Enhancing STDP After Spinal Cord Injury

Not Applicable

Completed

• Conditions: Spinal Cord Injury
• Interventions: Other: STDP; Behavioral: Training; Other: Sham STDP; Other: Multisite-STDP

• Registration Number: NCT02701777
• Lead Sponsor: VA Office of Research and Development

Brief Summary

The overall goal is to develop new clinical approaches to restore limb function after spinal cord injury (SCI). Corticospinal tract (CST) axons are involved in controlling limb function. Paired pulse induced spike-timing dependent plasticity (STDP) enhances synaptic strength between residual CST axons and spinal motoneurons (SMNs) resulting in temporary improvements in limb function in humans with incomplete SCI. Motor training will be combined with paired-pulse STDP stimulation to further enhance plasticity and behavioral recovery.

Detailed Description

To induce STDP with paired pulse, corticospinal volleys evoked by either transcranial magnetic stimulation over the primary motor cortex for upper extremities or electrical stimulation over the thoracic spine for lower extremities arrive at corticospinal-motor neuronal synapses of upper- or lower-limb muscles, 1-2 ms before antidromic potentials were elicited in motor neurons by electrical stimulation of corresponding peripheral nerves.

Study Timeline

• Study First Submitted: 2016-01-14
• Study Start: 2016-03-01
• Study First Submitted QC: 2016-03-02
• Study First Posted: 2016-03-08
• Primary Completion: 2020-10-30
• Study Completion: 2020-10-30
• Results First Submitted: 2020-11-13
• Results First Submitted QC: 2021-01-14
• Results First Posted: 2021-01-20
• Status Verified: 2022-07
• Last Update Submitted: 2022-07-14
• Last Update Posted: 2022-07-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 62

Inclusion Criteria

Participants who are unimpaired healthy controls:

• Male and females between ages 18-85 years
• Right handed
• Able to complete precision grips with both hands
• Able to complete full wrist flexion-extension bilaterally
• Able to walk unassisted
• Able to complete full ankle flexion-extension bilaterally

Participants who have had a spinal cord injury:

• Male and females between ages 18-85 years
• SCI ( 6 months of injury)
• Spinal Cord injury at or above L5
• The ability to produce a visible precision grip force with one hand
• Able to perform some small wrist flexion and extension
• The ability to perform a small visible contraction with dorsiflexion and hip flexor muscles
• No subjects will be excluded based on their race, religion, ethnicity, gender or HIV status.
• ASIA A,B,C, or D

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Exclusion Criteria

Exclusion criteria for enrollment For SCI and Healthy Control Subjects (4-8 exclusion for non-invasive brain stimulation only):

• 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
• Metal plate in skull
• History of seizures
• Receiving drugs acting primarily on the central nervous system, which lower the seizure threshold (see appendix 2)
• 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, MS, or herniated disk
• Individuals with scalp shrapnel, cochlear implants, or aneurysm clips.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
STDP + Training	Training	Paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined time. Motor training will follow paired stimulation.
Sham STDP + Training	Training	Sham or fake paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined times. Motor training will follow stimulation.
Sham STDP + Training	Sham STDP	Sham or fake paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined times. Motor training will follow stimulation.
Multisite-STDP + Training	Multisite-STDP	Prospective Single Cohort Multisite-Paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined time. Motor training will follow paired stimulation.
STDP	STDP	Paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined time.
Multisite-STDP + Training	Training	Prospective Single Cohort Multisite-Paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined time. Motor training will follow paired stimulation.
STDP + Training	STDP	Paired stimulation will be given to the brain and to a peripheral nerve so that the messages are received at the spinal cord at predetermined time. Motor training will follow paired stimulation.

Primary Outcome Measures

Name	Time	Method
Functional Assessment	Measured at baseline, after 10-20 sessions, and follow up (after 6 months) for STDP, STDP+Training, and Sham-STDP+Training groups . Measured at baseline, after 20 and 40 sessions, and follow up (after 9 months) for Multisite-STDP + Training group.	The Graded Redefined Assessment of Strength Sensibility and Prehension (GRASSP) assessment is a standardized test of functional abilities of the hand. We measure time required to complete the GRASSP test for upper extremity functional assessment. 10-m walk test is used to measure walking speed for lower extremity functional assessment. The time to complete the task is assessed in seconds for both measurements and normalized as percentage of Baseline. Normalization to baseline allows comparison across two different tasks.; For STDP, STDP+Training, and Sham-STDP+Training groups, either GRASSP or 10-m walk test was performed in each participant depending on the targeted muscle. For Multisite-STDP + Training group, both GRASSP and 10-m walk test were performed in each participant and the average of two tests were reported below.

Secondary Outcome Measures

Name	Time	Method
Amplitude of Motor Evoked Potential (MEP)	Measured at baseline, after 10-20 sessions, and follow up (after 6 months) for STDP, STDP+Training, and Sham-STDP+Training groups . Measured at baseline and after 20 and 40 sessions for Multisite-STDP + Training group.	We measure amplitude of a motor evoked potential evoked by transcranial magnetic stimulation (TMS) or thoracic spine stimulation. The amplitude of MEP is assessed in millivolts and normalized as percentage of Baseline. Normalization to baseline is necessary to allow comparison across different muscles because the targeted muscle is different for each individual depending on the level of injury.
Maximum Voluntary Contraction	Measured at baseline, after 10-20 sessions, and follow up (after 6 months) for STDP, STDP+Training, and Sham-STDP+Training groups . Measured at baseline and after 20 and 40 sessions for Multisite-STDP + Training group.	We measure maximum voluntary contraction (MVC) of muscles recorded by electromyography (EMG) in the targeted muscle(s). Average of muscles was reported for Multisite-STDP + Training group. The maximum voluntary contraction is assessed in millivolts and normalized as percentage of Baseline. Normalization to baseline is needed to allow comparison across different muscles because the targeted muscle is different for each individual depending on the level of injury.
ISNCSCI-motor Scores	ISNCSCI was performed at baseline and after 40 sessions of Multisite-STDP+Training.	Neurological recovery was measured by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam. Motor part of the exam is completed through the testing of key muscle functions corresponding to 10 myotomes (C5-T1 and L2-S1) for right and left side separately. The strength of each muscle function is graded on a six-point scale ranging from 0 meaning complete paralysis to 5 meaning full strength. The total motor score is sum of all motor scores across 10 myotomes for both sides and therefore ranges from 0-100. Higher scores represent better outcome. We reported the total motor score.
ISNCSCI-sensory Scores	ISNCSCI was performed at baseline and after 40 sessions of Multisite-STDP+Training.	Neurological recovery was measured by the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) exam. Sensory part of the exam is completed through the testing of a key point in each of the 28 dermatomes (from C2 to S4-5) on the right and left sides of the body. At each of these key points, two aspects of sensation are examined: light touch and pin prick (sharp-dull discrimination). Appreciation of light touch and pin prick sensation at each of the key points is separately scored on a three-point scale; 0-absent, 1-altered, and 2-normal or intact. Therefore, 56 is the maximum score for both light touch and pin prick and the total sensory score ranges from 0 to 112. Higher scores represent better outcome. We reported the total sensory score.
SCI-QOL-ambulation	Measured at baseline, after 40 sessions, and follow up (after 9 months) for Multisite-STDP + Training group.	We used questionnaire to assess changes in quality of life. The name of the questionnaire is Spinal Cord Injury Quality of Life (SCI-QOL) and we used four subdomains: ambulation, self-care, bowel management difficulties, and bladder management difficulties. Scores on all subdomains of SCI-QOL use a standardized T metric, with a mean of 50 and a standard deviation of 10. Ambulation subdomain assesses the ability to engage in walking activities in different locations that vary based on speed, time and condition and the ability to manage stairs under different conditions. Higher scores on Ambulation subdomain represent better outcome.
SCI-QOL-self-care	Measured at baseline, after 40 sessions, and follow up (after 9 months) for Multisite-STDP + Training group.	We used questionnaire to assess changes in quality of life. The name of the questionnaire is Spinal Cord Injury Quality of Life (SCI-QOL) and we used four subdomains: ambulation, self-care, bowel management difficulties, and bladder management difficulties. Scores on all subdomains of SCI-QOL use a standardized T metric, with a mean of 50 and a standard deviation of 10. Self-care subdomain assesses an individual's ability to perform daily self-care activities such as eating, dressing, grooming, and bathing. Higher scores on Self-care subdomain represent better outcome.
SCI-QOL- Bowel Management Difficulties	Measured at baseline, after 40 sessions, and follow up (after 9 months) for Multisite-STDP + Training group.	We used questionnaire to assess changes in quality of life. The name of the questionnaire is Spinal Cord Injury Quality of Life (SCI-QOL) and we used four subdomains: ambulation, self-care, bowel management difficulties, and bladder management difficulties. Scores on all subdomains of SCI-QOL use a standardized T metric, with a mean of 50 and a standard deviation of 10. Bowel management difficulties subdomain measures a range of difficulties associated with bowel management, including an ability to carry out a bowel program; concerns about incontinence and bowel accidents; concerns about difficulty implementing a bowel program; and the impact of bowel management on everyday living. Higher scores on bowel management difficulties subdomain represent better outcome.
SCI-QOL- Bladder Management Difficulties	Measured at baseline, after 40 sessions, and follow up (after 9 months) for Multisite-STDP + Training group.	We used questionnaire to assess changes in quality of life. The name of the questionnaire is Spinal Cord Injury Quality of Life (SCI-QOL) and we used four subdomains: ambulation, self-care, bowel management difficulties, and bladder management difficulties. Scores on all subdomains of SCI-QOL use a standardized T metric, with a mean of 50 and a standard deviation of 10. Bladder management difficulties subdomain measures a range of difficulties associated with bladder management, including ability to carry out a bladder program; worry about bladder accidents; concerns about implementing one's bladder program; and impact on everyday living. Higher scores on bladder management difficulties subdomain represent better outcome.

Trial Locations

Locations (1)

Edward Hines Jr. VA Hospital, Hines, IL; 🇺🇸 Hines, Illinois, United States