1Sensory Motor Performance Program, Rehabilitation Institute of Chicago, 2Department of Kinesiology and Nutrition, University of Illinois at Chicago, 3Department of Physical Therapy, University of Illinois at Chicago
Thompson, C. K., Jayaraman, A., Kinnaird, C., Hornby, T. G. Methods to Quantify Pharmacologically Induced Alterations in Motor Function in Human Incomplete SCI. J. Vis. Exp. (50), e2148, doi:10.3791/2148 (2011).
Spinal cord injury (SCI) is a debilitating disorder, which produces profound deficits in volitional motor control. Following medical stabilization, recovery from SCI typically involves long term rehabilitation. While recovery of walking ability is a primary goal in many patients early after injury, those with a motor incomplete SCI, indicating partial preservation of volitional control, may have the sufficient residual descending pathways necessary to attain this goal. However, despite physical interventions, motor impairments including weakness, and the manifestation of abnormal involuntary reflex activity, called spasticity or spasms, are thought to contribute to reduced walking recovery. Doctrinaire thought suggests that remediation of this abnormal motor reflexes associated with SCI will produce functional benefits to the patient. For example, physicians and therapists will provide specific pharmacological or physical interventions directed towards reducing spasticity or spasms, although there continues to be little empirical data suggesting that these strategies improve walking ability.
In the past few decades, accumulating data has suggested that specific neuromodulatory agents, including agents which mimic or facilitate the actions of the monoamines, including serotonin (5HT) and norepinephrine (NE), can initiate or augment walking behaviors in animal models of SCI. Interestingly, many of these agents, particularly 5HTergic agonists, can markedly increase spinal excitability, which in turn also increases reflex activity in these animals. Counterintuitive to traditional theories of recovery following human SCI, the empirical evidence from basic science experiments suggest that this reflex hyper excitability and generation of locomotor behaviors are driven in parallel by neuromodulatory inputs (5HT) and may be necessary for functional recovery following SCI.
The application of this novel concept derived from basic scientific studies to promote recovery following human SCI would appear to be seamless, although the direct translation of the findings can be extremely challenging. Specifically, in the animal models, an implanted catheter facilitates delivery of very specific 5HT agonist compounds directly onto the spinal circuitry. The translation of this technique to humans is hindered by the lack of specific surgical techniques or available pharmacological agents directed towards 5HT receptor subtypes that are safe and effective for human clinical trials. However, oral administration of commonly available 5HTergic agents, such as selective serotonin reuptake inhibitors (SSRIs), may be a viable option to increase central 5HT concentrations in order to facilitate walking recovery in humans. Systematic quantification of how these SSRIs modulate human motor behaviors following SCI, with a specific focus on strength, reflexes, and the recovery of walking ability, are missing.
This video demonstration is a progressive attempt to systematically and quantitatively assess the modulation of reflex activity, volitional strength and ambulation following the acute oral administration of an SSRI in human SCI. Agents are applied on single days to assess the immediate effects on motor function in this patient population, with long-term studies involving repeated drug administration combined with intensive physical interventions.
To assess the effects of acute oral administration of an SSRI (10 mg escitalopram oxalate, Lexapro, Forest Pharmaceuticals, Inc.) on motor activity in individuals with motor incomplete SCI, a double-blinded, randomized, placebo controlled crossover design is employed. As part of the inclusion criteria, subjects will be required to undergo a 14 day washout period for all anti-depressant medications, anti-spastic medications and other medications with known interactions to the SSRIs.
Two hours is required for each of the experimental protocols, consisting of clinical, quantitative static and quantitative dynamic assessments. A 4.5 hour delay is given following medication administration (time to peak plasma concentration)7. Subjects are re-tested following medication administration using an identical experimental set-up and paradigm employed during pre-medication testing. Following pre- and post-testing of the first medication (SSRI or placebo), a minimum of 7 days separates the two testing conditions (half-life of agents is approximately 27 hrs).
Part 1: Clinical assessments
Spasticity of the quadriceps and hamstring muscle groups is quantified using the Modified Ashworth Scale (mAsh).
Spinal cord assessment tool for spastic reflexes
The magnitude or duration of flexor spasms, extensor spasms, and clonus is quantified using the Spinal Cord Assessment Tool for Spastic Reflexes (SCATS)
Lower extremity motor score
The ability for an individual to volitionally contract muscles in accordance with myotomes is assessed using the ASIA Lower Extremity Motor Score (LEMS).
Part 2: Quantitative static assessments
Velocity dependent stretch reflex
Using isokinetic dynamometers in addition to electromyography (EMG), a precise stretch can be applied and a quantitative response can be assessed.
Precise quantification of volitional strength can be obtained using an isokinetic dynamometer.
Part 3: Quantitative dynamic assessments
Peak treadmill speed
Functional ambulation is assessed using a graded treadmill test to obtain treadmill speed.
During treadmill walking multiple kinematic measures including, peak range of motion, peak velocity and variability are assessed using motion capture system (Motion Analysis, Santa Rosa, CA). The consistency of intralimb coordination between the hip and knee joints is quantified by calculating the average coefficient of correspondence (ACC; 10). The ACC uses a vector coding technique to analyze the sagittal-plane hip and knee angles on an angle-angle plot.
Muscle activity during ambulation
Muscle activity during gait is quantified using EMG signals.
Metabolic recordings during ambulation
Cardiorespiratory/metabolic capacity is assessed using measures of peak oxygen uptake (VO2peak; mL/kg/min) during graded treadmill testing using a K4b2 portable metabolic system (Cosmed USA Inc., Chicago IL).
Figure 1. Following oral administration of SSRI in an individual with motor incomplete SCI there are notable alterations in clinical measures of motor activity. Both measures of involuntary reflex activity, mAsh (A) and SCATS (B) increased to varying degrees, suggesting the two clinical scales may be capturing a different aspect of the augmented involuntary activity. (C) Additionally, clinically detectable changes in volitional strength are observed following SSRI administration.
Figure 2. Following oral administration of SSRI in an individual with motor incomplete SCI there are notable alterations in quantitative static measures of motor activity. (A) Augmented and prolonged ankle plantarflexion torque and EMG are observed in response to repeated stretches of the plantarflexors following SSRI administration. Increased isometric torque is seen following SSRI administration. Interestingly, there is less activation deficit (greater CAR) following SSRI administration, indicating the individual is able to more fully activate their muscle during a maximal volitional contraction following SSRI administration.
Figure 3. Following oral administration of SSRI in an individual with motor incomplete SCI there are alterations in quantitative dynamic measures of motor activity. Analyses of variability of hip and knee kinematics (A) during ambulation using ACC (B) reveals that there is an increased consistency following SSRI medication, both pre and post measures are at 0.7 m/s. (C) Analysis lower extremity EMG activity during ambulation reveals an increase in inappropriate timing of muscle activity following SSRI medication, both pre and post measures are at 0.7 m/s. (D) Analysis of metabolic parameters during ambulation reveals a modest increase in O2 consumption during the graded treadmill test following SSRI administration.
|0||(0)||no increase in muscle tone|
|1||(1)||slight increase in muscle tone, manifested by a catch and release or by minimal resistance at the end of the range of motion when the affected part(s) is moved in flexion or extension|
|1+||(2)||slight increase in muscle tone, manifested by a catch, followed by minimal resistance throughout the remainder (less than half) of the ROM|
|2||(3)||more marked increase in muscle tone through most of the ROM, but affected part(s) easily moved|
|3||(4)||considerable increase in muscle tone, passive movement difficult|
|4||(5)||affected part(s) rigid in flexion or extension|
Table 1: mAsh scoring, Modified from 12
|0||no reaction||no reaction||no reaction|
|1||less than 10° of excursion in flexion at the knee and hip or extension of the great toe||activity is maintained less than 3 seconds||clonus is maintained less than 3 seconds|
|2||10° to 30° of flexion at the knee and hip||activity persists between 3 and 10 seconds||clonus persists between 3 and 10 seconds|
|3||30° or greater of knee and hip flexion||activity persists for more than 10 seconds||clonus persists for more than 10 seconds|
Table 2: SCATS scoring, Modified from 13
|0||No visible or palpable muscle contraction noted|
|1||Any visible or palpable muscle is noted|
|2||The muscle is able to move, at least once, the part of the extremity to which it is inserted through a full range of motion in the position in which gravity is eliminated|
|3||The muscle is able to move, at least once, the part of the extremity to which it is inserted through a full range of motion in the position in which gravity must be overcome|
|4||The muscle is able to perform the function described for grade 3 and is able to provide some resistance against the efforts of the examiner|
|5||The muscle is able to exert, in the examiners judgment, a normal amount of resistance against the examiner's efforts|
Table 3: LEMS scoring
|Muscle||Percent of Gait Cycle|
|RF||0-30 and 55-75||30-55 and 75-100|
|VL||0-30 and 55-75 and 95-100||30-55 and 75-95|
|MH||0-25 and 65-100||25-65|
|MG||5-55||0-5 and 55-100|
|SOL||5-55||0-5 and 55-100|
Table 4: Normative on and off times of LE muscles during gait
This video demonstration highlights methods to assess changes in reflex activity, volitional strength and ambulation following the acute oral administration of SSRIs in human SCI. This battery of assessments demonstrates that despite increases in so called abnormal reflex activity following acute oral administration of a SSRI, the individual with SCI demonstrated improvements in volitional strength, with only minor changes in locomotor ability. In these individuals the effects of augmented spasticity do not appear detrimental to ambulatory function. Additionally improvements in walking ability may be more pronounced in individuals with acute lesions. Continuing studies use these similar quantitative and clinical assessments to determine the efficacy of combined SSRIs and intensive physical interventions, as has been employed in animal models of SCI. With a sound theoretical framework based on long-standing and relatively new basic science research, these methods can help translate such information to a clinical population and may challenge some of the traditional protocols used in clinical practice to augment functional recovery in individuals with SCI.
No conflicts of interest declared.
NIH R21NS42516 to TGH
Craig H Nielsen Foundation Grant 83860 to TGH
APTA Doctoral Scholarship to CKT
|Isokinetic Dynamometer||Biodex||System 3 with Rehab Toolkit|
|EMG system||Delysis||Bagnoli 2.1|
|EMG system||Noraxon||Mayosystem 1400a|
|Force Treadmill||Bertek Pharmaceuticals||FIT|
|Motion Capture||Motion Analysis Corp.||Eagle 3|