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Recovery of Cardiovascular Function With Epidural Stimulation After Human Spinal Cord Injury

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ClinicalTrials.gov Identifier: NCT02037620
Recruitment Status : Recruiting
First Posted : January 16, 2014
Last Update Posted : April 14, 2017
Sponsor:
Information provided by (Responsible Party):

January 14, 2014
January 16, 2014
April 14, 2017
January 2014
December 2020   (Final data collection date for primary outcome measure)
Recovery of Autonomic control of Cardiovascular function [ Time Frame: 20 months ]
Not Provided
Complete list of historical versions of study NCT02037620 on ClinicalTrials.gov Archive Site
Recovery of Autonomic control of respiratory function [ Time Frame: 20 months ]
Not Provided
Not Provided
Not Provided
 
Recovery of Cardiovascular Function With Epidural Stimulation After Human Spinal Cord Injury
Recovery of Cardiovascular Function With Epidural Stimulation After Human Spinal Cord Injury

In this study, we would like to demonstrate that epidural stimulation can be used to recover significant levels of autonomic control of the cardiovascular and respiratory function as well as the ability to voluntarily control leg movements below the injury level. This intervention would provide an immediate therapeutic alternative to individuals who now have no recourse for treatment.

Rationale:

We propose to determine the functional gain that can be achieved in voluntary control of movements below the level of injury and autonomic nervous system function as a result of activation of spinal circuits with epidural stimulation (ES) in humans with complete motor paralysis. In addition to the scientific advances, the proposed experiments are essential to translating this therapeutic approach to a larger scale, which is needed to have a meaningful clinical impact. ES for recovery of neurological function in patients with severe SCI is not widely used because of uncertainty regarding the mechanisms of action and convincing evidence of efficacy in a larger numbers of subjects. Our approach will allow us to determine specific types of ES needed for voluntary movement and autonomic nervous system dysfunction which lays the groundwork for expedient translation to larger numbers of individuals with SCI.

Current clinical methods of diagnosis of clinically complete SCI may not be sensitive enough to detect residual functional synapses across the lesion. We propose to use a series of neurophysiological approaches that can detect different sources of supraspinal influence on spinal circuitry and identify specific pathways including vestibulospinal, reticulospinal, corticospinal and long propriospinal pathways that may remain viable or emerge with ES and task specific training after complete motor paralysis. Such residual connectivity would be identified by the presence of voluntarily controlled movement or evoked motor potentials occurring only in the presence of epidural stimulation. Identifying the essential supraspinal-spinal pathways needed to recovery these voluntary movements will advance our knowledge of human neural control of movement and provide critical information for developing repair and regeneration strategies and in determining the type and severity of patient that could benefit most readily in regaining voluntary control using epidural stimulation.

Methods and Procedures

  1. General Experimental Design. We will enroll 4 research participants who have sustained a motor complete SCI to participate in the proposed experiments. Our novel approach of conducting repeated experiments with comprehensive assessments in a smaller cohort of patients rather than a more traditional approach of including a large number of patients and focusing on a single outcome allows advancing both clinical and scientific knowledge. We have found success with the smaller cohort approach because we can employ more rigorous, quantitative and sensitive outcomes that not only inform us about the potential clinical efficacy but also provide further knowledge of the mechanisms of neural control of movement and other physiological mechanisms related to cardiovascular, respiratory and function and voluntary control of movement.
  2. Research participant enrollment. Each research participant will be screened for medical eligibility by the neurosurgeon and physiatrist and for scientific eligibility by the site principal investigator (see Human Subjects section below). After eligibility is determined and consent procedures are implemented, the individual will undergo all clinical and neurophysiological assessments for voluntary movement, cardiovascular and respiratory function. Magnetic resonance imaging (MRI) will be conducted at the time of enrollment to establish structural integrity of the nerve tissue and to establish the severity of injury and diffuse tensor imaging to establish the axonal integrity. A standard MRI of the area of injury will be conducted and it will be read by a radiologist and the following measures will be made: 1) the number of sagittal cuts in which the signal change is present, 2) maximum height of signal change, 3) maximum area of signal change, 4) maximal canal compromise will calculated (MCC) and 5) maximal spinal cord compression (MSCC). All of these measurements will be made on the mid sagittal view.

The individual will continue with their current daily activities for 4 months without any intervention (usual care) followed by all assessments. Surgical implantation of the 5-6-5 Specify electrode, and Restore Advance Pulse generator, (MEDTRONIC, Minneapolis, MN, USA) encompassing the lumbosacral spinal cord guided by neurophysiological mapping will then occur (implant).

ES is administered by a multi-electrode array implanted in the epidural space over the dorsum of cord. An implanted package containing stimulating circuits, rechargeable battery, and wireless communication activates the electrodes (16 platinum electrodes arranged in three columns of [5-6-5]). The pattern of electrically active electrodes, as well as electrode voltage, stimulating frequency, and stimulating pulse width can be remotely programmed. Since different spatial activation patterns and different frequency parameters affect different spinal circuits, the array can be reconfigured, within limits, to bias its facilitating effects toward different activities, such as cardiovascular control or voluntary movement.

Clinical and neurophysiological assessments will be repeated post implantation. Mapping of the motor evoked responses in response to spatial and amplitude/frequency responses will be conducted and the specific configurations and parameters optimal for voluntary movement, standing and cardiovascular function will be identified. The individual will then undergo ES stimulation optimizing cardiovascular function for 60 consecutive days for 2 hours per day.

The same clinical and neurophysiological assessments again will be repeated. The research participant will then undergo ES for voluntary movement sessions for 60 consecutive days for 2 hours per day. Both the cardiovascular sessions and voluntary movement sessions can be conducted at home. The remote device records the minutes of stimulation and parameters used so these will be collected on those days the research participants are not in the laboratory. For the first 5 sessions of each intervention, the sessions will be conducted in the laboratory under the supervision of the investigators. The optimal parameters will be identified and programmed into the remote device. For the next 35 sessions, the research participants will come to the laboratory for every fifth session and cardiovascular parameters will be collected and voluntary movement assessed. After 20 sessions, EMG will be conducted during attempted voluntary movements. The final 5 sessions will also be conducted in the laboratory.

The research participant will then complete the same clinical and neurophysiological assessments. The final intervention will include daily stand training sessions with ES stimulation parameters optimized for standing for one hour and 1 additional hour of cardiovascular and voluntary parameters for 60 sessions. All stand training and ES sessions will be conducted in the laboratory. Every 10 sessions the cardiovascular and voluntary sessions will also be conducted in the laboratory. Then the final clinical and neurophysiological assessments will be conducted.

Cardiovascular Function:

Orthostatic Stress Test will be assessed in the morning in a quiet, temperature-controlled (~22o C) room. After arriving, participants will be asked to empty their bladder before beginning the study. A butterfly catheter will be inserted into an antecubital vein during instrumentation to allow the collection of blood without additional stress to the participant by appropriate clinical staff. Continuous arterial BP will be acquired from a finger cuff placed around the left middle or index finger or thumb (Portapres-2; Finapres Medical Systems). The left hand will be placed in an arm sling and kept at the level of the heart throughout the study. Manual arterial blood pressure measurements will be taken at the beginning of the supine control period and at the end of the recovery period with a digital blood pressure measurement device. A three-lead ECG (ML132, AD Instruments) will be placed for ECG monitoring. Rib cage and abdomen kinematics (respiratory kinematics) will be acquired using an inductive plethysmograph (Inductotrace, Ambulatory Monitoring). Baseline recording for 15 minutes will begin after a 5-minute rest period that will follow subject preparation. At the end of 15-minute recording in the supine position, participants will be passively moved into the upright seated position. This position will be maintained for 15 minutes. Then the participants will be passively moved to the supine position for 10 minutes. Eight milliliters of venous blood will be drawn from an antecubital vein at the end of 15-minute supine to assess baseline catecholamine levels. Blood draw will be repeated at 3 and at the end of 15 minutes of upright position. The test will be aborted if subjects become lightheaded or symptomatic of syncope. The Hemodynamic Test during standing; sitting and supine positions with and without ES will be recorded using a Portapres-2 system as described above.

Blood pressure lability: 24-hour blood pressure monitoring Continuous blood pressure monitoring will be recorded over a period of 24 hours outside the lab (Meditech ABPM-04, Budapest, Hungary). In regards to the severity of AD, the participant's signs of OH (e.g. yawning, pallor) and subjective symptoms (e.g. light-headedness, dizziness) will also be assessed using validated autonomic questionnaires.

Arterial Stiffness aPWV (m/s) is calculated by dividing the distance between measurement sites, by the pulse transit time. Distance between the carotid and femoral arteries will be measured using measuring tape along the surface of the body, held parallel to the testing table. The pulse transit is determined from the arterial blood pressure waves, which are collected at each arterial site. A pen-like device (model SPT-301; Millar Instruments Inc., Houston, TX) will be applied to the carotid and femoral arterial sites using a light pressure to obtain arterial pressure waves. Heart rate will be recorded using a single-lead (lead I) electrocardiogram (ECG) (model ML 123, ADInstruments Inc., Colorado Springs, CO).

Arterial structure: Wall thickness and lumen diameter

Brachial and femoral arterial images will be collected using B-mode ultrasound (INFO) for 10 cardiac cycles. Images will be analyzed using internal ultrasound software to determine lumen diameter and intima-media thickness

Cardiac structure and function Cardiac images will be collected non-invasively using Doppler ultrasound (Vivid q, GE Healthcare, Buckinghamshire, UK). Briefly, apical four and two-chamber views, and parasternal short and long-axis views will be collected and stored on the ultrasound for offline analysis. Indices of interest will include volumes (end systolic (ESV), end diastolic (EDV)), diameters (intraventricular septum systole (IVSs) and diastole (IVSd), left ventricular internal diameter systole (LVIDs)), systolic function (left ventricular posterior wall systole (LVIDd) and diastole (LVPWd), ejection fraction (EF), cardiac output (CO), fractional shortening, mitral regurgitation (dP/dT)) and diastolic function (E/A, E/e' ratio, IVRT, DT).

International Autonomic Standards Evaluation Until recently individuals with SCI were only examined with use of motor and sensory neurological standards in order to establish the level and the severity of the neurological impartment or AIS (American Spinal Injury Association Impairment Scale) resulting from the SCI63. During the last decade, International Autonomic standards for evaluation of individuals with SCI were developed and implemented around the world64. These short standardized forms collect data on cardiovascular (AD and OH) as well as other autonomic dysfunctions including bladder bowel and sexual dysfunctions.

Body Composition Weight, height, and total body fat will be determined from a dual energy x-ray absorptiometry (DXA) scan (Hologic QDR 4500W, APEX System Software Version 2.3) at the Vancouver General Hospital, performed in the supine position. Waist circumference will be measured in the supine position following a normal expiration, to the nearest 1cm midway between the lowest lateral border of the ribs and the uppermost lateral iliac crest. Waist circumference is considered the most practical bedside measurement of visceral adipose tissue. Hip circumference will be measured supine over the widest part of the femoral great trochanter. Waist/hip ratio and body mass index (measured weight in kilograms divided by the measured height [meters2]) will be calculated.

Total body fat will be reported as total body fat in kilograms, and as a percent of total body weight determined by DXA scan. Height (length) will be measured using the electronic ruler function and weight from the DXA scan table scale feature. This is the preferred measure for assessing total body fat and has strong agreement with cadaver and chemical composition studies. Recent studies comparing DXA to CT and MRI have confirmed the validity and reliability of DXA to assess abdominal adiposity. In addition, its ease of use makes it ideal for studying large populations. All scans will be performed with a (Hologic Discovery QDR 4500W (Hologic Inc., Bedford, MA), which has an error of less than 1% for body fat scans. An experienced technician will conduct scans according established protocol. All participants will be scanned with this methodology to ensure high internal validity.

Metabolic Parameters

Certified clinical Laboratories at each site will analyze all blood samples. Blood work at our site will be done at the Autonomic Research Laboratory at ICORD. A trained technician will draw a venous blood sample. Participants will undergo a 12-hour fast the night before, including no food or drink including alcohol or caffeine (water is permitted). A complete blood count (white blood cells and differentials, erythrocytes, packed cell volume, hematocrit, platelets, hemoglobin and red cell indices) will be performed.

Blood glucose control (HbA1c), fasting glucose, fasting insulin, atherogenic dyslipidemia (triglycerides, TC, LDL-c, HDL-c, TC/HDL-c), a pro-thrombotic state (PAI-1 and TAFI), and a pro-inflammatory state (IL-6, and TNF-α) will also be measured. Blood samples for PAI-1, TAFI, IL-6, and TNF-α will be analyzed using enzyme-linked immunosorbent assays (ELISA).

Plasma levels of lipid and hemoglobin A1c will be analyzed through laboratory services using a Dade Behring RxL Max analyzer. This system has demonstrated very good intra and interassay reliability for lipid and glucose measures75.

Aerobic Fitness Evaluation:

Peak oxygen uptake test (VO2peak) Participants will perform an exercise regiment. Resting ECG, blood pressure (DinamapCarescape V100; GE Healthcare, Buckinghamshire, UK) and respiratory measures (ParvomedicsTruemax 2400, Sandy, UT, USA) will be collected two minutes prior to exercise. Heart rate will also be monitored with a chest strap heart rate monitor (Polar T31 heart rate monitor, Polar Electro Inc., Woodbury, NY, USA). For participants with tetraplegia who have limited handgrip function, tensor bandages will be used to secure hands to the ergometer handles. Participants will be instructed to maintain a cycling rate of 60 rev/min for the duration of the test. After an initial warm-up at 0W, power output will be increased at a rate of 5 W/min for participants with tetraplegia, or 10 W/min for participants with paraplegia, until volitional exhaustion (i.e. dropping below 30 rev/min). Participants will be asked to identify their ratings of perceived exertion (RPE) on the Borg scale76 every minute until the completion of exercise. Heart rate and oxygen consumption will be recorded on a breath-by-breathe basis for the duration of the test. The highest 15-second average of oxygen consumption during the test will be recorded as VO2peak.

Pulmonary Function Test, PFT

PFT's will be performed in the participant's wheelchair using BreezeSuite System (MedGraphics, St. Paul, MN). Forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) will be obtained. Three acceptable spirograms will be obtained and the result of their best attempt will be used. MP45-36-871-350 Differential Pressure Transducer (Validyne Engineering, Northridge, CA) will be used to measure the maximum inspiratory pressure (PImax) and the maximum expiratory pressure (PEmax). The PImax will be measured during maximal inspiratory effort beginning at near residual volume and PEmax will be measured during maximal expiratory effort starting from near total lung capacity. The assessment will require a sharp, forceful effort be maintained for a minimum of 2 seconds. The maximum pressure will be taken as the highest value that can be sustained for one second. The maximum value from three maneuvers that varied by less than 20% will be averaged.

Respiratory Surface Electromyography:

EMG measure of motor output will be recorded during voluntary respiratory motor tasks attempted in the sitting and supine position. The protocol will consist of 5 minutes of quiet breathing followed by Maximum Inspiratory Pressure Task (MIPT), Maximum Expiratory Pressure Task (MEPT), and cough. During MIPT/MEPT, subjects will be asked to produce maximum inspiratory or expiratory efforts for 5 seconds. Each maneuver will be cued by an audible tone and repeated three times using a Motion Lab EMG System with pairs of pre-amplified electrodes (Motion Lab Systems, Baton Rouge, LA) centered over the muscle belly. Bilateral recorded muscles include: clavicular portion of pectoralis (PEC); 6th intercostals (IC6); rectus abdominus (RA); obliquus abdominus(OBL); paraspinal (PSP). The incoming sEMG signals will be filtered at 30-1000 Hz and sampled at 2000 Hz.

EMG, kinematics and kinetics experiments:

During the experiments, the research participants will be placed on the treadmill in an upright position and suspended by a cable in a harness (i.e. BWST) or on an overground standing device. Voluntary leg movements will be performed on a mat. Following standard skin preparation techniques, bipolar surface EMG electrodes will be placed bilaterally on the soleus (SOL), medial gastrocnemious (MG), tibialis anterior (TA), medial hamstrings (MH), quadriceps (VL and RF) and adductor (AD) muscles. Fine-wire EMG electrodes will be used for deep muscles of the hip and foot. Limb kinematics including hip, knee and ankle angles will be acquired using high speed passive marker motion capture (Motion Analysis, Santa Rosa, CA). When appropriate we will measure individual ground reaction forces (GRF) using HRMat (TEKSCAN, Boston, MA) or forces during movement with a force transducer (Kistler, Amherst, NY).

E MG and Soleus H-reflex (Specific Aim 4): All EMG data will be collected at 2000 Hz with custom-written acquisition software (National Instruments, Austin, TX, USA). We will record bilateral EMG (Motion Lab Systems, Baton Rouge, LA, USA) from same muscles as above. The soleus H-reflex will be evoked by monopolar electrical stimulation of the posterior tibial nerve at the popliteal fossa using a 1-ms pulse, generated by a constant current stimulator (DS7A, Digitimer, UK) and will be recorded by surface monopolar differential electrodes placed over the soleus muscle. A minimum 10 control and conditioned reflexes will be recorded in every trial. The indifferent electrode will be placed above the patella for selective stimulation of the nerve trunk. The EMG signal will be amplified and band-pass filtered (10 Hz-500 Hz) before being sampled at 2 kHz (1401 plus running Spike 2 software). The digitized EMG signals will be rectified and the size of M-wave and H-reflex responses will be measured as the area under the full-rectified waveforms. Soleus H-reflexes will be recorded as designated by each specific supraspinal pathway protocol (described in detail below). For all conditioning experiments, amplitude and latency changes of the soleus H-reflex will be used to quantify the effects of the TMS, galvanic, auditory or ulnar nerve stimulation. Control H-reflexes will be evoked interleaved with those conditioned by the respective stimulation.

Corticospinal pathways We will administer single pulse transmagnetic stimulation using a Magstim 200 single-pulse stimulator with a double cone coil for activating lower extremity musculature while the research participants are in the supine position. We will position the coil approximately 0-2 cm anterior to the vertex to locate the hotspot left and right tibialis anterior and quadriceps muscles. We will position the coils tangentially to the scalp with intersection of both wings at 45 degrees to midline for optimal motor cortex stimulation. We will use Signal software (Cambridge electronic design, UK) to trigger motor evoked potential (MEP) data acquisition. We will perform MEP data analysis using Signal software (Cambridge electronic design, UK). Mean peak-to-peak MEP amplitudes (average of 8-10 trials) at intensities 10%, 20%, 30%, 40%, 50%, 60% and 70% above rMT will be used to generate stimulus response curves. Using SigmaPlot curve-fitting software, stimulus response curves will be fitted with the Boltzmann function: MEPa= P/1+exp ((I50-I)/k), where P is the Plateau amplitude, I is the intensity, I50 is the amplitude at 50% of plateau and k is slope parameter of the steepest portion of the curve.

Research participants will be in a supine position with a fixed hip, knee and joint angle. For those individuals who can maintain a voluntary contraction, an additional series of tests will be conducted with background EMG activity. For soleus H-reflex modulation single pulses will be used to condition the H-reflex induced by posterior tibial nerve stimulation at interstimulus intervals ranging between 0 and 100 s. We will measure the MEP's in response to incrementing levels of TMS over the leg area of the primary motor cortex and generate recruitment curves. We will measure changes in threshold, slope and the maximum amplitude of the recruitment curve to determine if severity of injury, time since injury, or locomotor training influences the excitability or functional connectivity of the corticospinal pathways. We will also compare the reproducibility of these parameters in non-disabled research participants to verify these changes are not attributed to inherent variability of the measurements. We will calculate peak-to-peak values for the MEP response and those responses at a given stimulation frequency will be averaged and plotted versus the stimulation intensity. If background EMG is elicited we will average the amplitude from a 25 ms window prior to stimulation.

Vestibulospinal pathways:

We will administer galvanic stimulation (rectangular pulses, 300 ms, 2-4.5 mA) with Digitimer DS5 Isolated Bipolar Constant Current Stimulator using 2.5 cm diameter electrodes placed over the mastoid processes for the assessment of the vestibulospinal pathways. The digitimer will be externally triggered by our Labview program and used to condition the soleus H-Reflex. The research participants will be lying with the head of the mat fixed (30 degrees) because posture influences the responses. Control H-reflexes will be evoked interleaved with those conditioned by auditory stimulation with the time randomly between 10 and 20 seconds to allow adequate recovery of the motoneuron pool. A minimum of 5 responses of control and condition will be measured and averaged with conditioned responses expressed as percentage of control values. Peak-to-peak amplitude will be calculated and the mean amplitude and standard deviation for each of the conditioned and control reflexes. The conditioned reflexes will be expressed as a percentage of the control reflexes.

Reticulospinal pathway:

The reticulospinal pathway will be evaluated using soleus H-reflex amplitude under conditioning stimulation via auditory stimulus (30 ms tone of 90 dB at 700 Hz) that will be delivered using binaural earphones. EMG will be recorded from the sternocleidomastoid muscle to confirm the startle response. The soleus H-reflex will be elicited 50 ms after the sound to peak after 75-125 ms and return to baseline values after 250 ms. Amplitude changes of the soleus H-reflex will be used to quantify the effects of the auditory stimulation. Control H-reflexes will be evoked interleaved with those conditioned by auditory stimulation with a time separation of at least 2 minutes. A minimum of 5 responses of control and condition will be measured peak-to-peak and averaged with conditioned responses expressed as percentage of control values.

Long propriospinal pathway:

The long propriospinal system will be evaluated using soleus H-reflex amplitude under conditioning stimulation of the ipsilateral ulnaris nerve at the wrist joint via surface electrodes with trains of 3 rectangular pulses (pulse duration: 0.5 ms, pulse interval: 3 ms). The soleus H-reflex will be elicited 100 ms after the ulnaris nerve stimulation. The intensities of the stimuli will be expressed as multiples of the threshold for the direct M response of the abductor pollicis brevis muscle. The stimulus will be applied every 3 s in a randomized, interleaved conditioned and unconditioned stimuli sequences.

Interventions:

  1. ES Cardiovascular Parameters during sitting or lying supine;
  2. ES Voluntary Parameters during voluntary leg movement training and
  3. ES during stand training and ES Voluntary Parameters during voluntary leg movement training.
Interventional
Not Provided
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Spinal Cord Injury
  • Device: 5-6-5 Specify electrode
  • Device: Restore Advance Pulse Generator
Experimental: Epidural Stimulation

5-6-5 Specify Electrode

Restore Advance Pulse Generator

Interventions:
  • Device: 5-6-5 Specify electrode
  • Device: Restore Advance Pulse Generator
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
4
December 2022
December 2020   (Final data collection date for primary outcome measure)

Inclusion Criteria:

  1. non-progressive SCI with complete motor paralysis above T1; American Spinal Injury Association Impairment Scale (AIS) A, B or C;
  2. 21 - 70 years of age;
  3. greater than 2 years post injury;
  4. stable medical condition;
  5. unable to voluntarily move all single joints of the legs;
  6. cardiovascular dysfunction including presence of persistent resting blood pressures and/or symptoms of autonomic dysreflexia and/or orthostatic hypotension; and
  7. respiratory dysfunction including at least 15% deficit in predicted pulmonary function outcomes;

Exclusion Criteria:

  1. ventilator dependent;
  2. painful musculoskeletal dysfunction, unhealed fracture, contracture, or pressure sore that might interfere with training;
  3. clinically significant depression or ongoing drug abuse;
  4. cardiovascular, respiratory, bladder, or renal disease unrelated to SCI;
  5. severe anemia (Hgb<8 g/dl) or hypovelemia; and
  6. HIV or AIDS related illness.
Sexes Eligible for Study: All
Child, Adult, Senior
No
United States
 
 
NCT02037620
IB140483CVEpiStim
ES2-CHN-2013(SH) ( Other Grant/Funding Number: CDRF )
No
Not Provided
Not Provided
Susan Harkema, University of Louisville
University of Louisville
Not Provided
Principal Investigator: Susan J Harkema, PhD University of Louisville
University of Louisville
April 2017

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP