Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI

The goal of this protocol is to describe changes in motor behaviors in individuals with incomplete spinal cord injury following administration of serotonergic medications. To accomplish this, standardized assessments are performed to evaluate clinical measures of baseline, lower extremity strength and reflex behaviors to obtain more precise measures, quantitative static assessments of strength and reflex function of selected muscle groups are determined with specific investigation of peak volitional torques, and stretch reflex excitability. Additional quantitative dynamic assessments are then performed to measure lower extremity kinematic patterns, muscle activity, and timing, and metabolic efficiency during treadmill ambulation.

Finally, serotonergic medications are administered in a blinded crossover design and assessments are repeated. This approach of translational medicine systematically assesses the effects of serotonergic medications on volitional strength reflexes, and walking ability in individuals with incomplete spinal cord injury. Spinal cord injury is a debilitating disease process, which produces profound deficits in motor control early after injury.

A primary goal for most patients is the recovery of walking in individuals with an incomplete lesion, meaning they still have residual motor control distal to the side of the lesion. This skull may be obtainable. Animal models have shown that pharmacological agents can help accelerate and promote the recovery of motor control and walking ability.

However, the translation of these findings into humans is limited. Our lab is trying to translate these animal findings into humans with incomplete spinal cord injury. We hope to ask the question, can pharmacological agents help promote the recovery of motor control and walking ability in individuals with incomplete spinal lesions?

I, spasticity of the quadriceps and hamstring muscle groups is quantified using the modified Ashworth scale to assess quadriceps spasticity. The examiner generates slow and brisk passive flexion movement about the knee joint. Similarly, to assess hamstring spasticity, the examiner generates slow and brisk passive extension about the knee joint.

The spastic reflexes are graded on a zero to four scale based on specific criteria. A composite score is obtained by converting these raw scores to an ordinal scale and summing bilaterally the magnitude or duration of flexor spasms. Extensor spasms and colonus are quantified using the spinal cord assessment tool.

For spastic reflexes, the patient's response is graded based on listed criteria. A composite score is obtained by adding scores within and between legs. The ability for an individual to volitionally contract muscles is assessed using the lower extremity motor score based upon the American Spinal Injury Association guidelines.

Specified criteria are used to grade the contraction about a joint on a zero to five scale. A composite score is obtained through evaluation of the L two, L three, L four, L five, and S one myotomes bilaterally and adding scores. Despite these clear deficits in clinical assessments in reflex activity and strength, this patient is able to take steps on the treadmill with body weight support.

Further, the patient is able to take steps overground with the assistance of a rolling walker. In order to further quantify the velocity dependent stretch reflex. A system combining isokinetic dynamometry with electromyography is used to measure muscle activity.

Surface recording electrodes are applied to the tibials anterior and medial gastric anus. The patient's leg is attached to a footplate, coupled to a six degree of freedom load cell, and the ankle joint axis is aligned to the center of the load cell. Passive or gravitational torques are obtained from the slow stretch perturbations.

This torque response is assumed not to have a reflex component and will be subtracted from the rapid stretches. To calculate the net reflex response to assess stretch reflex excitability, single or multiple stretches into dorsiflexion or plantar flexion are applied to the relaxed patient to assess changes in excitability with velocity. Various rotational speeds are measured including 30, 60 and 120 degrees per second.

The torque response is quantified using the torque signal, which was low pass, filtered at 200 hertz, sampled at 1000 hertz, and synchronized with EMG data. Prior to analysis, the torque due to passive and gravitational contributions is subtracted. The response of the muscle is quantified using the EMG signal, which was banned past, filtered at 20 to 450 hertz, sampled at 1000 hertz, and synchronized with the torque data prior to analysis.

The signal is rectified and smoothed at 10 hertz using a fourth order. Recursive Butterworth filter stretch reflex responses are analyzed from the condition to torque and EMG signals. The primary outcome measures of this analysis include both the peak torque and the prolonged muscle activity following the final stretch.

The isokinetic dynamometer is also used to obtain precise quantification of volitional strength.Surface. EMGs are affixed to four muscles of the thigh, including rectus femoris, vastus lateralis, vastus medias, and medial hamstring. The patient's shank is attached to a dynamometer arm that is coupled to a six degree of freedom load cell.

The axis of the knee joint is aligned to the center of the load cell. With the patient relaxed, the patient is instructed to generate maximal force about the joint. To ensure maximal volitional force production, vigorous verbal encouragement is provided to the patient during the contraction.

When the torque begins to decline during the contraction, a super maximal stimulus is delivered to the quadriceps through three by five inch self-adhesive gel plate stimulating electrodes. The torque and EMG signals are collected and conditioned as in the velocity dependent stretch reflex assessments. Maximal torque and associated EMG responses are assessed offline using the condition torque and EMG signals.

In addition, deficits in volitional activation are assessed using the central activation ratio or car. A graded treadmill test is used to assess walking capability. The subject is secured to the treadmill with a safety harness and testing equipment, including reflective markers, surface EMGs, a heart rate monitor, and a portable metabolic system to perform the graded treadmill test.

Initial treadmill speed is set at 0.1 meters per second and increased by 0.1 meters per second every two minutes until the patient's maximal speed is obtained. Peak treadmill speed is defined as the highest speed the patient was able to ambulate at for at least one minute prior to gait instability. Cardiovascular limitations are reached or voluntary termination of the test during treadmill walking, multiple measures are assessed using a motion capture system and EMG system and the portable metabolic system offline.

The motion capture data is manually tracked for accuracy and an epoch of at least 10 step cycles is chosen for analysis. The gait cycle is normalized to percent from heel strike to heel strike and interpolated using a cubic spline for both the hip and the knee angles. Peak joint angles and angular excursions during the gait cycle are determined for each subject.

In addition to a measure of intra limb coordination, a primary focus is on the coordination of sagittal plane, hip and knee kinematics, which can be assessed by looking at the consistency of hip knee angle angle plots. The average coefficient of correspondence is used to calculate the consistency of inter limb coordination. The hip knee angle angle plot is used to define the co-sign and sign of the direction of the vector.

As the change in hip and knee angles normalized to vector length for each frame to frame interval. These sign and co-sign values are averaged across all step cycles for each corresponding frame interval. Using these averaged values, the mean vector length for each frame to frame interval is calculated.

The arithmetic average of the mean vector length across all frame to frame intervals will be a value from zero to one and will represent the overall dispersion of hip and knee pairs across the gait cycle. To assess muscle activity during ambulation, muscle activity patterns from the EMG signals are synchronized with motion capture data offline, the smooth DMG signal is normalized to the percent gait cycle and averaged between at least 10 steps. The normative on and off time of lower extremity muscles during ambulation is established using a database of healthy controls for each muscle normative on and off times of the particular muscle are overlaid upon the EMG signals collected from the subject.

The EMG signal is integrated between the normative on and off times. The spasticity index is determined by dividing the off value by the on value. The peak oxygen uptake during graded treadmill test is determined following downloading of the portable metabolic data to a computer for analysis.

Once the treadmill test is completed, specifically the average of the last minute of VO O2 data for each two minute speed epoch is determined and results are plotted for each speed. Volitional movements are typically initiated from neural signals in the primary motor cortex. These signals travel via the corticospinal track to spinal inter neurons, including the central pattern generator and converge at the level of the spinal motor neuron.

The motor neuron directly innervates the muscle and causes muscle contraction. V volitional movements may also activate parallel brainstem spinal cord or bulbo spinal pathways. One function of these bulbo spinal pathways is to regulate the excitability of the spinal neurons through the release of neuromodulators, particularly serotonin and incomplete lesion to the spinal cord results in loss of full voluntary control due to the disruption of the corticospinal pathways.

In addition, the spinal circuits and the motor neuron itself become less excitable due to the partial loss of neuromodulators from the bulbo spinal pathways. These combined changes contribute to the deficits in motor functions observed in the first three parts of this video. In animal models, the application of neuromodulators like serotonin or their analogs directly to the spinal cord, can reanimate these spinal circuits leading to augmented motor output, increased reflex activity, and improved locomotor capacity.

The last part of this video will demonstrate how we are attempting to translate this basic science framework into humans. In a double-blinded, randomized, placebo controlled crossover design, the effects of acute oral administration of selective serotonin reuptake inhibitors on motor activity are assessed in individuals with motor incomplete spinal cord injury clinical measures, including the modified Ashworth, the spinal cord assessment tool for spastic reflexes and the lower extremity motor score indicate an increase in both involuntary reflex activity and voluntary force generation following oral administration of SSRI in an individual with motor incomplete SCI. Furthermore, quantitative static measures of motor activity show an augmented and prolonged ankle plantar flexion torque and EMG in response to repeated stretches of the plantar flexors and increased isometric torque and a lesser activation deficit indicated by a greater central activation ratio.

The quantitative dynamic measures of motor activity of hip and knee kinematics during ambulation using a CC reveal an increased consistency following SSRI medication. Interestingly, lower extremity EMG activity during ambulation shows an increase in inappropriate timing of muscle activity following SSRI medication. Finally, the metabolic parameters during ambulation reveal a modest increase in oxygen consumption during the graded treadmill test following SSRI administration.

While these changes are observed in individuals with chronic incomplete SCI, preliminary data suggests the changes in subacute incomplete SCI may be more striking. For example, an individual four months post SCI is unable to take steps without physical assistance prior to medication. After SSRI medication, the same individual is able to take steps Through these clinical and quantitative assessments.

We've seen that acute administration of selective serotonin reuptake inhibitors can improve motor function and walking ability in individuals with incomplete spinal cord injury. However, long-term training is necessary to make these changes permanent. A current goal of our laboratory is to combine these pharmacological interventions with intensive physical interventions to make these improvements in motor function and walking ability permanent.