Jill See

Anatomy of Stroke Injury Predicts Gains From Therapy

Background and Purpose— 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. Methods— 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. Results— 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. Conclusions— 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.

Safety and Behavioral Effects of High-Frequency Repetitive Transcranial Magnetic Stimulation in Stroke

Background and Purpose— Electromagnetic brain stimulation might have value to reduce motor deficits after stroke. Safety and behavioral effects of higher frequencies of repetitive transcranial magnetic stimulation (rTMS) require detailed assessment. Methods— Using an active treatment-only, unblinded, 2-center study design, patients with chronic stroke received 20 minutes of 20 Hz rTMS to the ipsilesional primary motor cortex hand area. Patients were assessed before, during the hour after, and 1 week after rTMS. Results— The 12 patients were 4.7±4.9 years poststroke (mean±SD) with moderate–severe arm motor deficits. In terms of safety, rTMS was well tolerated and did not cause new symptoms; systolic blood pressure increased from pre- to immediately post-rTMS by 7 mm Hg (P=0.043); and none of the behavioral measures showed a decrement. In terms of behavioral effects, modest improvements were seen, for example, in grip strength, range of motion, and pegboard performance, up to 1 week after rTMS. The strongest predictor of these motor gains was lower patient age. Conclusions— A single session of high-frequency rTMS to the motor cortex was safe. These results require verification with addition of a placebo group and thus blinded assessments across a wide spectrum of poststroke deficits and with larger doses of 20 Hz rTMS.

Neural function, injury, and stroke subtype predict treatment gains after stroke

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.

Connectivity measures are robust biomarkers of cortical function and plasticity after stroke.

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.

A standardized approach to the Fugl-Meyer assessment and its implications for clinical trials.

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.

Targeted engagement of a dorsal premotor circuit in the treatment of post-stroke paresis

BACKGROUND Good motor outcome after stroke has been found to correlate with increased activity in a dorsal premotor (PMd) brain circuit, suggesting that therapeutic strategies targeting this circuit might have a favorable, causal influence on motor status. OBJECTIVE This study addressed the hypothesis that a Premotor Therapy that exercises normal PMd functions would provide greater behavioral gains than would standard Motor Therapy; and that Premotor Therapy benefits would be greatest in patients with greater preservation of PMd circuit elements. METHODS Patients with chronic hemiparetic stroke (n = 15) were randomized to 2-weeks of Premotor Therapy or Motor Therapy, implemented through a robotic device. RESULTS Overall, gains were modest but significant (change in FM score, 2.1 ± 2.8 points, p < 0.02) and did not differ by treatment assignment. However, a difference between Therapies was apparent when injury to the PMd circuit was considered, as the interaction between treatment assignment and degree of corticospinal tract injury was significantly related to the change in FM score (p = 0.018): the more the corticospinal tract was spared, the greater the gains provided by Premotor Therapy. Similar results were obtained when looking at the interaction between treatment assignment and PMd function (p = 0.03). CONCLUSIONS Targeted engagement of a brain circuit is a feasible strategy for stroke rehabilitation. This approach has maximum impact when there is less stroke injury to key elements of the targeted circuit.

Role of corpus callosum integrity in arm function differs based on motor severity after stroke

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 (p < 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.

Validity of Robot-Based Assessments of Upper Extremity Function

OBJECTIVE To examine the validity of 5 robot-based assessments of arm motor function poststroke. DESIGN Cross-sectional study. SETTING Outpatient clinical research center. PARTICIPANTS Volunteer sample of participants (N=40; age, >18y; 3-6mo poststroke) with arm motor deficits that had reached a stable plateau. INTERVENTIONS Not applicable. MAIN OUTCOME MEASURES 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. RESULTS 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. CONCLUSIONS The present findings support using a battery of robot-based methods for assessing the upper extremity motor function in participants with chronic stroke.

A Home-Based Telerehabilitation Program for Patients With Stroke

Background. Although rehabilitation therapy is commonly provided after stroke, many patients do not derive maximal benefit because of access, cost, and compliance. A telerehabilitation-based program may overcome these barriers. We designed, then evaluated a home-based telerehabilitation system in patients with chronic hemiparetic stroke. Methods. Patients were 3 to 24 months poststroke with stable arm motor deficits. Each received 28 days of telerehabilitation using a system delivered to their home. Each day consisted of 1 structured hour focused on individualized exercises and games, stroke education, and an hour of free play. Results. Enrollees (n = 12) had baseline Fugl-Meyer (FM) scores of 39 ± 12 (mean ± SD). Compliance was excellent: participants engaged in therapy on 329/336 (97.9%) assigned days. Arm repetitions across the 28 days averaged 24,607 ± 9934 per participant. Arm motor status showed significant gains (FM change 4.8 ± 3.8 points, P = .0015), with half of the participants exceeding the minimal clinically important difference. Although scores on tests of computer literacy declined with age (r = −0.92; P < .0001), neither the motor gains nor the amount of system use varied with computer literacy. Daily stroke education via the telerehabilitation system was associated with a 39% increase in stroke prevention knowledge (P = .0007). Depression scores obtained in person correlated with scores obtained via the telerehabilitation system 16 days later (r = 0.88; P = .0001). In-person blood pressure values closely matched those obtained via this system (r = 0.99; P < .0001). Conclusions. This home-based system was effective in providing telerehabilitation, education, and secondary stroke prevention to participants. Use of a computer-based interface offers many opportunities to monitor and improve the health of patients after stroke.

Biomarkers of Rehabilitation Therapy Vary according to Stroke Severity

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.