Brian D. Schmit

Diffusion Tensor MR Imaging in Chronic Spinal Cord Injury

BACKGROUND AND PURPOSE: Diffusion tensor MR imaging is emerging as an important tool for displaying anatomic changes in the brain after injury or disease but has been less widely applied to disorders of the spinal cord. The aim of this study was to characterize the diffusion properties of the entire human spinal cord in vivo during the chronic stages of spinal cord injury (SCI). These data provide insight into the structural changes that occur as a result of long-term recovery from spinal trauma. MATERIALS AND METHODS: Thirteen neurologically intact subjects and 10 subjects with chronic SCI (>4 years postinjury) were enrolled in this study. A single-shot twice-refocused spin-echo diffusion-weighted echo-planar imaging pulse sequence was used to obtain axial images throughout the entire spinal cord (C1-L1) in <60 minutes. RESULTS: Despite heterogeneity in SCI lesion severity and location, diffusion characteristics of the chronic lesion were significantly elevated compared with those of uninjured controls. Fractional anisotropy was significantly lower at the chronic lesion and appeared dependent on the completeness of the injury. Conversely, mean diffusivity measurements in the upper cervical spinal cord in subjects with SCI were significantly lower than those in controls. These trends suggest that the entire neuraxis may be affected by long-term recovery from spinal trauma. CONCLUSION: These results suggest that diffusion tensor imaging may be useful in the assessment of SCI recovery.

Stretch Reflex Adaptation in Elbow Flexors During Repeated Passive Movements in Unilateral Brain-Injured Patients

OBJECTIVE To evaluate the effects of repeated, externally imposed, flexion-extension movements of the elbow on the resulting stretch reflex response in hemiparetic spastic brain-injured patients. These effects were compared within a recording session and across sessions for the same subject to determine the impact of movement history on the quantification of spastic hypertonia using the stretch reflex response. DESIGN Twenty to 30 sequential, constant velocity flexion-extension movements were applied to the impaired elbow of our cohort, with a 10-second hold interposed between flexion and extension. Movements were applied regularly at 1-minute intervals. Changes in stretch reflex responses were monitored during the applied movements. PARTICIPANTS We examined a convenience sample of seven hemiparetic brain-injured subjects between the ages of 26 and 60 yrs, with moderate-to-severe spastic hypertonia of elbow muscles (Ashworth score 2-4/4). Subjects participated in 2 to 9 sessions. MEASURES Elbow torque, position, velocity, and electromyograms of the biceps, brachioradialis, and triceps muscles were recorded for each flexion and extension movement. Stretch reflex torque was calculated by subtracting passive torque from total elbow torque, recorded over large amplitude movements. A linear regression analysis quantified both the initial torque response of the stretch reflex and the ensuing adaptation of the stretch reflex during sequential movements. Intersession variability was characterized both for spastic hypertonia measures and for stretch reflex adaptation. RESULTS Repeated, externally imposed, sequential flexion-extension movements of the elbow decreased the elbow flexor stretch reflex in six of seven subjects. The mean reduction in reflex torque after 30 movements was 50% of the initial torque values (p = .001, t test vs. 0% change). Intersession stretch reflex responses for each subject were found to vary greatly (SDs of reflex torque ranged from 0.1 to 4.0 Nm), and there were also significant variations in the degree of adaptation between subjects. CONCLUSIONS Stretch reflex adaptation must be taken into consideration when spastic hypertonia is quantified using repeated joint motion, as is often the case. The magnitude of intersession variation in spastic hypertonia measures suggests that ideally, such measurements should be made across multiple sessions before conclusions are made regarding the efficacy of spastic hypertonia interventions. This study provides quantitative evidence that repeated joint movements may have a significant short-term beneficial effect on spastic hypertonia.

Flexor reflexes in chronic spinal cord injury triggered by imposed ankle rotation

Hypersensitivity of the flexor reflexes to input from force‐sensitive muscle afferents may contribute to the prevalence and severity of muscle spasms in patients with spinal cord injuries. In the present study, we triggered flexor reflexes with constant‐velocity ankle movements into end‐range dorsiflexion and plantarflexion positions in 8 individuals with spinal cord injuries. We found that all 8 subjects had coordinated increases in flexion torque at the hip and ankle following externally imposed plantarflexion movements at the ankle. In addition, end‐range dorsiflexion movements also triggered flexor reflexes in 3 subjects, although greater loads were required to trigger such reflexes using dorsiflexion movements (compared to plantarflexion movements). These three‐joint reflex torque patterns triggered by ankle movement were broadly comparable to flexion withdrawal responses elicited by electrocutaneous stimuli applied to a toe, although the amplitude of the torque response was generally lower. We conclude that excitation of muscle and joint‐related afferents induced by end‐range movements may be responsible for exaggerated flexion reflex responses in spinal cord injury.

Effect of Muscle Biomechanics on the Quantification of Spasticity

AbstractThe impact of muscle biomechanics on spasticity was assessed by comparison of the reflex responses of the elbow and metacarpophalangeal (MCP) flexor muscles in individuals with chronic spastic hemiplegia following stroke. Specifically, methods were developed to quantify reflex responses and to normalize these responses for comparison across different muscle groups. Stretch reflexes were elicited in the muscles of interest by constant velocity ramp-and-hold stretches at the corresponding joint. The muscles were initially passive, with the joint placed in a midrange position. Estimates of biomechanical parameters were used to convert measured reflex joint torque and joint angle into composite flexor muscle stress and stretch. We found that the stretch reflex response for the MCP muscle group had a 74% greater mean stiffness modulus than that for the elbow muscle group, and that the reflex threshold was initiated at an 80% shorter mean muscle stretch. However, we determined that initial normalized fiber length was significantly greater for the experiments involving the MCP muscles than for those involving the elbow muscles. Increasing the initial composite fiber length of the elbow flexors produced significant reduction of the reflex threshold (p < 0.001), while decreasing the initial length of the MCP flexors significantly reduced their measured reflex stiffness (p < 0.001). Thus, biomechanical parameters of muscle do appear to have an important effect on the stretch reflex in individuals with impairment following stroke, and this effect should be accounted for when attempting to quantify spasticity.

Assessment of active and passive restraint during guided reaching after chronic brain injury.

AbstractWe report the use of a mechatronic device for assessing arm movement impairment after chronic brain injury. The device, called the “Assisted Rehabilitation and Measurement Guide,” is designed to guide reaching movements across the workspace, to measure movement and force generation, and to apply controlled forces to the arm along linear reaching paths. We performed a series of experiments using the device in order to identify the contribution of active muscle and passive tissue restraint to decreased active range of motion of guided reaching (i.e., “workspace deficits”) in a group of five chronic, spastic hemiparetic, brain-injured subjects. Our findings were that passive tissue restraint was increased in the spastic arms, as compared to the contralateral, nonparetic arms. Active muscle restraint, on the other hand, was typically comparable in the two arms, as quantified by measurements of active arm stiffness at the workspace boundary during reaching. In all subjects, there was evidence of movement-generated weakness, consistent with a small contribution of spasticity to workspace deficits. These results demonstrate the feasibility of mechatronic assessment of the causes of decreased functional movement, and could provide a basis for enhanced treatment planning and monitoring following brain injury.

Reflex Torque Response to Movement of the Spastic Elbow: Theoretical Analyses and Implications for Quantification of Spasticity

AbstractA parametric model of the human reflex torque response to a large-amplitude, constant angular velocity elbow extension was developed in order to help quantify spasticity in hemiparetic stroke patients, and to better understand its pathophysiology. The model accounted for the routinely observed leveling of torque (i.e., a plateau) at a mean angular increment of 51°±10° s.d. (n=98) after the initial rise. This torque “plateau” was observed in all eight subjects, and in 98 of 125 trials across 25 experimental sessions. The occurrence of this plateau cannot be explained by decreases in elbow flexor moment arms during elbow extension. Rather, the plateau is attributable to a consistent leveling in muscle activation as confirmed both qualitatively from recordings of rectified, smoothed electromyograph (EMG) activity, and quantitatively using an EMG coefficient model. A parametric model was developed in which the pattern of muscle activation in the stretch reflex response of elbow flexors was described as a cumulative normal distribution with respect to joint angle. Two activation functions, one related to biceps and the other to brachioradialis/brachialis, were incorporated into the model in order to account for observations of a bimodal angular stiffness profile. The resulting model yielded biologically plausible parameters of the stretch reflex response which may prove useful for quantifying spasticity. In addition, the model parameters had clear pathophysiological analogs, which may help us understand the nature of the stretch reflex response in spastic muscles.

Diffusion Tensor MR Imaging of the Neurologically Intact Human Spinal Cord

BACKGROUND AND PURPOSE: The aim of this study was to characterize the diffusion properties of the entire human spinal cord in vivo. These data are essential for comparisons to pathologic conditions as well as for comparisons of different pulse sequence design parameters aimed to reduce scan time and more accurately determine diffusion coefficients. MATERIALS AND METHODS: A total of 13 neurologically intact subjects were enrolled in this study. A single-shot, twice-refocused, spin-echo, diffusion-weighted, echo-planar imaging (EPI) pulse sequence was used to obtain axial images throughout the entire spinal cord (C1–L1) in 45 minutes. RESULTS: Diffusion images indicated slight geometric distortions; however, gray and white matter contrast was observed. All measurements varied across the length of the cord. Whole cord diffusion coefficients averaged 0.5–1.3 × 10−3 mm2/s depending on orientation, mean diffusivity (MD) averaged 0.83 ± 0.06 × 10−3 mm2/s, fractional anisotropy (FA) averaged 0.49 ± 0.05, and volume ratio (VR) averaged 0.73 ± 0.05. CONCLUSION: This study provided normative diffusion values for the entire spinal cord for use in comparisons with pathologic conditions as well as improvements in pulse sequence design.

A novel technique for examining human brain activity associated with pedaling using fMRI.

Advances in neural imaging technologies, such as functional magnetic resonance imaging (fMRI), have made it possible to obtain images of human brain activity during motor tasks. However, technical challenges have made it difficult to image the brain during multijoint lower limb movements like those involved in locomotion. We developed an MR compatible pedaling device and recorded human brain activity associated with rhythmic, alternating flexion and extension of the lower extremities. Ten volunteers pedaled at 30 RPM while recording fMRI signals in a GE 3T short bore MR scanner. We utilized a block design consisting of 3 runs of pedaling, each lasting 4 min. In a single run, subjects pedaled for 30 s and then rested for 30 s. This sequence was repeated 4 times. Conventional fMRI processing techniques, that correlate the entire BOLD signal with standard model, did not extract physiologically meaningful signal, likely due to magnetic field distortion caused by leg movement. Hence, we examined only the portion of the blood-oxygen-level dependent (BOLD) signal during movement-free periods. This technique takes advantage of the delayed nature of the BOLD signal and fits the falling portion of the signal after movement has stopped with a standard model. Using this approach, we observed physiologically plausible brain activity patterns associated with pedaling in the primary and secondary sensory and motor cortices and the cerebellum. To our knowledge, this is the first time that human brain activity associated with pedaling has been recorded with fMRI. This technique may be useful for advancing our understanding of supraspinal control of locomotor-like movements in health and disease.

A cable-driven locomotor training system for restoration of gait in human SCI

A novel cable-driven robotic locomotor training system was developed to provide compliant assistance/resistance forces to the legs during treadmill training in patients with incomplete spinal cord injury (SCI). Eleven subjects with incomplete SCI were recruited to participate in two experiments to test the feasibility of the robotic gait training system. Specifically, 10 subjects participated in one experimental session to test the characteristics of the robotic gait training system and one subject participated in repeated testing sessions over 8 weeks with the robotic device to test improvements in locomotor function. Limb kinematics were recorded in one experiment to evaluate the system characteristics of the cable-driven locomotor trainer and the overground gait speed and 6 min walking distance were evaluated at pre, 4 and 8 weeks post treadmill training of a single subject as well. The results indicated that the cable driven robotic gait training system improved the kinematic performance of the leg during treadmill walking and had no significant impact on the variability of lower leg trajectory, suggesting a high backdrivability of the cable system. In addition, results from a patient with incomplete SCI indicated that prolonged robotic gait training using the cable robot improved overground gait speed. Results from this study suggested that a cable driven robotic gait training system is effective in improving leg kinematic performance, yet allows variability of gait kinematics. Thus, it seems feasible to improve the locomotor function in human SCI using this cable driven robotic system, warranting testing with a larger group of patients.

Epidermal Neural Crest Stem Cell (EPI-NCSC)—Mediated Recovery of Sensory Function in a Mouse Model of Spinal Cord Injury

Here we show that epidermal neural crest stem cell (EPI-NCSC) transplants in the contused spinal cord caused a 24% improvement in sensory connectivity and a substantial recovery of touch perception. Furthermore we present a novel method for the ex vivo expansion of EPI-NCSC into millions of stem cells that takes advantage of the migratory ability of neural crest stem cells and is based on a new culture medium and the use of microcarriers. Functional improvement was shown by two independent methods, spinal somatosensory evoked potentials (SpSEP) and the Semmes-Weinstein touch test. Subsets of transplanted cells differentiated into myelinating oligodendrocytes. Unilateral injections of EPI-NCSC into the lesion of midline contused mouse spinal cords elicited bilateral improvements. Intraspinal EPI-NCSC did not migrate laterally in the spinal cord or invade the spinal roots and dorsal root ganglia, thus implicating diffusible factors. EPI-NCSC expressed neurotrophic factors, angiogenic factors, and metalloproteases. The strength of EPI-NCSC thus is that they can exert a combination of pertinent functions in the contused spinal cord, including cell replacement, neuroprotection, angiogenesis and modulation of scar formation. EPI-NCSC are uniquely qualified for cell-based therapy in spinal cord injury, as neural crest cells and neural tube stem cells share a higher order stem cell and are thus ontologically closely related.