Investigation of Brain Functional MRI as an Early Biomarker of Recovery in Individuals With Spinal Cord Injury

Cortical Functional Connectivity as an Early Biomarker of Recovery in Spinal Cord Injury (Study 239481)

Early detection of response to therapeutic intervention is vital, as it will enable early termination of intervention in non-responding patients, prevent unnecessary financial burden, and allow for early changes to the intervention program. Previous functional MRI (fMRI) studies have shown that changes in brain functional network in spinal cord injury (SCI) patients can occur after as little as one week of intervention. Resting state fMRI (rsfMRI) is a type of fMRI that does not require performance of explicit motor tasks, which makes the method especially suitable for SCI patient population. In this project, the investigators propose that rsfMRI outcome measures can be used to detect early brain functional network changes that occur during intervention, and that the changes will be predictive of recovery in chronic SCI patients.

Study Overview

• Status: Completed
• Conditions: Spinal Cord Injuries
• Intervention / Treatment: Device: Functional Electric Stimulation cycling; Device: Passive cycling

Detailed Description

Early detection of response to spinal cord injury (SCI) therapeutic intervention programs is vital, as it will enable early termination of intervention in non-responding patients, prevent unnecessary financial burden, and allow for early changes of the programs. In this project, the investigators propose that resting state functional MRI (rsfMRI) can be used to detect early brain functional network changes that occur during intervention, and that the changes will be predictive of recovery in chronic SCI patients. The long-term goal of this study is to establish rsfMRI as a new imaging biomarker that is predictive of progress towards recovery in response to therapy. International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI) scoring system is the most widely used clinical classification system of SCI that describes neurological injury level and degree of functional preservation. It is also used to monitor the progress and response to interventions such as functional electrical stimulation (FES) therapy. However, monitoring responses using ISNSCI is challenging, because its ability to describe the degree of functional loss is limited. Therefore, there is a need in the field of SCI for a biomarker that is more sensitive to changes in function. The investigators will recruit 2 groups of 24 chronic SCI patients. In one group, the investigators will characterize the baseline time profile of rsfMRI outcome measures acquired during a 4-weeks passive cycling program, where movement is driven only by the cycle's motor (no electric stimulation). RsfMRI data of the patients acquired at weeks 0, 2, and 4 will be used perform functional parcellation of the sensorimotor cortex using independent component analysis (ICA) and spectral clustering analysis (SCA) approaches. BNC will be calculated between pairs of sensory and motor brain parcels. Sensory and motor ISNCSCI scores will also be measured at weeks 0, 2, and 4. The investigators will then test the hypothesis that the investigators will observe stable baseline measures of sensory and motor cortex BNC and ISNCSCI scores of the patients during the 4-week passive cycling program, with minimal to no change in values. In the second group, the investigators will characterize the time profile of the cortical reorganization in chronic SCI patients that occurs during the four-week FES cycling. Specifically, the investigators predict that the investigators will observe early functional network changes in the sensorimotor cortex of SCI patients (measured using BNC) at week 2 of the four-week FES cycling program, which will be predictive of changes in ISNSCI scores (neurological outcomes) at week 4. Finally, the longitudinal intra-subject reproducibility of the two parcellation methods will be investigated. If successful, the study will: 1) provide a new and effective clinical tool to study plastic cortical changes that occur after SCI, 2) provide a new non-invasive imaging biomarker that is predictive of progress towards recovery in response to therapy, and 3) extend our knowledge about the functional reorganization that takes place during and after therapeutic intervention.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ann S Choe, Ph.D.; Phone Number: 443-923-9500; Email: annschoe@jhmi.edu

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21205
      • Kennedy Krieger Institute, International Center for Spinal Cord Injury

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult (18-65 years) men and women of all ethnic groups
• SCI, traumatic
• Thoracic neurological level, without the involvement of lower motor neurons.
• ASIA classification A-D
• Chronic injury: > 6 months from the injury
• Satisfactory general health
• No FES ergometer (i.e. RT300 or equivalent) use within 4 weeks.
• Ability to comply with procedures and follow-up

Exclusion Criteria:

• Contra-indication to MR study (e.g., cardiac pacemaker, claustrophobia, aneurysm clip, etc.)
• History or clinical evidence of moderate or severe brain injury
• Major spine deformity (e.g. scoliosis, kyphosis, subluxation)
• Movement disorder or severe spasticity preventing ability to lay still for extended periods required for imaging.
• Women who are pregnant
• Concurrent lower motor neuron disease such as peripheral neuropathy that would exclude lower extremity electrical excitability
• Unstable long bone fractures of the lower extremities.
• Subjects with history of inability to tolerate electrical stimulation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Functional Electric Stimulation cycling; The Functional Electrical Stimulation (FES) cycling group will use RT300 ergometer (Restorative Therapies, Inc) with stimulation on.	Device: Functional Electric Stimulation cycling; The Functional Electrical Stimulation (FES) cycling group will use RT300 ergometer (Restorative Therapies, Inc). Bilateral glutei, quadriceps and hamstrings will be stimulated. The stimulation parameters will be set as follows: waveform biphasic, charged balanced; phase duration of 250 microseconds; pulse rate 33-45 pps. The stimulus intensity will be adjusted for individual patients and muscle group so that a tolerable stimulation is provided that will generate a cycling action. Target cycling speed is 50 RPM. Resistance will be automatically adjusted by the FES bike according to the subject's performance. When fatigue occurs, participants will continue cycling with electrical stimulation and motor support. FES therapy will be administered for one hour per session 3 times a week.; Other Names: RT300 ergometer
Sham Comparator: Passive Cycling; The passive cycling group will use the same RT300 ergometer with stimulation off.	Device: Passive cycling; The passive cycling group will use the same RT300 ergometer however during this period stimulation will not be turned on. Instead, continuous motor support will be activated resulting in passive cycling. Target cycling speed is 50 RPM. Participants assigned to passive cycling will be required to have one hour of passive therapy 3 times a week for the entire duration of treatment assignment.; Other Names: RT300 ergometer

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI) score	Developed by the American Spinal Injury Association (ASIA) as a universal classification tool for spinal cord injury (SCI), the classification tool involves a sensory and motor examination to determine the neurological level of the injury and whether the injury is complete or incomplete. The tool also provides sensory and motor scores of upper and lower, as well as right and left sides of the body. The value of the total motor score ranges between 0-100, where 0 represents no residual motor function, and 100 represents normal motor function. The sensory scores consists of two sub-scores - specifically, light touch and pin-prick scores. The values of each sub-score ranges between 0-112, where 0 represents no residual sensory function, and 112 represents normal sensory function. The ISNCSCI defines neurological level as the most caudal level at which sensory and motor function are intact. The completeness of the injury is graded according to the ASIA Impairment Scale (AIS).	Change from baseline ISNCSCI scores at 2 weeks and 4 weeks after the start of intervention.
Resting state fMRI functional connectivity	RsfMRI functional connectivity is defined as the temporal dependency of neuronal activation patterns (represented by the blood oxygenation level dependent (BOLD) signal time courses as measured using rsfMRI) of anatomically separated brain regions. There are number of methodologies one can use to characterize the degree and type of rsfMRI functional connectivity. One example is between-network-connectivity (BNC), which is defined as the degree of correlation between two time courses obtained from a pair of brain regions. Summary statistics of BNC (e.g., mean, variance), as well as the dynamic properties of BNC (e.g., dynamic functional connectivity) can be used to further summarize the characteristics of the functional connectivity in SCI population	Change from baseline functional connectivity at 2 weeks and 4 weeks after the start of intervention.
Resting state fMRI brain parcels	RsfMRI functional connectivity can also be used to identify functionally homogeneous brain regions, or parcels of the brain. The parcels' center of mass, average and variance of the BOLD signal time courses within the parcels can be used to characterize brain functional organization.	Change from baseline fMRI brain parcels at 2 weeks and 4 weeks after the start of intervention.

Collaborators and Investigators

• Sponsor: Hugo W. Moser Research Institute at Kennedy Krieger, Inc.
• Collaborators: National Institute of Neurological Disorders and Stroke (NINDS)
• Investigators: Principal Investigator: Ann S Choe, Ph.D., Johns Hopkins University

Publications and helpful links

General Publications

• Choe AS. Advances in Spinal Functional Magnetic Resonance Imaging in the Healthy and Injured Spinal Cords. Curr Phys Med Rehabil Rep. 2017 Sep;5(3):143-150. doi: 10.1007/s40141-017-0161-x. Epub 2017 Jul 31.
• Choe AS, Nebel MB, Barber AD, Cohen JR, Xu Y, Pekar JJ, Caffo B, Lindquist MA. Comparing test-retest reliability of dynamic functional connectivity methods. Neuroimage. 2017 Sep;158:155-175. doi: 10.1016/j.neuroimage.2017.07.005. Epub 2017 Jul 5.
• Choe AS, Jones CK, Joel SE, Muschelli J, Belegu V, Caffo BS, Lindquist MA, van Zijl PC, Pekar JJ. Reproducibility and Temporal Structure in Weekly Resting-State fMRI over a Period of 3.5 Years. PLoS One. 2015 Oct 30;10(10):e0140134. doi: 10.1371/journal.pone.0140134. eCollection 2015.
• Choe AS, Belegu V, Yoshida S, Joel S, Sadowsky CL, Smith SA, van Zijl PC, Pekar JJ, McDonald JW. Extensive neurological recovery from a complete spinal cord injury: a case report and hypothesis on the role of cortical plasticity. Front Hum Neurosci. 2013 Jun 25;7:290. doi: 10.3389/fnhum.2013.00290. eCollection 2013.

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2019
• Primary Completion (Actual): December 31, 2023
• Study Completion (Actual): December 31, 2023

Study Registration Dates

• First Submitted: January 22, 2019
• First Submitted That Met QC Criteria: February 22, 2019
• First Posted (Actual): February 26, 2019

Study Record Updates

• Last Update Posted (Estimated): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 18, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Rehabilitation; Spinal Cord Injuries; Neuronal Plasticity; MRI, Functional
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Trauma, Nervous System; Spinal Cord Diseases; Wounds and Injuries; Spinal Cord Injuries
• Other Study ID Numbers: 00182576; R21NS104644 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: All research material will be kept confidential and any means of subject identification (name and history number) will be removed from all material for analysis or presentation. No identifying information will be made publicly available. In some cases, the study protocol, statistical analysis plan, individual scans, and all IPD that underlie results in a publication will be included in published papers or meeting papers or posters, but the identity of the subject in question will not be revealed.
• IPD Sharing Time Frame: Starting immediately after publication
• IPD Sharing Access Criteria: All IPD that underlie results in a publication will be available to the extent the related publication(s) allows it. However, under no circumstances any IPD that contains subject identification information will be shared.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: Yes
• product manufactured in and exported from the U.S.: Yes