Functional and Structural Changes in the Central Nervous System Following Spinal Cord Injury

Study Overview
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Brief Summary
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Building on recent improvements, state-of-the-art functional MRI will be applied as an advanced diagnostic tool for the lumbosacral cord in spinal cord injury (SCI) patients to characterize the remaining neuronal activity of the motor and sensory neurons. Alterations in the activity pattern will reveal the effect upon task-related spinal cord activity of the lower motor neurons and sensory neurons undergoing trauma-induced neurodegeneration, at a spatial specificity that has not been possible so far. Results of this study will be of crucial importance because SCI patients can only profit from regeneration-inducing therapies if spinal neuronal function is preserved below the level of lesion.

Official Title
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Functional and Structural Changes in the Central Nervous System Following Spinal Cord Injury

Conditions
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Spinal Cord Injuries, Neurogenic Bladder Dysfunction, Degenerative Cervical Spinal Stenosis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years Informed consent Willing to take part and follow requirements of the protocol Patients additionally need to fulfil the following study-specific inclusion criteria: Cross-sectional study: Chronic traumatic SCI (> 12 months after injury) or Diagnosed degenerative spondylotic myelopathy (DCM) Longitudinal study: Acute traumatic SCI (< 2 months after injury) or Patients with neurogenic lower urinary tract dysfunction (NLUTD) who undergo routine tibial nerve stimulation (TNS) treatment as part of their rehabilitation (but independently of this study) at Balgrist University Hospital Exclusion Criteria: Age < 18 years Contraindications for MRI (presence of pacemaker or other type of stimulator in the body, presence of metallic foreign body in or on the body, etc.); we will comply with the imaging center's (SCMI) guidelines and in case of doubt we will exclude the participant from the study No informed consent History of psychiatric or neurological disease, apart from those induced by SCI (e.g.epilepsy) History of skull opening or head trauma Known or suspected non-adherence, drug or alcohol abuse Inability to follow the procedures of the study, e.g. due to language problems, psychological disorders, dementia, etc. Women who are pregnant (when uncertain, participants will undergo urine testing) or breastfeeding Intention to become pregnant during the course of the study Body mass index (BMI) > 35 Individuals especially in need of protection (according to Research with Human Subjects published by the Swiss Academy of Medical Sciences)

Ages Eligible for Study
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Minimum Age: 18 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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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cross-sectional study: healthy controls<br> | |
| Cross-sectional study: chronic traumatic SCI patients<br> | |
| Cross-sectional study: non-traumatic SCI patients with degenerative spondylotic myelopathy<br> | |
| Longitudinal study: healthy controls<br> | |
| Longitudinal study: acute traumatic SCI patients (< 2 months after SCI)<br> | |
| Longitudinal study: patients with neurogenic lower urinary tract dysfunction<br> | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cross-sectional study: lumbosacral functional fMRI | Activations in the gray matter of the lumbosacral cord, as a response to sensory, motor, and somatosensory stimulations, or no stimulation (resting state). Spatiotemporal components of the BOLD signal as well as the couplings and anti-couplings between these components | Baseline only | 
| Longitudinal study: lumbosacral functional fMRI | Activations in the gray matter of the lumbosacral cord, as a response to sensory, motor, and somatosensory stimulations, or no stimulation (resting state). Spatiotemporal components of the BOLD signal as well as the couplings and anti-couplings between these component | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: brain functional MRI | Activations in the cortical and subcortical areas of the brain as a response to sensory, motor, and somatosensory stimulations, or no stimulation (resting state) | Baseline only | 
| Longitudinal study: brain functional MRI | Activations in the cortical and subcortical areas of the brain as a response to sensory, motor, and somatosensory stimulations, or no stimulation (resting state) | Change from baseline at 2-month, 6-month, and 12-month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cross-sectional study: diffusion MRI in the spinal cord | Directional diffusivities in the spinal cord (units of mm2/s) | Baseline only | 
| Cross-sectional study: diffusion MRI in the spinal cord | Fractional anisotropy in the spinal cord (unitless) | Baseline only | 
| Longitudinal study: diffusion MRI in the spinal cord | Directional diffusivities in the spinal cord, measured (units of mm2/s) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: diffusion MRI in the spinal cord | Fractional anisotropy in the spinal cord (unitless) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: structural MRI in spinal cord | Cross-sectional areas of the spinal cord gray and white matter (units of mm2) | Baseline only | 
| Longitudinal study: structural MRI in spinal cord | Cross-sectional areas of the spinal cord gray and white matter (units of mm2) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: magnetic resonance neurography of the lumbosacral plexus | Thickness of nerves and nerve roots (units of mm2) | Baseline only | 
| Cross-sectional study: magnetic resonance neurography of the lumbosacral plexus | Nerve entry points into the spinal cord (for determining neurological levels) | Baseline only | 
| Longitudinal study: magnetic resonance neurography of the lumbosacral plexus | Thickness of nerves and nerve roots (units of mm2) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: magnetic resonance neurography of the lumbosacral plexus | Nerve entry points into the spinal cord (for determining neurological levels) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: diffusion MRI in the brain | Directional diffusivities in the brain (units of mm2/s) | Baseline only | 
| Cross-sectional study: diffusion MRI in the brain | Fractional anisotropy in the brain (unitless) | Baseline only | 
| Longitudinal study: diffusion MRI in the brain | Directional diffusivities in the brain (units of mm2/s) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: diffusion MRI in the brain | Fractional anisotropy in the brain (unitless) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: structural MRI in the brain | Cortical thickness (units of mm) | Baseline only | 
| Cross-sectional study: structural MRI in the brain | Volumes of the brain gray and white matter (units of mm3) | Baseline only | 
| Longitudinal study: structural MRI in the brain | Cortical thickness (units of mm) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: structural MRI in the brain | Volumes of the brain gray and white matter (units of mm3) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: nerve conduction study | Latencies of F waves (units of ms). Period between initial stimulation and F wave elicitation in the tibial and peroneal motor nerves. | Baseline only | 
| Cross-sectional study: nerve conduction study | Amplitudes of F waves in the tibial and peroneal motor nerves (units of microV) | Baseline only | 
| Cross-sectional study: nerve conduction study | Duration of F waves in the tibial and peroneal motor (units of ms) | Baseline only | 
| Longitudinal study: nerve conduction study | Latencies of F waves (units of ms). Period between initial stimulation and F wave elicitation in the tibial and peroneal motor nerves. | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: nerve conduction study | Amplitudes of F waves in the tibial and peroneal motor nerves (units of microV) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: nerve conduction study | Duration of F waves in the tibial and peroneal motor (units of ms) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: motor evoked potentials (MEP) | Latencies (units of ms) | Baseline only | 
| Cross-sectional study: motor evoked potentials (MEP) | Amplitudes (units of mV) | Baseline only | 
| Longitudinal study: motor evoked potentials (MEP) | Latencies (units of ms) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: motor evoked potentials (MEP) | Amplitudes (units of mV) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: American Spinal Injury Association Impairment Scale (AIS) from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | AIS quantifies the severity of the spinal cord injury. AIS (ASIA Impairment Scale) grades from A-E, whereas grade A (complete spinal cord injury) is worse than grade E (no impairment) | Baseline only | 
| Cross-sectional study: Lower Extremities Motor Scale (LEMS) from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | LEMS is based on assessments of ISNCSCI and composed from the sum of muscle function grading of the five key muscles of the lower limbs. It consists of a 6-point scale (0=no; 5=normal activity) for each muscle and body site. The lowest possible score in the total LEMS score for one body site is 0 (symptomatic); the highest possible score is 50 (asymptomatic) | Baseline only | 
| Cross-sectional study: Upper Extremities Motor Scale (UEMS) from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | UEMS is based on assessments of ISNCSCI and composed from the sum of muscle function grading of the five key muscles of the upper limbs. It consists of a 6-point scale (0=no; 5=normal activity) for each muscle and body site. The lowest possible score in the total UEMS score for one body site is 0 (symptomatic); the highest possible score is 50 (asymptomatic) | Baseline only | 
| Cross-sectional study: Light touch (LT) score from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | The LT score is based on assessments of ISNCSCI and represents the sum of sensory function of 28 dermatome pairs in terms of light touch sensation. It consists of a 2-point scale (0=absent sensation; 1=altered (impaired or partial sensation, including hyperesthesia); 2 = normal or intact sensation) for each dermatome and body site. The lowest and highest possible LT score for one body site is 0 and 56, respectively | Baseline only | 
| Cross-sectional study: Pin prick (PP) score from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | The PP score is based on assessments of ISNCSCI and represents the sum of sensory function of 28 dermatome pairs in terms of pin prick discrimination. It consists of a 2-point scale (0=absent discrimination; 1=altered (impaired or partial discrimination); 2 = normal or intact discrimination) for each dermatome and body site. The lowest and highest possible PP score for one body site is 0 and 56, respectively | Baseline only | 
| Longitudinal study: American Spinal Injury Association Impairment Scale (AIS) from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | AIS quantifies the severity of the spinal cord injury. AIS (ASIA Impairment Scale) grades from A-E, whereas grade A (complete spinal cord injury) is worse than grade E (no impairment). | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: Lower Extremities Motor Scale (LEMS) from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | LEMS is based on assessments of ISNCSCI and composed from the sum of muscle function grading of the five key muscles of the lower limbs. It consists of a 6-point scale (0=no; 5=normal activity) for each muscle and body site. The lowest possible score in the total LEMS score for one body site is 0 (symptomatic); the highest possible score is 50 (asymptomatic) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: Upper Extremities Motor Scale (UEMS) from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | UEMS is based on assessments of ISNCSCI and composed from the sum of muscle function grading of the five key muscles of the upper limbs. It consists of a 6-point scale (0=no; 5=normal activity) for each muscle and body site. The lowest possible score in the total UEMS score for one body site is 0 (symptomatic); the highest possible score is 50 (asymptomatic) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: Light touch (LT) score from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | The LT score is based on assessments of ISNCSCI and represents the sum of sensory function of 28 dermatome pairs in terms of light touch sensation. It consists of a 2-point scale (0=absent sensation; 1=altered (impaired or partial sensation, including hyperesthesia); 2 = normal or intact sensation) for each dermatome and body site. The lowest and highest possible LT score for one body site is 0 and 56, respectively | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: Pin prick (PP) score from the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) protocol | The PP score is based on assessments of ISNCSCI and represents the sum of sensory function of 28 dermatome pairs in terms of pin prick discrimination. It consists of a 2-point scale (0=absent discrimination; 1=altered (impaired or partial discrimination); 2 = normal or intact discrimination) for each dermatome and body site. The lowest and highest possible PP score for one body site is 0 and 56, respectively | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: Graded and Redefined Assessment of Strength, Sensation and Prehension (GRASSP) | GRASSP measures sensorimotor and prehension function through three domains (strength, sensation and prehension) which are important in describing arm and hand function. The total GRASSP score ranges from 0 to 116 points, where a higher score indicates a better outcome | Baseline only | 
| Longitudinal study: Graded and Redefined Assessment of Strength, Sensation and Prehension (GRASSP) | GRASSP measures sensorimotor and prehension function through three domains (strength, sensation and prehension) which are important in describing arm and hand function. The total GRASSP score ranges from 0 to 116 points, where a higher score indicates a better outcome | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: European Multicenter Study about SCI (EMSCI) pain questionnaire | The EMSCI pain questionnaire rates various aspects of pain (e.g., current pain intensity, mean and maximal pain intensity during the last week before the assessment, location and quality of pain, intensity of allodynia and paresthesia). Pain intensity is quantified on an 11-point numeric scale (0=no pain; 10=worst imaginable pain) | Baseline only | 
| Longitudinal study: European Multicenter Study about SCI (EMSCI) pain questionnaire | The EMSCI pain questionnaire rates various aspects of pain (e.g., current pain intensity, mean and maximal pain intensity during the last week before the assessment, location and quality of pain, intensity of allodynia and paresthesia). Pain intensity is quantified on an 11-point numeric scale (0=no pain; 10=worst imaginable pain) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: sympathetic skin response including hand, sole and perineum recordings | Latencies (units of ms) | Baseline only | 
| Cross-sectional study: sympathetic skin response including hand, sole and perineum recordings | Amplitudes (units of microV) | Baseline only | 
| Longitudinal study: sympathetic skin response including hand, sole and perineum recordings | Latencies (units of ms) | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: sympathetic skin response including hand, sole and perineum recordings | Amplitudes (units of microV) | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: Spinal Cord Independence Measure (SCIM III) | The SCIM-III (Spinal Cord Independence Measure III) score is based on questions concerning independence of persons with a spinal cord injured. It consists of 19 items covering 3 domains, self-care, respiration and sphincter management, and mobility. The self-care subscale ranges from 0 to 20. The respiration and sphincter management subscale ranges from 0 to 40. The mobility subscale ranges from 0 to 40. Total score ranges from 0 (symptomatic) to 100 (asymptomatic). Higher scores reflect higher levels of independence. | Baseline only | 
| Longitudinal study: Spinal Cord Independence Measure (SCIM III) | The SCIM-III (Spinal Cord Independence Measure III) score is based on questions concerning independence of persons with a spinal cord injured. It consists of 19 items covering 3 domains, self-care, respiration and sphincter management, and mobility. The self-care subscale ranges from 0 to 20. The respiration and sphincter management subscale ranges from 0 to 40. The mobility subscale ranges from 0 to 40. Total score ranges from 0 (symptomatic) to 100 (asymptomatic). Higher scores reflect higher levels of independence | Change from baseline at 2-month, 6-month, and 12-month | 
| Cross-sectional study: Walking index for Spinal Cord Injury (WISCI) | WISCI is an ordinal 20-point scale (0=unable to stand and/or participate in walking; 20=ambulates with no devices, with brace and no assistance) to assess walking function | Baseline only | 
| Longitudinal study: Walking index for Spinal Cord Injury (WISCI) | WISCI is an ordinal 20-point scale (0=unable to stand and/or participate in walking; 20=ambulates with no devices, with brace and no assistance) to assess walking function | Change from baseline at 2-month, 6-month, and 12-month | 
| Longitudinal study: International Prostate Symptom Score (IPSS) (only in patients with neurogenic lower urinary tract dysfunction) | The IPSS score is based on questions concerning urinary symptoms and quality of life (QoL). It consists of 8 items covering 7 urinary symptoms related dimensions (subscales) and 1 additional item assessing quality of life. Each item is rated on a 6-point scale (0=not at all; 5=almost always). The lowest possible score in the total IPSS score is 0 (asymptomatic); the highest possible score is 35 (symptomatic). The QoL index is rated on a 7-point scale, with 0 indicating delighted and 6 terrible | Change between baseline and follow-up (6-12 weeks of tibial nerve stimulation) | 
| Longitudinal study: Qualiveen questionnaire (only in patients with neurogenic lower urinary tract dysfunction) | Qualiveen-30 assesses the Specific Impact of Urinary Problems (SIUP) on Quality of Life. It consists of 30 items covering 4 domains, namely inconvenience (9 questions), restrictions (8 questions), fears (8 questions), and impact on daily life (5 questions). Each item is rated on a 5-point ordinal scale (0=asymptomatic; 4=symptomatic). The index of the SIUP on Quality of Life is the mean of the four individual scores. The lowest possible overall score in the Qualiveen-30 is 0 (Urinary problems have no specific impact on QoL); the highest possible score is 30 (Urinary problems have a huge specific impact on QoL) | Change between baseline and follow-up (6-12 weeks of tibial nerve stimulation) | 
| Longitudinal study: Urinary Symptom Profile (USP) (only in patients with neurogenic lower urinary tract dysfunction) | The USP score is based on questions concerning urinary symptoms and their severity in males and females. It consists of 13 items covering 3 dimensions (subscales) with 7 overactive bladder (OAB), 3 stress urinary incontinence (SUI), and 3 low stream (LS) related items. Each item is rated on a 4-point scale. The lowest score is 0 (asymptomatic); the highest score is 3 (symptomatic) | Change between baseline and follow-up (6-12 weeks of tibial nerve stimulation) | 
| Longitudinal study: Overactive Bladder (ICIQ-OAB) questionnaire (only in patients with neurogenic lower urinary tract dysfunction) | International Consultation on Incontinence Questionnaire Overactive Bladder Quality of Life ICIQ-OAB-QoL is a 26-item questionnaire evaluating quality of life (QoL) in patients with overactive bladder. Scores range from 25-160, with greater values indicating increased impact on quality of life | Change between baseline and follow-up (6-12 weeks of tibial nerve stimulation) |