Spasticity After Spinal Cord Injury

Study Overview
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Brief Summary
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Very often, people who have a SCI have difficulty doing things with their arms or hands as a result of muscle stiffness , or spasticity. Spastacity can cause problems performing even the simplest of everyday tasks. This research will help us understand how the body recovers and changes neurologically after SCI.

Detailed Description
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After spinal cord injury (SCI), damage to descending motor pathways has been associated with the development of spasticity (Frigon and Rossignol, 2006; Trompetto et al., 2014). Self-reported questionnaires and clinical exams indicate that individuals with incomplete SCI, who showed residual descending connectivity, have a high prevalence of spasticity compared to individuals with complete SCI (Little et al., 1989; Holtz et al., 2017). In agreement, our recent electrophysiological and spinal cord imaging data in humans with a diagnosis of a clinically motor complete SCI showed the presence of descending motor pathway connectivity in individuals with spasticity compared to those without spasticity (Sangari et al., 2019). However, which descending motor pathways influence spasticity following SCI, and to what extent, remains poorly understood. This proposal has two main goals: 1) to examine the contribution of cortico- and reticulo-spinal pathways to spasticity in upper and lower limb muscles, and 2) to develop strategies to promote functional recovery of upper and lower limb spastic muscles in humans with chronic incomplete SCI. The aims below will test two main hypotheses. In Aim 1, we will use transcranial magnetic stimulation and startle acoustic stimuli to examine the contribution of the cortico- and reticulo-spinal pathway to upper and/or lower limb muscles electromyographic activity. Spinal cord atrophy and morphological characterization of cortico- and reticulo-spinal pathways will be assessed with high-resolution magnetic resonance imaging. Physiological and neuroimaging outcomes will be associated with clinical assessment of spasticity. In Aim 2, we propose to enhance cortico- and reticulo-spinal contribution to upper and/or lower limb function in spastic muscles by using a novel intervention combining startle acoustic stimuli with motor training. This research will provide new knowledge about the contribution of descending motor pathways to the control of spasticity in upper and lower limb muscles following incomplete cervical SCI (Aim1) and might lead to the development of a novel rehabilitation intervention to improve upper and lower limb motor function recovery by enhancing residual descending control over spinal networks (Aim 2).

Official Title
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Spasticity After Spinal Cord Injury

Conditions
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Spinal Cord Injuries

Intervention / Treatment
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* Behavioral: Acoustic stimuli (Startle)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria for individuals with SCI Chronic SCI (≥1 year of injury) Incomplete spinal cord injury at T12 or above Males and Females Ages 18-75 years Inclusion criteria for non-spastic individuals with SCI -MAS scores of 0 and 1 Inclusion criteria for spastic individuals with SCI MAS scores of 2, 3 and 4 The ability to perform a voluntary flexion and extension of the elbow and/or knee or ankle The ability to reach and grasp an object Inclusion criteria for health controls Males and females Ages 18-75 years Right-handed Able to perform elbow and/or knee or ankle flexion and extension Exclusion Criteria for individuals with SCI and healthy controls: Uncontrolled medical problems including pulmonary, cardiovascular, or orthopedic disease Any debilitating disease prior to the SCI that caused exercise intolerance Premorbid, ongoing major depression or psychosis, altered cognitive status History of head injury or stroke Pacemaker Metal plate in skull History of seizures Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold such as antipsychotic drugs (chlorpromazine, clozapine) or tricyclic antidepressants Pregnant females Ongoing cord compression or a syrinx in the spinal cord or who suffer from a spinal cord disease such as spinal stenosis, spina bifida, or herniated cervical disk

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Aim 1<br>To accomplish this aim, we will conduct one experiment in two sessions separated by 2- 3 days using a crossover design. Participants will be assigned into one of three groups: spastic SCI, non-spastic SCI, and controls. We expect that people enrolled in Aim 1 will complete 2 visits within 1 week. Visit 1 Measurements: MVCs MEP Recruitment Curves iMEPs StartReact Visit 2 Measurements: Participant Reported Spasticity MAS PSAD KINARM MRI of brain and spinal cord | Behavioral: Acoustic stimuli (Startle)<br>* A startle stimulus (120 dB, 500 Hz, 50 ms) will be delivered through headphones<br>|
| Experimental: Aim 2<br>To accomplish this aim, we will use a randomized crossover design study with spastic SCI participants receiving a single intervention combining non-invasive acoustic stimuli (Startle) or sham-Startle with motor training to enhance cortico- and reticulo-spinal contribution, separated by  2 weeks. Visit 1 and Visit 2 Single intervention of: Startle + exercise training OR sham-Startle + exercise training Pre and post measurements: MVCs MEP recruitment curves iMEPs StartReact Participant reported spasticity MAS PSAD KINARM Neuromechanical hand and/or leg testing GRASSP TRI-HFT 10-meter walk test Pendulum Test | Behavioral: Acoustic stimuli (Startle)<br>* A startle stimulus (120 dB, 500 Hz, 50 ms) will be delivered through headphones<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MEP recruitment curves | Ten stimuli (0.2 Hz) will be delivered at each intensity to plot the mean peak-to-peak amplitude of the MEP from the non-rectified response against the TMS intensity in each subject (MEP recruitment curve). | 3-4 hours | 
| Ipsilateral MEPs (iMEPs) | Ten stimuli will be delivered during head straight and ten stimuli will be delivered during lateral head rotation, randomly alternated (0.2 Hz). | 3-4 hours | 
| StartReact | Here, participants will be asked to observe a light-emitting diode (LED) located in front of their head. When the LED will illuminate, individuals will be asked to move their arm or leg. In some trials, the LED will be presented with either a quiet acoustic stimulus (80 dB, 500 Hz, 50 ms) or a startling acoustic stimulus (SAS, 120 dB, 500 Hz, 50 ms) delivered through a headphone. | 3-4 hours | 
| Participant reported spasticity | Spasticity questionnaire | 3-4 hours | 
| Modified Ashworth Scale (MAS) | This scale measures resistance encountered during manual passive muscle stretching using a six-point ordinal scale. | 3-4 hours | 
| Portable Spasticity Assessment Device (PSAD)' | The PSAD combine biomechanical and electrophysiological measurements for an objective quantification of active and passive component of muscle stiffness | 3-4 hours | 
| Pendulum Test | As part of the physical exam, we will use the pendulum test to measure muscle tone at the knee by using gravity to provoke muscle stretch reflexes during passive swinging of the lower limb. | 3-4 hours | 
| 10-meter walk test | 10-meter walk test will be used to assess walking speed | 3-4 hours | 
| Graded and Redefined Assessment of Strength, Sensibility and Prehension (GRASSP). | This exam measures clinical impairment that incorporates three domains vital to upper-limb function: sensation, strength, and prehension. | 3-4 hours | 
| Toronto Rehabilitation Institute-Hand Function Test (TRI-HFT) | This exam measures gross motor function frequently used to manipulate objects that participants may encounter in their daily lives. | 3-4 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Spinal cord injury, Spasticity, TMS