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Summary
Background Repeated periods of stimulation of the spinal cord and training increased the ability to control movement
in animal models of spinal cord injury. We hypothesised that tonic epidural spinal cord stimulation can modulate
spinal circuitry in human beings into a physiological state that enables sensory input from standing and stepping
movements to serve as a source of neural control to undertake these tasks.
Methods A 23-year-old man who had paraplegia from a C7T1 subluxation as a result of a motor vehicle accident in
July 2006, presented with complete loss of clinically detectable voluntary motor function and partial preservation of
sensation below the T1 cord segment. After 170 locomotor training sessions over 26 months, a 16-electrode array was
surgically placed on the dura (L1S1 cord segments) in December 2009, to allow for chronic electrical stimulation.
Spinal cord stimulation was done during sessions that lasted up to 250 min. We did 29 experiments and tested several
stimulation combinations and parameters with the aim of the patient achieving standing and stepping.
Findings Epidural stimulation enabled the man to achieve full weight-bearing standing with assistance provided only
for balance for 425 min. The patient achieved this standing during stimulation using parameters identied as
specic for standing while providing bilateral load-bearing proprioceptive input. We also noted locomotor-like patterns
when stimulation parameters were optimised for stepping. Additionally, 7 months after implantation, the patient
recovered supraspinal control of some leg movements, but only during epidural stimulation.
Interpretation Task-specic training with epidural stimulation might reactivate previously silent spared neural
circuits or promote plasticity. These interventions could be a viable clinical approach for functional recovery after
severe paralysis.
Funding National Institutes of Health and Christopher and Dana Reeve Foundation.
Introduction
The mammalian spinal cord can generate locomotor
output in the absence of input from the brain13 by central
pattern generation.46 Cats with complete transection of the
spinal cord (spinal cats) can stand and step when sensory
input is provided to the lumbosacral pattern generator
circuitry.79 Spinal cats can learn to stand, fully supporting
their hindquarters, and to step at a range of speeds and
load-bearing levels with task-specic training. Adult
spinally transected rats can step only with a combination
of interventions of locomotor training, pharmacological
intervention, and epidural stimulation.10,11 This evidence
led to the hypothesis that if similar spinal circuits exist in
human beings, then electrically stimulating the lumbosacral spinal cord epidurally coupled with intense training
could facilitate standing and stepping in patients with a
clinically motor complete spinal cord injury (SCI).
Improvements in walking have been achieved with
intense locomotor training in patients with SCI who have
detectable voluntary movement of the legs1214 but not in
those with clinically motor complete SCI.1517 Rhythmic
eerent activity timed to the step cycle can occur during
manually facilitated stepping, and bilateral tonic activity
Published Online
May 20, 2011
DOI:10.1016/S01406736(11)60547-3
See Online/Comment
DOI:10.1016/S01406736(11)60711-3
Department of Neurological
Surgery, Kentucky Spinal Cord
Research Center, University of
Louisville, KY, USA
(Prof S Harkema PhD,
J Hodes MD, C Angeli PhD,
Y Chen PhD, C Ferreira BSc,
A Willhite BA); Frazier Rehab
Institute, Louisville, KY, USA
(S Harkema, C Angeli, Y Chen,
C Ferreira, A Willhite); Pavlov
Institute of Physiology,
St Petersburg, Russia
(Y Gerasimenko PhD);
Department of Integrative
Biology and Comparative
Physiology, University of
California, Los Angeles,
Los Angeles, CA, USA
(Y Gerasimenko,
Prof V R Edgerton PhD); Division
of Engineering and Applied
Sciences, California Institute of
Technology, Pasadena, CA, USA
(Prof J Burdick PhD);
Department of Biomedical
Sciences and Technologies,
University of Udine, Udine,
Italy (E Rejc MSc); and
Department of Neurosurgery,
The Neurological Institute,
The Methodist Hospital, Texas,
Houston, TX, USA
(Prof R G Grossman MD)
Correspondence to:
Prof V Reggie Edgerton,
Department of Integrative
Biology and Comparative
Physiology, Department of
Neurobiology and Brain Research
Institute, University of California,
Los Angeles, Los Angeles,
CA 90095, USA
vre@ucla.edu
Methods
Clinical characteristics before implantation
A 23-year-old man, who was hit by a motor vehicle in July
2006, 34 years before implantation in December 2009,
Articles
Procedures
Our research team sponsored an international 2-day
workshop consisting of scientists and clinicians with
knowledge of electrical stimulation of the spinal cord
and the neural control of posture and locomotion.
The study design for implantation and training of a
patient with clinically motor complete SCI was discussed
and assessed.
Before electrode implantation, the patient received
170 locomotor training sessions14 over 26 months from
Oct 19, 2007, to Nov 23, 2009, with bodyweight support
and manual facilitation on a treadmill, resulting in 108 h
of step training and 54 h of stand training, with no
detectable change in electromyography (EMG) activity
(gure 1). During manually facilitated stepping, sporadic
EMG activity was noted bilaterally in the lower leg
muscles most often in the medial hamstrings. No
improvement was observed in EMG over the course of
the training.
We used an epidural spinal cord stimulation unit
(RestoreADVANCED, Medtronic, Minneapolis, MN, USA)
to electrically stimulate the lumbosacral enlargement. A
16-electrode array (Specify 5-6-5, Medtronic) was implanted
under uoroscopic control at T11L1 over spinal cord
2
Articles
Standing
Stepping
RF
VL
MH
TA
Sol
MG
FSCAN
February, 2008, after 66 step sessions
RF
VL
MH
TA
Sol
MG
FSCAN
November, 2009, after 170 step sessions
RF
VL
MH
TA
Sol
MG
02 mV
FSCAN
1000 N
1s
C
0010
1s
Right side muscles
Stand Step
Step session 0
Step session 66
Step session 170
0005
0
RF
VL
MH
TA
Sol
MG
RF
VL
MH
TA
Sol
MG
Figure 1: Leg EMG activity during standing and stepping with bodyweight support before implantation
EMG activity while standing (A) and stepping (B) with bodyweight support and manual facilitation on a treadmill before implantation. (C) Mean EMG amplitude for
standing (solid symbols) and stepping (open symbols) at three timepoints (0, 66, and 170 step training sessions). EMG=electromyography. RF=rectus femoris.
VL=vastus lateralis. MH=medial hamstrings. TA=tibialis anterior. Sol=soleus. MG=medial gastrocnemius. FSCAN=ground reaction force data.
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L RF
2 mV
L MH
1 mV
L TA
2 mV
L MG
1 mV
R RF
2 mV
R MH
1 mV
R TA
2 mV
R MG
1 mV
Stimulation
intensity
8V
1
8V
8V
900 N
Load
BWS
65%
45%
15 s
30%
25%
20%
15%
10%
5%
BWS
15 s
Figure 2: Leg EMG activity with epidural stimulation of the lumbosacral segments during standing
Please also see webvideo 1. (A) EMG activity increases in amplitude and becomes more constant bilaterally in most muscles as stimulation is increased in strength
from 1 to 8 V (15 Hz) with a constant level of BWS (585/900 N [65%]). (B) Reduction of BWS from 45% to 5% (405/900 N to 45/900 N) and with constant
stimulation (8 V; 15 Hz) changed the EMG amplitudes and oscillatory patterns dierently among muscles. The array diagram at the bottom of (A) shows the
stimulation conguration: anode electrodes are black and cathode electrodes are grey. The interpulse interval, which shows the stimulation frequency, is also shown
at the bottom of (A). EMG=electromyography. BWS=bodyweight support. L=left. R=right. RF=rectus femoris. MH=medial hamstrings. TA=tibialis anterior.
MG=medial gastrocnemius.
Results
Articles
No stimulation
Rostral stimulation
Caudal stimulation
R IL
10 mV
R VL
R MH
R TA
R Sol
R MG
1 mV
15 s
Stim
Sitting
15 s
Standing
15 s
75 V
75 V
0066 s
(15 Hz)
0066 s
(15 Hz)
Mean EMG
amplitude (mV)
R IL (10)
Mean EMG
amplitude (mV)
75 V
R TA
12
Sitting
Sitting to standing
Standing
Caudal stimulation
Rostral stimulation
No stimulation
0
R VL
R Sol
R MH
R MG
Shoulder
12
Mean EMG
amplitude (mV)
Hip
Knee
12
Toe
Ankle
Heel
0
75
75
75
75
Stimulation strength (V)
75
75
75
75
Stimulation strength (V)
Figure 3: Leg EMG activity during sitting and standing with and without epidural stimulation
Transition (white) from sitting (grey) to standing (orange) with (A) no stimulation, (B) rostral (spinal segments L1L2) stimulation (575 V, 15 Hz), and (C) caudal
(spinal segments L4S1) stimulation (475 V, 15 Hz). With increasing levels of epidural stimulation, EMG amplitudes were modulated in a tonic pattern while the
patient remained sitting. During the transition from sitting to standing, amplitudes and patterns of EMG were modulated in all recorded muscles. (D) Mean EMG
amplitude responses on the right side during sitting and standing with no stimulation, and rostral and caudal stimulation at 75 V (15 Hz). (E) Kinematic
representation of sitting to standing transition with caudal stimulation (illustration at 10 frames per s; webvideo 2). Array diagrams at the bottom of (B) and (C)
show the stimulation congurations; anode electrodes are black and cathode electrodes are grey. The interpulse interval, which shows the stimulation frequency, is
shown at the bottom of (B) and (C). IL was measured with ne-wire electrodes. VL, MH, TA, Sol, and MG were measured with surface EMG. EMG=electromyography.
R=right. IL=iliopsoas. VL=vastus lateralis. MH=medial hamstrings. TA=tibialis anterior. Sol=soleus. MG=medial gastrocnemius. Stim=stimulation intensity.
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Sagittal shifting
Backward
Forward
30 mm
L TA
L MG
R TA
R MG
04 mV
Stim
75 V
3s
0066 s
(15 Hz)
L MH
Discussion
L TA
L Sol
L MG
R VL
R MH
R TA
R Sol
16 mV
R MG
Stim
9V
3s
004 s
(25 Hz)
Articles
L VL
03 mV
L MH
04 mV
L TA
01 mV
L MG
01 mV
R VL
10 mV
R MH
05 mV
R TA
015 mV
R MG
01 mV
2s
2s
2s
Stim
75 V
Load (N)
450 N
L Hip
85
R Hip
FS
85
L
R
50% BWS, 107 m/s
Medial hamstring
Preimplant, step session 170
Postimplant, stepping with no stimulation
Postimplant , stepping with stimulation
0015
0033 s
(30 Hz)
0010
0005
0
0
Step
Figure 5: Leg EMG activity during standing and stepping with bodyweight support and manual facilitation with and without epidural stimulation of
lumbosacral segments
The EMG patterns were modied by stimulation and by dierent patterns of sensory input. EMG activity during (A) manually facilitated stepping (450/900 N
[50% BWS], 107 m/s) without stimulation, (B) standing (225/900 N [25% BWS], 0 m/s) with epidural stimulation (75 V, 30 Hz), and (C) manually facilitated
stepping (450/900 N [50% BWS], 107 m/s) with epidural stimulation (75 V, 30 Hz). The grey shaded area shows one full step of the right leg. (D) Mean EMG activity
for the MH during stepping after 170 step training sessions before implantation (see gure 1B), and during stepping after implantation with (C) and without (A)
stimulation. The horizontal lines represent the baseline variation in the noise of each signal. The array diagram at the bottom of (C) shows the stimulation
conguration; anode electrodes are black and cathode electrodes are grey. The interpulse interval, which shows stimulation frequency, is also shown at the bottom of
(C). EMG=electromyography. L=left. R=right. VL=vastus lateralis. MH=medial hamstrings. TA=tibialis anterior. MG=medial gastrocnemius. Load=load cell reading.
L Hip=left hip sagittal joint angle. R Hip=right hip sagittal joint angle. FS=footswitches. Stim=stimulation intensity.
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Stimulation
Left
Right
Sol
02 mV
Sol
02 mV
EHL
20 mV
EHL
20 mV
EDL
40 mV
EDL
20 mV
TA
02 mV
TA
02 mV
PL
02 mV
PL
02 mV
VL
02 mV
Toe
20
MH
02 mV
Ankle
30
AD
02 mV
GL
02 mV
2s
2s
4V
IL
20 mV
ES
02 mV
AB
02 mV
Sol
02 mV
IC
04 mV
EHL
20 mV
EDL
40 mV
TA
02 mV
PL
02 mV
Toe
20
Toe
20
Ankle
30
Knee
80
Hip
80
2s
30
Ankle
2s
2s
2s
4V
4V
0033 s
(30 Hz)
Stimulation
Toe
Hip
Knee
Ankle
Heel
Articles
be needed for practical application of epidural stimulation, and the addition of pharmacological drugs might
further improve functional recovery.
A key limitation of this study is that data were from one
research patient and thus generalisability to a population
should be cautioned. There were also technical limitations
of the stimulator that prevented us from dierentially
manipulating parameters (voltage and frequency) needed
to optimise the completion of dierent motor tasks. A
third limitation was the inability to eectively assess
which anatomical connections still existed after the injury
and after the stimulation period.
Articles
Contributors
SH, YG, JB, CA, and VRE designed the study. JH did the surgical
implantation. SH, CA, YC, and CF did the electrophysiological testing
during surgery. SH, CA, CF, and AW, collected data and developed the
gures. YC designed the data collection system. YG and ER also
developed the gures. SH and VRE supervised the study. All authors
interpreted the data and wrote the manuscript.
Conicts of interest
SH, YG, JH, JB, CA, and VRE have a provisional patent pending for an
electrode array stimulator system. All other authors declare that they
have no conicts of interest.
Acknowledgments
This study was funded by the National Institutes of Health and
Christopher and Dana Reeve Foundation. We thank Milan Dimitrijevic,
Karen Minassian, Frank Rattay, and Antonio Buccalo for the conceptual
and technical formulation of the present experiments;
Michael Sofroniew, David Magnuson, and Jerey Petruska for their
feedback on the manuscript; and the research team members who did
experiments and provided intense training. Finally, we thank the
research patient whose dedication, motivation, and perseverance made
these ndings possible.
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