANCE: Our results show that healthy human adults change gait kinematics, but not weight-bearing symmetry with asymmetrical footwear. This suggests that healthy humans prioritize maintaining vertical impulse by changing their kinematics. Further, the changes in gait kinematics are short-lived, suggesting feedback-based control, and a lack of feedforward motor adaptations.

Comparison of EEG Source Localization Using Simplified and Anatomically Accurate Head Models in Younger and Older Adults.

Accuracy of electroencephalography (EEG) source localization relies on the volume conduction head model. A previous analysis of young adults has shown that simplified head models have larger source localization errors when compared with head models based on magnetic resonance images (MRIs). As obtaining individual MRIs may not always be feasible, researchers often use generic head models based on template MRIs. It is unclear how much error would be introduced using template MRI head models in older adults that likely have differences in brain structure compared to young adults. The primary goal of this study was to determine the error caused by using simplified head models without individual-specific MRIs in both younger and older adults. We collected high-density EEG during uneven terrain walking and motor imagery for 15 younger (22±3 years) and 21 older adults (74±5 years) and obtained [Formula: see text]-weighted MRI for each individual. We performed equivalent dipole fitting after independent component analysis to obtain brain source locations using four forward modeling pipelines with increasing complexity. These pipelines included: 1) a generic head model with template electrode positions or 2) digitized electrode positions, 3) individual-specific head models with digitized electrode positions using simplified tissue segmentation, or 4) anatomically accurate segmentation. We found that when compared to the anatomically accurate individual-specific head models, performing dipole fitting with generic head models led to similar source localization discrepancies (up to 2 cm) for younger and older adults. Co-registering digitized electrode locations to the generic head models reduced source localization discrepancies by  âˆ¼  6 mm. Additionally, we found that source depths generally increased with skull conductivity for the representative young adult but not as much for the older adult. Our results can help inform a more accurate interpretation of brain areas in EEG studies when individual MRIs are unavailable.

Spatiotemporal gait changes in people with multiple sclerosis with different disease progression subtypes.

BACKGROUND: Gait impairment is common in people with multiple sclerosis (MS), but less is known about gait differences between MS disease progression subtypes. The objective here was to examine differences in spatiotemporal gait in MS and between relapsing-remitting and progressive subtypes during the timed-25-ft-walk test. Our specific aims were to investigate (1) spatiotemporal, (2) spatiotemporal variability, and (3) gait modulation differences between healthy controls and MS subtypes at preferred and fast walking speed. METHODS: This study included 27 controls, 18 relapsing-remitting MS, and 13 progressive MS participants. Participants wore six inertial sensors and walked overground without walking aids at preferred and fast-as-possible speeds. FINDINGS: Both MS groups had significantly lower walking speed than controls, with a trend towards lower preferred gait speed in progressive compared to relapsing-remitting MS (ES = 0.502). Although most spatiotemporal gait parameters differed between controls and MS groups, differences were not significant between MS subtypes in these parameters and their variability, with low to moderate effect sizes during preferred and fast walking. Both MS groups showed reduced modulation in gait compared to controls and no significant differences between MS subtypes. INTERPRETATION: Gait in MS is altered compared to controls. Although gait may change with progressive MS, the overall small differences in the gait parameters between the MS subtypes observed in this sample suggests that those with the progressive form of MS who are independently ambulatory and without further clinically meaningful changes in gait speed may not show gait decrements greater than the relapsing-remitting form of the disease.

Corticospinal drive is associated with temporal walking adaptation in both healthy young and older adults.

Healthy aging is associated with reduced corticospinal drive to leg muscles during walking. Older adults also exhibit slower or reduced gait adaptation compared to young adults. The objective of this study was to determine age-related changes in the contribution of corticospinal drive to ankle muscles during walking adaptation. Electromyography (EMG) from the tibialis anterior (TA), soleus (SOL), medial, and lateral gastrocnemius (MGAS, LGAS) were recorded from 20 healthy young adults and 19 healthy older adults while they adapted walking on a split-belt treadmill. We quantified EMG-EMG coherence in the beta-gamma (15-45 Hz) and alpha-band (8-15 Hz) frequencies. Young adults demonstrated higher coherence in both the beta-gamma band coherence and alpha band coherence, although effect sizes were greater in the beta-gamma frequency. The results showed that slow leg TA-TA coherence in the beta-gamma band was the strongest predictor of early adaptation in double support time. In contrast, early adaptation in step length symmetry was predicted by age group alone. These findings suggest an important role of corticospinal drive in adapting interlimb timing during walking in both young and older adults.

Neural Control of Human Locomotor Adaptation: Lessons about Changes with Aging.

Walking patterns are adaptable in response to different environmental demands, which requires neural input from spinal and supraspinal structures. With an increase in age, there are changes in walking adaptation and in the neural control of locomotion, but the age-related changes in the neural control of locomotor adaptation is unclear. The purpose of this narrative review is to establish a framework where the age-related changes of neural control of human locomotor adaptation can be understood in terms of reactive feedback and predictive feedforward control driven by sensory feedback during locomotion. We parse out the effects of aging on (a) reactive adaptation to split-belt walking, (b) predictive adaptation to split-belt walking, (c) reactive visuomotor adaptation, and (d) predictive visuomotor adaptation, and hypothesize that specific neural circuits are influenced differentially with age, which influence locomotor adaptation. The differences observed in the age-related changes in walking adaptation across different locomotor adaptation paradigms will be discussed in light of the age-related changes in the neural mechanisms underlying locomotion.

Visuomotor errors drive step length and step time adaptation during 'virtual' split-belt walking: the effects of reinforcement feedback.

Precise foot placement is dependent on changes in spatial and temporal coordination between two legs in response to a perturbation during walking. Here, we used a 'virtual' split-belt adaptation task to examine the effects of reinforcement (reward and punishment) feedback about foot placement on the changes in error, step length and step time asymmetry. Twenty-seven healthy adults (20 ± 2.5 years) walked on a treadmill with continuous feedback of the foot position and stepping targets projected on a screen, defined by a visuomotor gain for each leg. The paradigm consisted of a baseline period (same gain on both legs), visuomotor adaptation period (split: one high = 'fast', one low = 'slow' gain) and post-adaptation period (same gain). Participants were divided into 3 groups: control group received no score, reward group received increasing score for each target hit, and punishment group received decreasing score for each target missed. Re-adaptation was assessed 24 ± 2 h later. During early adaptation, the slow foot undershot and fast foot overshot the stepping target. Foot placement errors were gradually reduced by late adaptation, accompanied by increasing step length asymmetry (fast < slow step length) and step time asymmetry (fast > slow step time). Only the punishment group showed greater error reduction and step length re-adaptation on the next day. The results show that (1) explicit feedback of foot placement alone drives adaptation of both step length and step time asymmetry during virtual split-belt walking, and (2) specifically, step length re-adaptation driven by visuomotor errors may be enhanced by punishment feedback.

Non-ambulatory measures of lower extremity sensorimotor function are associated with walking function in Multiple Sclerosis.

BACKGROUND: Disease progression of multiple sclerosis (MS) is often monitored by ambulatory measures, but how non-ambulatory sensorimotor measures differentially associate to walking measures in MS subtypes is unknown. We determined whether there are characteristic differences between relapsing-remitting MS (RRMS), progressive MS (PMS), and non-MS controls in lower extremity sensorimotor function and clinical walking tasks and the sensorimotor associations with walking function in each group. METHODS: 18 RRMS, 13 PMS and 28 non-MS control participants were evaluated in their plantar cutaneous sensitivity (vibration perception threshold, Volts), proprioception during ankle joint position-matching (|∆°| in dorsiflexion), motor coordination (rapid foot-tap count/10 s), and walking function with three tests: Timed 25-foot walk (T25FW) at preferred and fast speeds (s), and timed-up-and-go (TUG, s). RESULTS: Foot-tapping (p = 0.039, Mean difference (MD)= 5.65 taps) and plantar cutaneous sensation (p = 0.026, MD= -10.30 V) differed between the MS subtypes. For the RRMS group faster walking was related to better proprioceptive function (preferred T25FW: p = 0.019, Root mean square error (RMSE)=1.94; fast T25FW: p = 0.004, RMSE=1.65; TUG: p = 0.001, RMSE=2.12) and foot-tap performance (preferred T25FW: p = 0.033, RMSE = 2.74; fast T25FW: p = 0.010, RMSE=2.02). These associations were not observed in the PMS group. CONCLUSIONS: Foot-tap performance and plantar cutaneous sensitivity but not ankle proprioception differed between MS subtypes. Lower walking performance was associated with lower foot-tapping and plantar cutaneous sensitivity in the RRMS but not the PMS group. This result suggests a change in the relationship of lower extremity sensorimotor function to walking performance in the PMS subtype.

Verbal feedback enhances motor learning during post-stroke gait retraining.

BACKGROUND: Fast treadmill walking combined with functional electrical stimulation to ankle muscles (FastFES) is a well-studied gait intervention that improves post-stroke walking function. Although individualized verbal feedback is commonly incorporated during clinical gait training, and a variable practice structure is posited to enhance learning, the influence of these two factors on motor learning during locomotor interventions such as FastFES is poorly understood. OBJECTIVES: To determine if the addition of individualized verbal feedback or variable practice to a FastFES training session enhances motor learning of targeted gait patterns. METHODS: Nine individuals with post-stroke hemiparesis completed a crossover study comprising exposure to 3 dose-matched types of gait training: (1) FastFES (FF), comprising five 6-minute bouts of training with intermittent FES, (2) FF with addition of individualized verbal instructions and faded feedback delivered by a physical therapist (FF+PT), (3) FF with variable gait speed and FES timing (FF+Var). Gait biomechanics data were collected before (Pre), immediately after (Post), and 24-h following (Retention) each training type. Within-session and retention change scores of 3 targeted gait variables were calculated to assess locomotor learning. RESULTS: FF+PT resulted in larger improvements within-session and at retention in trailing limb angle, and a trend for larger improvements in paretic pushoff compared to FF. FF+Var failed to show greater learning of biomechanical variables compared to FF. CONCLUSIONS: Addition of individualized verbal feedback (FF+PT) to a single session of gait training may enhance within- and across-session learning of targeted gait variables in people post-stroke, and merits more investigation.

Sensorimotor function in progressive multiple sclerosis.

BACKGROUND: A sensitive test reflecting subtle sensorimotor changes throughout disease progression independent of mobility impairment is currently lacking in progressive multiple sclerosis. OBJECTIVES: We examined non-ambulatory measures of upper and lower extremity sensorimotor function that may reveal differences between relapsing-remitting and progressive forms of multiple sclerosis. METHODS: Cutaneous sensitivity, proprioception, central motor function and mobility were assessed in 32 relapsing-remitting and 31 progressive multiple sclerosis patients and 30 non-multiple sclerosis controls. RESULTS: Cutaneous sensation differed between relapsing-remitting and progressive multiple sclerosis at the foot and to a lesser extent the hand. Proprioception function in the upper but not the lower extremity differed between relapsing-remitting and progressive multiple sclerosis, but was different for both upper and lower extremities between multiple sclerosis patients and non-multiple sclerosis controls. Foot-tap but not hand-tap speed was slower in progressive compared to relapsing-remitting multiple sclerosis, suggestive of greater central motor function impairment in the lower extremity in progressive multiple sclerosis. In addition, the non-ambulatory sensorimotor measures were more sensitive in detecting differences between relapsing-remitting and progressive multiple sclerosis than mobility assessed with the 25-foot walk test. CONCLUSION: This study provides novel information about changes in sensorimotor function in progressive compared with relapsing-remitting forms of multiple sclerosis, and in particular the importance of assessing both upper and lower extremity function. Importantly, our findings showed loss of proprioceptive function in multiple sclerosis but also in progressive compared to relapsing-remitting multiple sclerosis.

Rapid foot-tapping but not hand-tapping ability is different between relapsing-remitting and progressive multiple sclerosis.

BACKGROUND: Rapid tapping tests have been shown to be reliable measures of upper motor neuron disease, and effectively examine motor function differences between multiple sclerosis (MS) and non-MS controls (CON), and between relapsing-remitting and progressive MS subtypes. To successfully perform rapid repetitive movements such as tapping, a person must be able to consistently turn on and off motor units to switch between the up and down movement phases. However, it is not clear which specific movement phase that occurs during tapping is different between MS subtypes. The objective of this study was to quantify and characterize performance differences during rapid hand- and foot-tapping tests between relapsing-remitting (RRMS) and progressive (PMS) forms of MS, as well as how both subtypes differ from non-MS controls. METHODS: Participants in this study included 30 non-MS controls, 32 RRMS, and 31 PMS. Participants wore inertial sensors on all hands and feet and were instructed to tap as fast as possible for 10 s. Angular velocity from the gyroscope was used to quantify inter-tap interval (ms), coefficient of variation of inter-tap interval (COV), and up- and down-movement characteristics (duration (ms), COV, peak angular velocity (rad/s)). Differences between groups were examined with ANOVA and independent t-tests. Inter-tap interval was examined for its ability to distinguish between RRMS and PMS by a binary logistic regression analysis. Up-down movement characteristics were further evaluated for within-group directional differences (up- vs. down-phase movement components) with paired-sample t-tests. RESULTS: Inter-tap interval for both hand- and foot-tapping differed between controls and MS, but only foot tapping was different between RRMS and PMS (RRMS = 286.7 ± 83.0 ms; PMS = 379.5 ± 170.9 ms; mean difference (d) = -92.8 ms). Logistic regression analysis showed foot-tap interval but not hand-tap interval has the potential to distinguish between RRMS and PMS (Area under the ROC = 0.71). Both up- and down-movement duration differences were consistent with the results for inter-tap interval, but up-movement duration showed larger mean group differences than down-movement differences. No significant group differences in overall inter-tap interval COV were detected for either hand- or foot-tapping; however, up-movement foot-tapping variation (CON = 18.7 ± 6.1; RRMS = 25.5 ± 11.2; PMS = 23.3 ± 8.6; CON vs RRMS d = -6.8; CON vs PMS d = -4.7), but not down-movement variation was different between controls and MS. Up- and down-peak angular velocity during foot-tapping were different between controls and PMS (CON Up = 1.4 ± 0.5 rad/s; PMS Up = 1.0 ± 0.4 rad/s; Up d = 0.4 rad/s; CON Down= 1.5 ± 0.6 rad/s; PMS Down = 1.2 ± 0.5 rad/s; Down d = 0.3 rad/s), and up-movement peak angular velocity differences showed larger mean group differences than the down-movement peak angular velocity between controls and PMS. CONCLUSION: Foot-tapping differs between MS disease subtypes and has greater potential than hand-tapping to distinguish between subtypes. Performance in the up-movement showed larger group differences than the down-movement, suggesting that the anti-gravity up-movement during tapping may be more important diagnostically. Future studies should be conducted on the nature of the physiological mechanisms underlying impairments in anti-gravity movements in people with MS.

Increased intramuscular coherence is associated with temporal gait symmetry during split-belt locomotor adaptation.

When walking on a split-belt treadmill where one belt moves faster than the other, the nervous system consistently attempts to maintain symmetry between legs, quantified as deviation from double support time or step length symmetry. It is known that the cerebellum plays a critical role in locomotor adaptation. Less is known about the role of corticospinal drive in maintaining this type of proprioceptive-driven locomotor adaptation. The objective of this study was to examine the functional role of oscillatory drive in relation to changes in spatiotemporal gait parameters during split-belt walking adaptation. Eighteen healthy participants adapted and deadapted on a split-belt treadmill; 13 out of 18 participants repeated the paradigm two more times to examine the effects of reexposure. Coherence analysis was used to quantify the coupling between electromyography (EMG) from the proximal (TAprox) and distal tibialis anterior (TAdist) muscle during the swing phase of walking. EMG-EMG coherence was examined within the alpha (8-15 Hz), beta (15-30 Hz), and gamma (30-45 Hz) frequencies. Our results showed that 1) beta- and gamma-band coherence (markers of corticospinal drive) increased during early split-belt walking compared with baseline walking in the slow leg, 2) beta-band coherence decreased from early to late split-belt adaptation in the fast leg, 3) alpha-, beta-, and gamma-band coherence decreased from first to third split-belt exposure in the fast leg, and 4) there was a relationship between higher beta coherence in the slow leg TA and smaller double support asymmetry. Our results suggest that corticospinal drive may play a functional role in the temporal control of split-belt walking adaptation.NEW & NOTEWORTHY This is the first study to examine the functional role of intramuscular coherence in relation to changes in spatiotemporal gait parameters during split-belt walking adaptation. We found that the corticospinal drive measured by intramuscular coherence in tibialis anterior changes with adaptation and that the corticospinal drive is related to temporal but not spatial parameters. This study may give insight as to the specific role of the motor cortex during gait.

Opportunities for concurrent transcranial magnetic stimulation and electroencephalography to characterize cortical activity in stroke.

Stroke is the leading cause of disability in the United States. Despite the high incidence and mortality of stroke, sensitive and specific brain-based biomarkers predicting persisting disabilities are lacking. Both neuroimaging techniques like electroencephalography (EEG) and non-invasive brain stimulation (NIBS) techniques such as transcranial magnetic stimulation (TMS) have proven useful in predicting prognosis, recovery trajectories and response to rehabilitation in individuals with stroke. We propose, however, that additional synergetic effects can be achieved by simultaneously combining both approaches. Combined TMS-EEG is able to activate discrete cortical regions and directly assess local cortical reactivity and effective connectivity within the network independent of the integrity of descending fiber pathways and also outside the motor system. Studying cortical reactivity and connectivity in patients with stroke TMS-EEG may identify salient neural mechanisms underlying motor disabilities and lead to novel biomarkers of stroke pathophysiology which can then be used to assess, monitor, and refine rehabilitation approaches for individuals with significant disability to improve outcomes and quality of life after stroke.