Faculty Bibliography

Introduction: Spasticity, muscle stiffness, and contracture cause severe disability after central nervous system injury. However, current treatment options for spasticity produce muscle weakness which can impede movement and do not directly address muscle stiffness. Here we propose that the accumulation of hyaluronan within muscles promotes the development of muscle stiffness and report that treatment with the enzyme hyaluronidase increases upper limb movement and reduces muscle stiffness without producing weakness. Methods: 20 patients with unilateral upper limb spasticity received multiple intramuscular injections of human recombinant hyaluronidase with saline at a single visit. The safety and efficacy of the injections, passive and active movement, and muscle stiffness at eight upper limb joints were assessed at four time points: pre-injection (T0), within 2 weeks (T1), within 4- 6 weeks (T2), and within 3-5 months post-injection (T3). There were no clinically significant adverse effects from the injections. Results: Passive movement at all joints and active movement at most joints increased at T1, and persisted at T2 and T3 for most joints. The modified Ashworth scores also declined significantly over time post-injection. Conclusion: Hyaluronidase injections offer a safe and potentially efficacious treatment for muscle stiffness in neurologically impaired individuals. These results warrant confirmation in placebo-controlled clinical trials.

Spasticity develops as a result of central nervous system (CNS) injury; however, secondary changes within the muscles and connective tissue also contribute to muscle stiffness. The hyaluronan hypothesis postulates that the accumulation of hyaluronan promotes the development of muscle stiffness. Intramuscular injections of the enzyme hyaluronidase, which hydrolyzes long-chained hyaluronan polymers to smaller polymers, was shown to reduce muscle stiffness and increase passive and active range of motion in patients with spasticity. These results provide preliminary evidence of the hyaluronan hypothesis and suggest an emerging therapy to reduce muscle stiffness using the enzyme hyaluronidase.

A common goal in data-analysis is to sift through a large data-matrix and detect any significant submatrices (i.e., biclusters) that have a low numerical rank. We present a simple algorithm for tackling this biclustering problem. Our algorithm accumulates information about 2-by-2 submatrices (i.e., 'loops') within the data-matrix, and focuses on rows and columns of the data-matrix that participate in an abundance of low-rank loops. We demonstrate, through analysis and numerical-experiments, that this loop-counting method performs well in a variety of scenarios, outperforming simple spectral methods in many situations of interest. Another important feature of our method is that it can easily be modified to account for aspects of experimental design which commonly arise in practice. For example, our algorithm can be modified to correct for controls, categorical- and continuous-covariates, as well as sparsity within the data. We demonstrate these practical features with two examples; the first drawn from gene-expression analysis and the second drawn from a much larger genome-wide-association-study (GWAS).

OBJECTIVES/OBJECTIVE:To identify the characteristics of stroke survivors with poor physical function. STUDY DESIGN/METHODS:Cross-sectional. METHODS:Secondary data analyses were performed with the 2015 Behavioral Risk Factor Surveillance System data set. Unadjusted and adjusted logistic regressions were employed to determine the correlates of poor physical function in stroke survivors. Self-reported difficulty with walking and stairs was used as a proxy for physical function. Characteristics such as age, race, sex, difficulty doing errands alone, difficult dressing or bathing alone, health care coverage, time since last routine checkup, and reported financial difficulty with regard to health care access were examined as contributing factors to physical function. RESULTS:Approximately half of all stroke survivors reported having difficulty with walking and stairs (50.3%). As expected, the odds of reporting difficulty with walking and stairs were higher among stroke survivors aged 40 years and above (p < 0.0001). Interestingly, black/African American and multiracial respondents had higher odds of reporting difficulty with walking and stairs than whites, whereas Hispanic respondents had lower odds of reporting difficulty with walking and stairs than whites (p < 0.0001). Further analyses revealed that the disparity of physical function was preserved (p < 0.0001) after adjusting for age, race, sex, education level, family income, marital status, employment status, health insurance status, affordability of healthcare, and length of time from last doctor's visit. CONCLUSIONS:There were racial/ethnic disparities in physical function. Specifically, blacks/ African Americans had a 5.6% increase in the odds of reporting difficulty with walking and stairs than whites. Moreover, Hispanics reported significantly fewer problems than whites. Overall, similar sociocultural patterns in non-stroke and stroke populations were observed in this study.

Introduction/Background: Few options exist for training arm movements in patients with little active movement in their affected arm after a stroke. The purpose of this study was to test the efficacy of bimanual-to-unimanual training in reducing upper limb motor impairment and active movement in the affected arm, and to examine the effect of training dose on motor learning. Material and method: Twenty subjects with chronic post-stroke hemiparesis underwent 6 weeks of usual care. They then received 12 one-hour sessions of bimanual-to-unimanual training using the Bimanual Arm Trainer (BAT, Mirrored Motion Works, Inc.). The training consisted of bimanual training of both arms followed by unimanual training of the affected arm alone. Some patients received the 12 sessions over 4 weeks, whereas others received it within 6 weeks. Extent of motor impairment on the Fugl-Meyer scale and active movement at upper limb joints was examined at baseline and pre- and post-training. The degree of improvement in the affected arm was computed both within and between training sessions as well as pre- and post-training. Repeated measures ANOVA was performed on the variables of interest. Results: Bimanual-to-unimanual training led to a significant improvement in upper limb Fugl-Meyer scores and active movement compared with usual care (P < 0.05). The difference was significantly greater in patients who underwent 12 sessions of training within 4 weeks compared with those who underwent training over 6 weeks. Changes in within and between session learning curves enable characterization of patterns of motor learning across individuals that can facilitate the development of algorithms for precision rehabilitation for post-stroke motor learning and recovery. Conclusion: Bimanual-to-unimanual arm training can reduce motor impairment in patients with chronic post-stroke hemiparesis. Higher frequency of training leads to greater improvements despite the same total dose. The study provides a means for understanding dosing of treatment for motor learning post-stroke.

BACKGROUND:While the cognitive sequelae of traumatic brain injury (TBI) are well known, emotional impairments after TBI are suboptimally characterized. Lack of awareness of emotional difficulties can make self-report unreliable. However, individuals with TBI demonstrate involuntary changes in heart rate variability which may enable objective quantification of emotional dysfunction. METHODS:Sixteen subjects with chronic TBI and 10 age-matched controls were tested on an emotional function battery during which they watched a series of film clips normed to elicit specific positively and negatively valenced emotions: amusement, sexual amusement, sadness, fear and disgust. Subjective responses to the emotional stimuli were also obtained. Additionally, surface electrodes measured cardiac and respiratory signals to compute heart rate variability (HRV), from which measures of parasympathetic activity, the respiratory frequency area (RFA) and sympathetic activity, the low frequency area (LFA), of the HRV frequency spectrum were derived. The Neurobehavioral Rating Scale-Revised (NRS-R) and the King-Devick (KD) test were administered to assess neurobehavioral dysfunction. RESULTS:The two groups showed no differences in subjective ratings of emotional intensity. Subjects with TBI showed significantly decreased sympathetic activity when viewing amusing stimuli and significantly increased sympathetic activity when viewing sad stimuli compared to controls. Most of the subjects did not show agitation, anxiety, depression, blunted affect, emotional withdrawal, decreased motivation or mental fatiguability on the NRS-R. However, 13/16 subjects with TBI demonstrated attention difficulty on the NRS-R which was positively correlated with the increased sympathetic activity during sad stimuli. Both attention difficulty and abnormal autonomic responses to sad stimuli were correlated with the timing on the KD test, which reflected difficulty with visual attention shifting. CONCLUSIONS:The HRV spectrum may be useful to identify subclinical emotional dysfunction in individuals with TBI. Attention difficulites, specifically impairment in visual attention shifting, may contribute to abnormal reactivity to sad stimuli that may be detected and potentially treated to improve emotional function.

OBJECTIVE: To determine the feasibility and efficacy of using a structured Nintendo Wii protocol to improve range of motion, strength, and quality of life in patients with shoulder impingement syndrome. METHODS: A total of 14 patients with shoulder pain were randomized to perform a structured Wii protocol (n=8) or conventional therapy (n=6). Pain-free shoulder range of motion, strength, shoulder pain and disability, and quality of life were assessed pre- and post-treatment. RESULTS: All 8 patients completed the Wii protocol, and 3 completed conventional therapy. The Wii protocol conferred significant improvements in shoulder range of motion, pain and disability, and quality of life but not strength, whereas conventional therapy conferred a significant improvement in strength. CONCLUSIONS: As compared to conventional treatment, the structured Wii protocol implemented in this pilot study was a viable adjunct to therapy for shoulder impingement syndrome. Gaming may have a supplemental benefit by increasing motivation, pleasure, and/or adherence. Further investigation in larger cohorts is warranted.

BACKGROUND: Few options exist for training arm movements in participants with severe post-stroke hemiparesis who have little active range of motion. The purpose of this study was to test the safety and feasibility of training with a non-powered device, the Bimanual Arm Trainer (BAT), to facilitate motor recovery in individuals with severe hemiparesis. The BAT enabled coupled bimanual training of shoulder external rotation, which is reduced in individuals with severe post-stroke hemiplegia. The rationale for bimanual training was to harness contralesional cortical activity to drive voluntary movement in the affected arm in patients who could barely perform unimanual movements. METHODS: Nine participants with post-stroke hemiparesis, preserved passive range of motion and Modified Ashworth score of <3 in the shoulder and elbow joints, trained with the device for 45 minutes, twice a week for six weeks, and were assessed pre- and post-training. RESULTS: All participants tolerated the training and no adverse events were reported. Participants showed significant improvement in the upper extremity Fugl-Meyer score post-training with an effect size of 0.89. Changes in the flexor synergy pattern accounted for 64.7% of the improvement. Improvement in active range of motion in the paretic limb occurred for both trained and untrained movements. Some participants showed improvement in the time taken to perform selected tasks on the Wolf Motor Function Test post-training. CONCLUSION: The results demonstrate the safety and feasibility of using the Bimanual Arm Trainer to facilitate motor recovery in individuals with severe hemiparesis.

Saccades rapidly direct the line of sight to targets of interest to make use of the high acuity foveal region of the retina. These fast eye movements are instrumental for scanning visual scenes, foveating targets, and, ultimately, serve to guide manual motor control, including eye-hand coordination. Cerebral injury has long been known to impair ocular motor control. Recently, it has been suggested that alterations in control may be useful as a marker for recovery. We measured eye movement control in a saccade task in subjects with chronic middle cerebral artery stroke with both cortical and substantial basal ganglia involvement and in healthy controls. Saccade latency distributions were bimodal, with an early peak at 60 ms (anticipatory saccades) and a later peak at 250 ms (regular saccades). Although the latencies corresponding to these peaks were the same in the two groups, there were clear differences in the size of the peaks. Classifying saccade latencies relative to the saccade "go signal" into anticipatory (latencies up to 80 ms), "early" (latencies between 80 and 160 ms), and "regular" types (latencies longer than 160 ms), stroke subjects displayed a disproportionate number of anticipatory saccades, whereas control subjects produced the majority of their saccades in the regular range. We suggest that this increase in the number of anticipatory saccade events may result from a disinhibition phenomenon that manifests as an impairment in the endogenous control of ocular motor events (saccades) and interleaved fixations. These preliminary findings may help shed light on the ocular motor deficits of neurodegenerative conditions, results that may be subclinical to an examiner, but clinically significant secondary to their functional implications.