Clinical trial NCT04157400: Effect of Epidural Stimulation on Muscle Activation and Sensory Perception
Official title: Neuromodulation of Motor and Sensory Spinal Pathways in Subjects Undergoing Epidural Spinal Cord Stimulation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Pain
Lead sponsor: Medical University of South Carolina
Sponsor class: OTHER
First posted: 2019-11-08
Enrollment: 5
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: BASIC_SCIENCE

Brief summary: Each year, an estimated 34,000 individuals undergo epidural spinal cord stimulation (SCS) surgery to address debilitating chronic low back and leg pain (CLBLP). Although the commercial application of SCS to treat CLBLP was approved by the FDA in 1989, only in the past decade have significant advancements in stimulator technology been introduced. For instance, traditional SCS devices achieved reduction in pain using a type of stimulation known as low-frequency tonic stimulation (LFTS, below 100 Hz), which was dependent on induction of paresthesias (i.e., a tingling sensation) over the areas of pain perception. However, investigators now know that LFTS compromises sensory information flowing back to the spinal cord, which can be important in other spinal cord functions such as proprioception and movement. On the other hand, recent innovations in stimulator technology now provide the capability to apply stimulation frequencies up to 10,000 Hz along with complex waveform patterns - known as high frequency burst stimulation or HFBS - that can mitigate pain perception without the induction of paresthesias and the negative consequences on proprioception and movement. We propose to study the effects of these recently introduced features in SCS technology on motor and sensory spinal thresholds, proprioception and movement in subjects with CLBLP.

The spinal cord relies on input from the motor cortex and surrounding extremities to initiate specific muscle recruitment, and recent evidence suggests that preservation of temporally specific proprioceptive information via dorsal column primary afferent fibers is critical for natural motor behaviors such as ambulation. Since the spinal cord is exposed during the placement of the SCS device, information about a subject's motor and sensory spinal pathways can be easily obtained during the regular course of the procedure and compared to proprioceptive and motor responses once the subject is awake and moving with the device turned on. Our lab specializes in electrophysiological recordings in subjects undergoing spinal cord stimulator (SCS) implantation for CLBLP, while MUSC's Locomotion Laboratory specializes in quantifying proprioception and movement in human subjects. In this proposal, investigators will apply these techniques to subjects with CLBLP to determine effects of spinal neuromodulation on motor and sensory thresholds, proprioception, and kinematics.

Detailed description: Definitions and nomenclature:

Spinal cord stimulation (SCS) will be performed using a 32-electrode paddle array implanted in the dorsal epidural space along the thoracolumbar region of the spinal cord. The array will be powered by a multiple independent current-controlled (MICC) implantable pulse generator (IPG) connected to the paddle per standard of care procedures for SCS implantation. In addition, as per standard of care, motor evoked potential (MEP), somatosensory evoked potential (SSEP) and electromyography (EMG) will be performed via the IOMAX intraoperative neuromonitoring system. The SCS system will be placed for clinical purposes, i.e., treatment of chronic pain, however, the investigators will collect data at various points during the placement. The study procedures will add 15 minutes to the surgery. MUSC's Locomotion Rehabilitation Laboratory - located at the College of Health Professions Building C - houses a Biodex Pro System 4 isokinetic/isometric dynamometer. The Biodex will standardize application of passive isokinetic knee flexion/extension trials to each blinded subject for proprioceptive investigations, which will be referred to as threshold to detect passive movement (TTDPM) throughout the rest of this document. Finally, MUSC's Locomotor Energetics and Assessment Laboratory - also located at the College of Health Professions Building C - houses a dual belt Instrumental Treadmill that is coplanar with the floor and will be used during all walking events. The laboratory also has a 12-camera motion capture system that utilizes active infrared LED tracers to track kinematic positioning data and will be used during all walking events. Another tool offered by the lab is a 16-channel EMG system which utilizes surface electrodes to detect target muscle activity and will also be used during all walking events. In all, expected total duration of the study to be approximately 30 days.

Device use:

The epidural stimulator paddle and IPG are FDA-approved, commercially available devices designed to treat chronic pain of the back and lower extremities and will be used for their intended clinical purpose - electrical stimulation of dorsal column fibers to mitigate pain perception. The research use of this device, which will add approximately 15 minutes to the surgery, involves recording/stimulating from the device during the standard of care intraoperative neuromonitoring protocol. Regardless of study participation, the stimulator paddle and IPG will be implanted according to standard of care for the pre-planned SCS surgery. The IOMAX intraoperative neuromonitoring system, equipment owned by MUSC and operated by MUSC neurophysiology staff, is a commercially available device used during standard of care spinal surgical procedures, such as SCS implantation. Regardless of study participation, intraoperative neuromonitoring via IOMAX will take place according to standard of care for the pre-planned SCS surgery. The following devices are used for research purposes only. The Biodex Pro System 4, used regularly by physical rehabilitation researchers here at MUSC, is a commercially available device that will be used solely as a research tool to deliver passive isokinetic knee flexion/extension during the TTDPM. The Instrumental Treadmill, GAITRite mat, motion capture system, and MA300 EMG system are all commercially available devices that are used by MUSC researchers at the College of Health Professions to perform extensive gait analysis in subjects with various neurological deficits. Gait analysis is being performed for research purposes only, and is not standard of care for patients receiving SCS surgery.

Number of Subjects:

Investigators propose to study 5 individuals with CLBLP. A prior study conducted by Formento et al, 2018 using SCS and proprioceptive testing published a standard error and 95% confidence interval using successful and unsuccessful SCS trial attempts (p \< 0.05 among LFTS parameters and no stimulation, with a minimum of 10 trials per stimulation setting.) Based on this, investigators expect that a small population will exhibit similar variance. The subject sample size is in direct comparison to sample sizes of previous proof of concept studies regarding SCS for spinal cord physiology biomarker sampling. The research team plans to use a two-way repeated measures ANOVA model in order to investigate the varying differences in stimulation type and kinematic parameters. A Post hoc comparison will be made using a Tukey adjustment.

Recruitment Methods:

During the subject's preoperative clinic visit, the PI will ask the potential participant if they would like to learn more about the study. If so, the PI will introduce the study and ask if he can answer any further questions about the study before inviting in the PI's physician assistant (listed as a study team member). If not, the PI will leave the room and the PI's physician assistant will review a prescreening checklist to determine whether subjects may be eligible for the study (no information obtained during the prescreening will be documented as research data). Potential participants will be asked to confirm that they are between the ages of 18 and 80, that they have been previously diagnosed with CLBLP by a pain specialist, whether they feel they cannot provide research consent physically and/or cognitively, and whether they have any prior history of spinal neoplasm, infection, arteriovenous malformation and/or radiation to the spine. If potential participants answer no to either of the first two questions or yes to either of the remaining questions, they will be considered ineligible for the study.

Careful attention will be placed on good communication. It will be emphasized that participation in the study is not necessary for standard of care medical treatment for their condition. It will also be emphasized that the subject can withdraw from the study at any time.

Data Management:

Once a potential participant is asked if they would like to learn more about the study, they will be assigned a participant ID. Participant IDs will be assigned consecutively. Investigators will maintain a database that accurately reflects all potential subjects that were approached about the study and the results of eligibility evaluation. For eligible subjects, the specific types of data that will be collected include: 1) analog local field potentials from the SCS, MEP, SSEP and EMG electrodes, 2) digital and analog output signals from the IOMAX intraoperative neuromonitoring device, 3) digital, time-stamped, physical displacement data captured from the Biodex machine, 3) digital, time-stamped, positioning data produced by the PhaseSpace software, 5) videography data, and 6) any available imaging data (dicom files). Raw data will remain on lab-owned data acquisition machines with encrypted hard drives and stored behind a locked door when not directly supervised. Data will be copied from all lab-owned data acquisition machines and/or hospital-owned data servers to a password protected network server accessible from the lab under the IRB protocol number and participant ID. This will constitute the master copy of all data for the lab and will consist of separately stored coded and identifiable folders. The purpose of keeping a copy of the raw data is in case the server is interrupted, and it is necessary to reconstruct the data. Portions of data will be copied to end-user devices (e.g., desktop, laptop, etc) for data analysis, however only the portion needed for analysis will be copied. Any end-user device such as a laptop that physically leaves the lab will be encrypted with MUSC-approved software which uses the AES encryption algorithm in cipher block chaining or XTS mode with a 256-bit key. Desktop machines used for analysis that do not leave the lab and are stored in a locked laboratory will not be encrypted. All data on data acquisition and end-user devices will be deleted at the conclusion of the study. No PHI will be stored on any data acquisition machine or end-user device. A linking database associating the participant ID and subject identifiers will be maintained on MUSC Box, separately from the research data. Subject identifiers to be collected include first and last name, gender, date of birth, social security number, medical record number, mailing address and telephone numbers. Telephone and medical record numbers are required for an approximate 7-day phone call made to subjects following SCS implantation. Additionally, investigators will collect information pertaining to disease severity for each subject, including Visual Analog Scale (VAS) scores, a common pain scale, and any other available rating scale scores. These measures will assist in correlating our physiological data with severity of disease for each subject. Videography data will be stored in the identifiable folder on the password protected network server. The purpose of this data is to correlate movement dynamics with physiology data. Finally, investigators will save imaging data on a password protected network server in order to analyze and correlate with the collected physiological data. Only IRB-approved personnel will have access to the linking database. Consent forms will be stored in a locked cabinet in a locked laboratory in the Clinical Sciences Building at MUSC.

Risks to Subjects:

All procedures will follow standard of care guidelines. Research staff will follow up with each participant by phone approximately one week after the surgical procedure, and during the approximate 30-day return, to make sure the participants are not having any problems. Nevertheless, this study still poses certain risks as outlined in the following sections:

Surgical complication

Due to the 15 extra minutes added to the surgery, connection of the paddle terminals outside the surgical field, and extra personnel in the room, there is a slightly increased risk of surgical infection. The extra risk of infection due to the research protocol does not increase this risk beyond the 1-5% overall historical risk of complications from the SCS surgical procedure.

TTDPM

While testing for proprioception retention of the lower extremities, subjects may encounter discomfort due to non-volitional muscle activation that hinders passive movement. To mitigate this risk, the Biodex system has a subject-controlled trigger that immediately stops the dynamometer's passive motion and may be activated at any time a subject experiences discomfort of pain during the test.

Overground and Treadmill Walking

Subjects will be asked to walk on a pressure sensitive mat at self-selected walking speeds and on a treadmill at self-selected walking speeds with each scenario having the subject in an upper thoracic safety harness which is tethered to the ceiling for fall protection. Despite the aforementioned safety measures, there still exists a risk of loss of balance, fall and potential injury. The risk to subjects through these tasks do not exceed risks involved with general physical therapy settings and may result in mild muscle fatigue or discomfort that generally subsides within a few days. Subjects will be given ample rest time and may have additional rest time at any point throughout data collection periods. Furthermore, subjects will be assisted during large movements or during potential transfers across different surfaces by an IRB-approved study member.

Photography and videography

Subjects will be videotaped during performance of supine / walking SCM and EMG moduling protocols. Investigators will also photograph and/or videotape any other aspect of the subject's research participation that will help investigators correlate the subject's condition with the EMG and kinematic data. The videos and photos recorded can include the full face, upper body, arms, and legs. Photography and videography carry a risk of loss of privacy. Photos and videos will be stored on a secure server. Only approved study personnel will have access to these files.

Loss of Confidentiality

Additional risks include loss of confidentiality. To mitigate this risk, a linking database associating the participant ID and subject identifiers will be maintained separately from the research data on a password protected server and only IRB-approved personnel will have access to the linking database.

Eligibility criteria: Research Inclusion Criteria

* Subjects diagnosed with CLBLP by a pain specialist with a documented referral for evaluation of SCS surgery by the pain specialist
* Subjects with the ability to walk
* Age 18-80

Research Exclusion Criteria

* Subjects with the inability to consent for themselves.
* Prior history of spinal neoplasm, infection, arteriovenous malformation and/or radiation to the spine

Primary outcomes:
measure: Electromyography Response Amplitude
timeFrame: Data collection for step one is expected to last approximately fifteen minutes during the spinal cord stimulation surgery.
measure: Proprioception Testing
timeFrame: Data collection for step two is expected to last approximately two hours.
measure: Change in Electromyography Microvoltage Signal During Walking
timeFrame: Data collection for step three is expected to last approximately two hours.
Secondary outcomes:
Other outcomes:
Locations:
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
Study officials:
affiliation: Medical University of South Carolina
name: Nathan Rowland, MD
role: PRINCIPAL_INVESTIGATOR
References: