Valid biomarkers of motor system function after stroke could improve clinical decision-making. Electroencephalography-based measures are safe, inexpensive, and accessible in complex medical settings ...and so are attractive candidates. This study examined specific electroencephalography cortical connectivity measures as biomarkers by assessing their relationship with motor deficits across 28 days of intensive therapy. Resting-state connectivity measures were acquired four times using dense array (256 leads) electroencephalography in 12 hemiparetic patients (7.3 ± 4.0 months post-stroke, age 26-75 years, six male/six female) across 28 days of intensive therapy targeting arm motor deficits. Structural magnetic resonance imaging measured corticospinal tract injury and infarct volume. At baseline, connectivity with leads overlying ipsilesional primary motor cortex (M1) was a robust and specific marker of motor status, accounting for 78% of variance in impairment; ipsilesional M1 connectivity with leads overlying ipsilesional frontal-premotor (PM) regions accounted for most of this (R(2) = 0.51) and remained significant after controlling for injury. Baseline impairment also correlated with corticospinal tract injury (R(2) = 0.52), though not infarct volume. A model that combined a functional measure of connectivity with a structural measure of injury (corticospinal tract injury) performed better than either measure alone (R(2) = 0.93). Across the 28 days of therapy, change in connectivity with ipsilesional M1 was a good biomarker of motor gains (R(2) = 0.61). Ipsilesional M1-PM connectivity increased in parallel with motor gains, with greater gains associated with larger increases in ipsilesional M1-PM connectivity (R(2) = 0.34); greater gains were also associated with larger decreases in M1-parietal connectivity (R(2) = 0.36). In sum, electroencephalography measures of motor cortical connectivity-particularly between ipsilesional M1 and ipsilesional premotor-are strongly related to motor deficits and their improvement with therapy after stroke and so may be useful biomarkers of cortical function and plasticity. Such measures might provide a biological approach to distinguishing patient subgroups after stroke.
Objective
This study was undertaken to better understand the high variability in response seen when treating human subjects with restorative therapies poststroke. Preclinical studies suggest that ...neural function, neural injury, and clinical status each influence treatment gains; therefore, the current study hypothesized that a multivariate approach incorporating these 3 measures would have the greatest predictive value.
Methods
Patients 3 to 6 months poststroke underwent a battery of assessments before receiving 3 weeks of standardized upper extremity robotic therapy. Candidate predictors included measures of brain injury (including to gray and white matter), neural function (cortical function and cortical connectivity), and clinical status (demographics/medical history, cognitive/mood, and impairment).
Results
Among all 29 patients, predictors of treatment gains identified measures of brain injury (smaller corticospinal tract CST injury), cortical function (greater ipsilesional motor cortex M1 activation), and cortical connectivity (greater interhemispheric M1–M1 connectivity). Multivariate modeling found that best prediction was achieved using both CST injury and M1–M1 connectivity (r2 = 0.44, p = 0.002), a result confirmed using Lasso regression. A threshold was defined whereby no subject with >63% CST injury achieved clinically significant gains. Results differed according to stroke subtype; gains in patients with lacunar stroke were best predicted by a measure of intrahemispheric connectivity.
Interpretation
Response to a restorative therapy after stroke is best predicted by a model that includes measures of both neural injury and function. Neuroimaging measures were the best predictors and may have an ascendant role in clinical decision making for poststroke rehabilitation, which remains largely reliant on behavioral assessments. Results differed across stroke subtypes, suggesting the utility of lesion‐specific strategies. ANN NEUROL 2015;77:132–145
Background. Standardizing scoring reduces variability and increases accuracy. A detailed scoring and training method for the Fugl-Meyer motor assessment (FMA) is described and assessed, and ...implications for clinical trials considered. Methods. A standardized FMA scoring approach and training materials were assembled, including a manual, scoring sheets, and instructional video plus patient videos. Performance of this approach was evaluated for the upper extremity portion. Results. Inter- and intrarater reliability in 31 patients were excellent (intraclass correlation coefficient = 0.98-0.99), validity was excellent (r = 0.74-0.93, P < .0001), and minimal detectable change was low (3.2 points). Training required 1.5 hours and significantly reduced error and variance among 50 students, with arm FMA scores deviating from the answer key by 3.8 ± 6.2 points pretraining versus 0.9 ± 4.9 points posttraining. The current approach was implemented without incident into training for a phase II trial. Among 66 patients treated with robotic therapy, change in FMA was smaller (P ≤ .01) at the high and low ends of baseline FMA scores. Conclusions. Training with the current method improved accuracy, and reduced variance, of FMA scoring; the 20% FMA variance reduction with training would decrease sample size requirements from 137 to 88 in a theoretical trial aiming to detect a 7-point FMA difference. Minimal detectable change was much smaller than FMA minimal clinically important difference. The variation in FMA gains in relation to baseline FMA suggests that future trials consider a sliding outcome approach when FMA is an outcome measure. The current training approach may be useful for assessing motor outcomes in restorative stroke trials.
Many therapies are emerging that aim to improve motor function in people with stroke. Identifying key biological substrates needed for treatment gains would help to predict treatment effects and to ...maximize treatment impact. The current study addressed the hypothesis that behavioral gains from therapy targeting distal upper extremity are predicted by the structural integrity of key motor system white matter tracts.
Twenty-three subjects with chronic left-sided stroke underwent robotic therapy targeting the distal right upper extremity. MRI was obtained at baseline and used to outline the infarct. For each subject, the degree to which stroke injured each of 4 descending white matter tracts (from the primary motor cortex, supplementary motor area, dorsal premotor cortex, and ventral premotor cortex, respectively) was determined. Correlations between tract-specific injury and behavioral gains from therapy were then examined.
Numerous examples were found whereby tract-specific injury predicted treatment gains. The strongest correlations pertained to stroke injury to tracts descending from the primary motor cortex and dorsal premotor cortex. Infarct volume and baseline behavior were weak predictors of treatment gains.
Extent of injury to specific motor tracts predicts behavioral gains from treatment in subjects with chronic stroke. This supports a role for these tracts in mediating treatment effects and reinforces the importance of lesion location in stroke. Tract-specific injury was stronger than infarct volume or baseline clinical status at predicting gains, identifies subjects with sufficient biological substrate to improve from therapy, and so might be useful as an entry criterion in repair-based trials.
While the corpus callosum (CC) is important to normal sensorimotor function, its role in motor function after stroke is less well understood. This study examined the relationship between structural ...integrity of the motor and sensory sections of the CC, as reflected by fractional anisotropy (FA), and motor function in individuals with a range of motor impairment level due to stroke. Fifty-five individuals with chronic stroke (Fugl-Meyer motor score range 14 to 61) and 18 healthy controls underwent diffusion tensor imaging and a set of motor behavior tests. Mean FA from the motor and sensory regions of the CC and from corticospinal tract (CST) were extracted and relationships with behavioral measures evaluated. Across all participants, FA in both CC regions was significantly decreased after stroke (
< 0.001) and showed a significant, positive correlation with level of motor function. However, these relationships varied based on degree of motor impairment: in individuals with relatively less motor impairment (Fugl-Meyer motor score > 39), motor status correlated with FA in the CC but not the CST, while in individuals with relatively greater motor impairment (Fugl-Meyer motor score ≤ 39), motor status correlated with FA in the CST but not the CC. The role interhemispheric motor connections play in motor function after stroke may differ based on level of motor impairment. These findings emphasize the heterogeneity of stroke, and suggest that biomarkers and treatment approaches targeting separate subgroups may be warranted.
Biomarkers that capture treatment effects could improve the precision of clinical decision making for restorative therapies. We examined the performance of candidate structural, functional, and ...angiogenesis-related MRI biomarkers before and after a 3-week course of standardized robotic therapy in 18 patients with chronic stroke and hypothesized that results vary significantly according to stroke severity. Patients were 4.1 ± 1 months poststroke, with baseline arm Fugl-Meyer scores of 20–60. When all patients were examined together, no imaging measure changed over time in a manner that correlated with treatment-induced motor gains. However, when also considering the interaction with baseline motor status, treatment-induced motor gains were significantly related to change in three functional connectivity measures: ipsilesional motor cortex connectivity with (1) contralesional motor cortex (p=0.003), (2) contralesional dorsal premotor cortex (p=0.005), and (3) ipsilesional dorsal premotor cortex (p=0.004). In more impaired patients, larger treatment gains were associated with greater increases in functional connectivity, whereas in less impaired patients larger treatment gains were associated with greater decreases in functional connectivity. Functional connectivity measures performed best as biomarkers of treatment effects after stroke. The relationship between changes in functional connectivity and treatment gains varied according to baseline stroke severity. Biomarkers of restorative therapy effects are not one-size-fits-all after stroke.
High doses of activity-based rehabilitation therapy improve outcomes after stroke, but many patients do not receive this for various reasons such as poor access, transportation difficulties, and low ...compliance. Home-based telerehabilitation (TR) can address these issues. The current study evaluated the feasibility of an expanded TR program.
Under the supervision of a licensed therapist, adults with stroke and limb weakness received home-based TR (1 h/day, 6 days/week) delivered using games and exercises. New features examined include extending therapy to 12 weeks duration, treating both arm and leg motor deficits, patient assessments performed with no therapist supervision, adding sensors to real objects, ingesting a daily experimental (placebo) pill, and generating automated actionable reports.
Enrollees (
= 13) were median age 61 (IQR 52-65.5), and 129 (52-486) days post-stroke. Patients initiated therapy on 79.9% of assigned days and completed therapy on 65.7% of days; median therapy dose was 50.4 (33.3-56.7) h. Non-compliance doubled during weeks 7-12. Modified Rankin scores improved in 6/13 patients, 3 of whom were >3 months post-stroke. Fugl-Meyer motor scores increased by 6 (2.5-12.5) points in the arm and 1 (-0.5 to 5) point in the leg. Assessments spanning numerous dimensions of stroke outcomes were successfully implemented; some, including a weekly measure that documented a decline in fatigue (
= 0.004), were successfully scored without therapist supervision. Using data from an attached sensor, real objects could be used to drive game play. The experimental pill was taken on 90.9% of therapy days. Automatic actionable reports reliably notified study personnel when critical values were reached.
Several new features performed well, and useful insights were obtained for those that did not. A home-based telehealth system supports a holistic approach to rehabilitation care, including intensive rehabilitation therapy, secondary stroke prevention, screening for complications of stroke, and daily ingestion of a pill. This feasibility study informs future efforts to expand stroke TR.
Clinicaltrials.gov, # NCT03460587.
Background In the United States, there are over seven million stroke survivors, with many facing gait impairments due to foot drop. This restricts their community ambulation and hinders functional ...independence, leading to several long-term health complications. Despite the best available physical therapy, gait function is incompletely recovered, and this occurs mainly during the acute phase post-stroke. Therapeutic options are limited currently. Novel therapies based on neurobiological principles have the potential to lead to long-term functional improvements. The Brain-Computer Interface (BCI) controlled Functional Electrical Stimulation (FES) system is one such strategy. It is based on Hebbian principles and has shown promise in early feasibility studies. The current study describes the BCI-FES clinical trial, which examines the safety and efficacy of this system, compared to conventional physical therapy (PT), to improve gait velocity for those with chronic gait impairment post-stroke. The trial also aims to find other secondary factors that may impact or accompany these improvements and establish the potential of Hebbian-based rehabilitation therapies. Methods This Phase II clinical trial is a two-arm, randomized, controlled, longitudinal study with 66 stroke participants in the chronic (> 6 months) stage of gait impairment. The participants undergo either BCI-FES paired with PT or dose-matched PT sessions (three times weekly for four weeks). The primary outcome is gait velocity (10-meter walk test), and secondary outcomes include gait endurance, range of motion, strength, sensation, quality of life, and neurophysiological biomarkers. These measures are acquired longitudinally. Discussion BCI-FES holds promise for gait velocity improvements in stroke patients. This clinical trial will evaluate the safety and efficacy of BCI-FES therapy when compared to dose-matched conventional therapy. The success of this trial will inform the potential utility of a Phase III efficacy trial. Trial registration The trial was registered as "BCI-FES Therapy for Stroke Rehabilitation" on February 19, 2020, at clinicaltrials.gov with the identifier NCT04279067. Keywords: Stroke, Brain-computer interface, Electroencephalography, Functional electrical stimulation, Lower extremity rehabilitation, Gait velocity, Brain plasticity, Motor learning, Neurorehabilitation
Developing oligodendrocytes undergo a well-characterized maturation process that is controlled by extrinsic factors that promote specification, proliferation, and differentiation. Inhibitory factors ...also influence oligodendrocyte development and may regulate the location and number of oligodendrocytes available for myelination. These factors may also repress regeneration and remyelination after injury. Bone morphogenetic proteins (BMPs) comprise a family of factors that inhibit oligodendrocyte development in vitro and when they are overexpressed in vivo. These effects seem to be mediated by the actions of inhibitors of DNA-binding protein on transcription factors that promote myelination. Bone morphogenetic protein signaling deletion studies have generated a complex picture in which the main effect of BMPs is on oligodendrocyte differentiation and depends on the level of signaling. Bone morphogenetic proteins are significantly upregulated in demyelinated areas in models of myelin injury and disease, and blocking of BMP signaling aids recovery. It is not yet known, however, whether this occurs by promoting differentiation of oligodendrocyte precursors or by inhibiting astrogliosis because BMPs also promote astrogliogenesis. Understanding the actions of BMPs will be important for promoting recovery in patients with demyelinating diseases and other types of CNS injury.
To examine the validity of 5 robot-based assessments of arm motor function poststroke.
Cross-sectional study.
Outpatient clinical research center.
Volunteer sample of participants (N=40; age, >18y; ...3-6mo poststroke) with arm motor deficits that had reached a stable plateau.
Not applicable.
Clinical standards included the arm motor domain of the Fugl-Meyer Assessment (FMA) and 5 secondary motor outcomes: hand/wrist subsection of the arm motor domain of the FMA, Action Research Arm Test, Box and Block test (BBT), hand motor subscale of the Stroke Impact Scale Version 2.0, and Barthel Index. Robot-based assessments included wrist targeting, finger targeting, finger movement speed, reaction time, and a robotic version of the BBT. Anatomical measures included percent injury to the corticospinal tract (CST) and extent of injury of the hand region of the primary motor cortex obtained from magnetic resonance imaging.
Participants had moderate to severe impairment (arm motor domain of the FMA scores, 35.6±14.4; range, 13.5-60). Performance on the robot-based tests, including speed (r=.82; P<.0001), wrist targeting (r=.72; P<.0001), and finger targeting (r=.67; P<.0001), correlated significantly with the arm motor domain of the FMA scores. Wrist targeting (r=.57-.82) and finger targeting (r=.49-.68) correlated significantly with all 5 secondary motor outcomes and with percent CST injury. The robotic version of the BBT correlated significantly with the clinical BBT but was less prone to floor effects. Robot-based assessments were comparable to the arm motor domain of the FMA score in relation to percent CST injury and superior in relation to extent of injury to the hand region of the primary motor cortex.
The present findings support using a battery of robot-based methods for assessing the upper extremity motor function in participants with chronic stroke.
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