Recovery of Cardiovascular Function With Epidural Stimulation After Human Spinal Cord Injury
| Status: | Recruiting |
|---|---|
| Conditions: | Hospital, Orthopedic |
| Therapuetic Areas: | Orthopedics / Podiatry, Other |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 4/21/2016 |
| Start Date: | January 2014 |
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.
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.
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.
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.
We found this trial at
1
site
500 S Preston St
Louisville, Kentucky
Louisville, Kentucky
(502) 852-5555
Principal Investigator: Susan J Harkema, PhD
Phone: 502-581-7443
University of Louisville The University of Louisville is a state supported research university located in...
Click here to add this to my saved trials
