Effect of Epidural Stimulation on Muscle Activation and Sensory Perception
Condition: Chronic Pain
MeSH terms: Chronic Pain
Study type: Interventional

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.
    

Intervention name(s): Intraoperative Parameter Testing; Proprioception Testing During Stimulation; Gait Analysis During Stimulation
Intervention type(s): Device; Device; Device
Intervention description(s): Step 1: Recording and stimulation of spinal potentials during insertion of epidural spinal stimulator paddle
Once the epidural paddle is placed, study procedures will begin by connecting the terminals of the paddle to an electrophysiological recording device for signal amplification and filtering. Using this recording setup, motor evoked potential (MEP) and somatosensory evoked potential (SSEP) protocols will be performed to determine motor and sensory thresholds, respectively. Next, the surgical procedure will resume and after the implantable pulse generator (IPG) has been placed, study procedures will begin again and include activation of both low-frequency tonic stimulation (LFTS) and high-frequency burst stimulation (HFBS) patterns from the inserted paddle while recording EMG signals.; Step 3: Proprioception testing
The research team will investigate the perceived change in knee joint angle and direction of movement reported by the subject in a Threshold to Detect Passive Movement (TTDPM). The TTDPM protocol will begin with the subject sitting in the Biodex testing seat, with the non-tested leg hanging freely and the tested leg strapped to the rotating arm of the dynamometer at the lower shank. The subject will be blinded as to the mode and intensity of stimulation: HFBS, LFTS, or no stim. The TTDPM will consist of at least 10 trials for each stimulation condition chosen based on SCM outcomes. The subject has control of a kill-switch that immediately halts movement of the rotating arm, which is to be activated once the subject perceives movement OR if the subject begins to feel any pain or discomfort throughout the task.; Step 4: Body weight support and treadmill (BWST) testing
Similar to step 2, LFTS and HFBS patterns will be compared by systematically testing each individual contact on the paddle while investigating for changes in stepping speed, pattern and EMG moduling complexity. Regarding EMG module analysis, muscle activity will be recorded bilaterally via surface EMG from lower extremity musculature. Furthermore, subjects will also have active LED markers placed over their clothes in order to track whole body kinematics throughout this portion of the study.
To optimize capture of steady state data on the treadmill, each subject will walk for approximately 10 sec prior to the 30 sec of data collection (40 sec per trial). This will allow capture of at least 10 consecutive steady state gait cycles (depending on cadence) per each amplitude selection for each stimulation delivery technique, which will be defined by parameters found during walking SCM.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science