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Author Manuscript
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Published in final edited form as:
Lancet. 2011 June 4; 377(9781): 1938–1947. doi:10.1016/S0140-6736(11)60547-3.

Effect of Epidural stimulation of the lumbosacral spinal cord on
voluntary movement, standing, and assisted stepping after
motor complete paraplegia: a case study
Susan Harkema, Ph.D.,
Department of Neurological Surgery, Kentucky Spinal Cord Research Center, University ofLouisville. Frazier Rehab Institute, Louisville KY, 220 Abraham Flexner Way, Louisville KY 40202- USA

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Yury Gerasimenko, Ph.D,
Pavlov Institute of Physiology, St. Petersburg, Russia. Department of Integrative Biology andComparative Physiology, University of California, Los Angeles USA, Los Angeles, CA 90095 USA
Jonathan Hodes, M.D.,
Department of Neurological Surgery, Kentucky Spinal Cord Research Center, University ofLouisville, 401 East Chestnut Street – Suite 580, Louisville, KY 40202 - USA
Joel Burdick, Ph.D.,
Division of Engineering and Applied Sciences, California Institute of Technology, Pasadena, CA
91125 - USA
Claudia Angeli, Ph.D.,
Frazier Rehab Institute, Louisville KY. Department of Neurological Surgery, Kentucky Spinal Cord
Research Center, University of Louisville, 220 Abraham Flexner Way, Louisville KY 40202 - USA
Yangsheng Chen, Ph.D.,
Department of Neurological Surgery, Kentucky Spinal Cord Research Center, University ofLouisville. Frazier Rehab Institute, Louisville KY, 220 Abraham Flexner Way, Louisville KY 40202- USA

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Christie Ferreira, B.S.,
Department of Neurological Surgery, Kentucky Spinal Cord Research Center, University ofLouisville. Frazier Rehab Institute, Louisville KY, 220 Abraham Flexner Way, Louisville KY 40202- USA
Andrea Willhite, B.S.,© 2011 Elsevier Ltd. All rights reserved.
Corresponding Author: vre@ucla.edu, 310-825-1910.
Contributors
RE, SH, YG, JB and CA were responsible for the study concept and design. JH performed surgical implant, SH. YC, CA and CF
conducted the electrophysiological testing during surgery. SH, CA, CF, AW conducted all data collections and figure development.
YC designed the data collection system. YG and ER also contributed to figure development. SH and RE were responsible forsupervision of the study. All authors contributed to data interpretation and writing of the manuscript.
Conflicts of interest
No authors have any conflicts of interest.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to ourcustomers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of
the resulting proof before it is published in its final citable form. Please note that during the production process errors may bediscovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Department of Neurological Surgery, Kentucky Spinal Cord Research Center, University ofLouisville. Frazier Rehab Institute, Louisville KY, 220 Abraham Flexner Way, Louisville KY 40202- USA
Enrico Rejc, M.S.,
Department of Biomedical Sciences and Technologies, University of Udine, P.le Kolbe 4, 33100,
Udine, Italy
Robert G. Grossman, M.D., andDepartment of Neurosurgery, The Neurological Institute, The Methodist Hospital, Texas USA,6560 Fannin, Suite 944, Houston, TX 77030 - USA
V. Reggie Edgerton, Ph.D.
Department of Integrative Biology and Comparative Physiology, Department of Neurobiology andBrain Research Institute, University of California, Los Angeles, Los Angeles, CA 90095 - USA

Summary
Background—Repeated periods of stimulation of the spinal cord and training seems to haveamplified the ability to consciously control movement.

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Methods—An individual three years post C7-T1 subluxation presented with a complete loss ofclinically detectable voluntary motor function and partial preservation of sensation below the T1
cord segment. Following 170 locomotor training sessions, a 16-electrode array was surgicallyplaced on the dura (L1-S1 cord segments) to allow for chronic electrical stimulation. After
implantation and throughout stand retraining with epidural stimulation, 29 experiments were
performed. Extensive stimulation combinations and parameters were tested to achieve standing
and stepping.
Findings—Epidural stimulation enabled the human lumbosacral spinal circuitry to dynamicallyelicit full weight-bearing standing with assistance provided only for balance for 4·25 minutes in a
subject with a clinically motor complete SCI. This occurred when using stimulation at parametersoptimized for standing while providing bilateral load-bearing proprioceptive input. Locomotorlike patterns were also observed when stimulation parameters were optimized for stepping. In
addition, seven months after implantation, the subject recovered supraspinal control of certain leg
movements, but only during epidural stimulation.

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Interpretation—Even after a severe low cervical spinal injury, the neural networks remaining
within the lumbosacral segments can be reactivated into functional states so that it can recognize
specific details of ensembles of sensory input to the extent that it can serve as the source of neuralcontrol. In addition, newly formed supraspinal input to this same lumbosacral segments can reemerge as another source of control. Task specific training with epidural stimulation may havereactivated previously silent spared neural circuits or promoted plasticity. This suggests that theseinterventions 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 thebrain1–3 by central pattern generation.4–6 Cats with complete spinal cord transection can
execute standing and stepping when sensory input is provided to the lumbosacral patterngenerator circuitry.7–9 Spinal cats can learn to stand, fully supporting their hindquarters, andto step over a range of speeds and load-bearing levels with task specific training. Adult
spinally transected rats generate stepping only with combined interventions of locomotor
training, pharmacological intervention and/or epidural stimulation.10,11 This evidence leads

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NIH-PA Author Manuscriptto the hypothesis that if similar spinal circuits exist in humans, then electrically stimulating
the lumbosacral spinal cord epidurally coupled with intense training can facilitate standing
and stepping in an individual with a clinically motor complete spinal cord injury (SCI).
Improvements in walking have been achieved with intense locomotor training in individuals
who have detectable voluntary movement of the legs after SCI12–14 but not in thoseclassified as clinically motor complete.15–17 Rhythmic efferent activity timed to the step
cycle can occur during manually facilitated stepping, and bilateral tonic activity can occur
during partial weight-bearing standing after a clinically complete SCI. Rhythmic and tonic
motor patterns of the legs have been induced with18–22 and without23–25 epidural
stimulation in humans after motor complete SCI while lying supine. This suggests thatspinal circuitry for locomotion is present in the human but cannot functionally execute thesetasks without some critical level of excitability from supraspinal centers present after
incomplete SCI.

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We hypothesized that tonic epidural spinal cord stimulation can modulate the human spinal
circuitry into a physiological state that enables sensory input, derived from standing andstepping movements, to serve as a source of neural control to perform these tasks. We
observed that the spinal circuitry was able to generate full weight-bearing standing withbalance assistance in response to task specific sensory cues in the presence of epidural
stimulation. This occurred in a paraplegic subject with a clinically motor complete SCI.
Stepping-like patterns were also generated with epidural stimulation during manuallyfacilitated stepping on a treadmill using body weight support. The subject also regainedsome supraspinally mediated control of the legs after intense stand training with epidural
stimulation. Unexpectedly, clinical assessments indicated improvements in otherphysiological functions including bladder, sexual function, and temperature regulation. One
possible explanation for this recovery is that residual supraspinal connections that existed
but could not be detected clinically were reactivated or that new supraspinal connections tothe spinal networks were formed.

Methods
Clinical characteristics prior to implantation

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A 23-year-old male struck by a motor vehicle 3·4 years prior to implantation was enrolled inthis study. Neurological examination revealed paraplegia from a C7-T1 subluxation withinjury to the lower cervical and upper thoracic spinal cord. The triceps and intrinsic handmuscles exhibited weak voluntary contraction. He had no contraction of trunk or leg
muscles. He was treated emergently, subluxation was reduced by anterior interbody fusion
and instrumentation. MRI of the injury site obtained prior to implantation revealed
myelomalacia and atrophy of the cord segment adjacent to the T1 vertebral body(supplemental figure 1a).
Prior to implantation, his neurological deficit on the American Spinal Injury Association(ASIA) impairment scale (AIS)26 as AIS B (pinprick and light-touch present below thelesion). He had no motor function of trunk or leg muscles, a flaccid anal sphincter, and novoluntary bladder contraction (supplemental figure 1b). Sensation was abnormal below C7.
Somatosensory evoked potentials showed bilateral delay of cortical responses from posterior
tibial nerve stimulation. Lower extremity nerve conduction studies were normal. Motorcortex transcranial magnetic stimulation elicited no response from leg muscles. He wasunable to stand or walk independently or voluntarily move his legs despite standard-of-carerehabilitation and additional intensive locomotor training. The research subject signed an
informed consent for electrode implantation, stimulation, and physiological monitoring

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Page 4studies approved by the University of Louisville and the University of California, Los
Angeles Institutional Review Boards.

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Prior to the electrode implantation, the participant received 170 locomotor training
sessions14 over a period of 26 months using body weight support on a treadmill with manual
facilitation resulting in 108 hours of step training and 54 hours of stand training with nodetectable change in electromyographic (EMG) activity (figure 1). During manuallyfacilitated stepping, sporadic EMG activity was observed in the lower leg muscles, mostoften in the medial hamstrings. No improvement was observed in EMG over the course of
the training.
Surgical Implantation of electrode array and stimulator

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An epidural spinal cord stimulation unit (RestoreADVANCED, Medtronics) was used toelectrically stimulate the lumbosacral enlargement. A 16-electrode array (5-6-5 Specify,
Medtronics) was implanted under fluoroscopic control at T11-L1 over spinal cord segments
L1-S1 (supplemental figure 2a). The electrode array was positioned over the midline of the
exposed dura. The location of the array was evaluated during surgery with thresholds andamplitudes of EMG recorded from leg muscles21 elicited by stimulation at 2 Hz. Multiple
stimulations were tested using a midline stimulation configurations, with each electrode pairbeing 6 mm apart. Symmetry was tested by using left and right side electrodes within thearray. The electrode lead was tunneled to a subcutaneous abdominal pouch where the pulse
generator was implanted. Two weeks after implantation, the position of the array wasreconfirmed using the same stimulation protocols while the subject was lying supine(supplemental figure 2c–d).
Experimental Design
Varying combinations of stimulation were systematically evaluated to elicit optimal efferent
patterns for standing and stepping. Spinal cord stimulation was conducted during sessions
lasting up to 250 minutes. During these sessions, stimulation duration ranged from 40 to 120
minutes. Stimulation amplitudes and frequencies ranged from 0·5 to 10·0V and 5 to 40 Hz,
respectively, using either a 210 or 450 ȝs pulse width. The optimal standing configurations
evoked sustainable tonic co-activation specifically when standing; stepping configurations
evoked rhythmic activity with alternation of right and left leg and intralimb flexors andextensors. EMG activity of 14 lower extremity muscles and hip, knee, and ankle joint angles
were measured.

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During experimental sessions on the treadmill, three trainers provided manual facilitation,
when needed. Two trainers provided facilitation by placing their hands distal to the patelladuring the stance phase and at the popliteal fossa and anterior distal tibia for foot clearance
during the swing phase.14 The third trainer held the pelvis for stabilization and weightshifting during stepping. Stand training was performed using a device comprised of verticaland horizontal bars surrounding the individual allowing him to assist balance. Bungees wereattached to the device to provide support only if the knees or hips flexed beyond the normal
standing posture (supplemental note). The total duration of stimulation averaged 54 ± 13
minutes per session. Epidural stimulation was not provided outside laboratory sessions.
Data Acquisition
EMG, joint angles, footswitch, ground reaction forces and body weight support (Innoventor,
St. Louis, MO) data were collected at 2,000 Hz using a custom-written acquisition software(National Instruments, Austin, TX). Bilateral EMG (Motion Lab Systems, Baton Rouge,LA) from the soleus, medial gastrocnemius, tibialis anterior, medial hamstrings, quadriceps,
and gluteus maximus muscles was recorded using bipolar surface electrodes with fixed
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NIH-PA Author Manuscriptinter-electrode distance.16 Bilateral EMG from the iliopsoas was recorded with fine-wireelectrodes. Two surface electrodes placed symmetrically lateral to the electrode array
incision site over the paraspinal muscles were used to record the stimulation artifact. Hip,knee, and ankle joint angles were acquired using a high-speed optical motion capture system(Motion Analysis, Santa Rosa, CA). Ground reaction forces were collected using shoeinsole pressure sensors (TEKSCAN, Boston, MA).

Role of funding source
The sponsors of this study had no role in study design, data collection, data analysis andinterpretation, or writing of the manuscript. All authors had full access to all the datareported in the manuscript. All authors had responsibility for the decision to submit themanuscript.

Results

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The patient was always cognizant of the presence of the stimulation. The most common
sensation was a tingling feeling localized to the electrode implantation site and in thosemuscles that were targeted for activation. Parasthesias were also routinely perceived in thetrunk, hips, and legs and varied according to the stimulation intensity; however, thesesensations never reached a level of significant discomfort or pain and never precluded theuse of epidural stimulation.
Standing with epidural stimulation
Epidural stimulation (15 Hz, 8V) of the caudal segments (L5-S1) of the spinal cord
combined with sensory information related to bilateral extension and loading was sufficientto generate standing without manual facilitation when first attempted (figure 2) with 65%(585/900N) body weight support (figure 2a, supplemental video 1). The subject was able tosustain standing without manual facilitation while the level of body weight support was
progressively reduced to full weight-bearing (figure 2b, supplemental video 1).

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Transitioning from sitting to standing without body weight support altered the EMG activity
during epidural stimulation even though the stimulation parameters remained constant(figure 3). When loading of the legs was initiated, the EMG activity increased dramaticallyand was sufficient to support the subject’s body weight with minimal assistance required by
the trainers (supplemental note). During this transition, the stimulation remained constantusing the same location, frequency and intensity parameters (figure 3b–e). The EMG
activity was also modulated by the site and intensity of stimulation. The caudal (L5-S1)
stimulation at higher intensities resulted in a more optimal motor pattern for standing (figure3a–c). During caudal stimulation, there was a greater increase in the EMG amplitude
bilaterally in the more proximal muscles compared to that of the more distal muscles whichwere initially markedly reduced (figure 3c and e, supplemental video 2). Once standing wasachieved, there was more co-contraction of both flexors and extensors and proximal anddistal muscles.
Postural responses with epidural stimulation
Postural responses were observed in the leg EMG activity when the subject shifted his
center of gravity sagittally while standing with epidural stimulation and intermittent manual
facilitation (figure 4a). The EMG burst of the medial gastrocnemius increased with forward
deviation, whereas backward deviation induced EMG bursts in the tibialis anterior. Standing
bouts with tonic bilateral EMG activity routinely occurred for several continuous minutes
and increased in frequency and duration as training progressed (figure 4b). After 80 sessions(supplemental note), the subject could initiate and maintain continuous full weight-bearing
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standing without manual facilitation (maximum 4·25 min) with bilateral tonic EMG activity(figure 4b, supplemental video 3). Oscillatory patterns, often clonic-like, emerged and thenwere followed by little or no EMG activity, requiring a return to manually facilitatedstanding. This sequence occurred repeatedly during the 60 minute standing sessions.
Locomotor patterns with epidural stimulation
Epidural stimulation at 30–40 Hz and task specific sensory cues were needed to generate
locomotor-like patterns. Sensory cues from manually facilitated stepping included load
alternation and leg positioning with appropriate kinematics of the hips, knees, and ankles
timed to the step cycle. Without epidural stimulation, manually facilitated stepping produced
little or no EMG activity (figure 5a). The EMG activity in the legs was dramaticallydifferent depending on the loading and kinematic patterns when using identical stimulation
parameters. Consistent oscillatory EMG patterns did not occur when the legs were extended
and bilaterally loaded, but emerged ‘with alternating loading and flexion and extension of
the legs (figure 5b and c).
Supraspinal control of movements with epidural stimulation

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Supraspinal control of toe extension and ankle and leg flexion emerged only with epidural
stimulation. This occurred after 80 stand training sessions (seven months after implantation)(figure 6 and supplementary videos 4 and 5). Voluntary movement was observed in both
lower extremities, although the stimulation parameters were different. Technical limitationsof the stimulator prevented simultaneous movements of the legs. When the subject was
instructed to flex (draw the leg upward), the toe extended, the ankle dorsi-flexed and the hipand knee flexed with the appropriate muscle activation. When instructed to dorsi-flex theankle, the foot moved upward with tibialis anterior activation. When instructed to extend thegreat toe, the toe moved upward with activation of the extensor hallucis longus. The subject
could consciously activate the appropriate muscles for the intended movement, and thetiming of activation was closely linked to the verbal commands (figure 6e).
Clinical Impressions

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With training and epidural stimulation, the subject had functional gains in bladder andsexual function and temperature regulation (supplemental note). The subject has been able tovoluntarily void with minimal residual volume and reports improved sexual response andperformance. The subject regained diaphoretic capability and ability to tolerate temperature
extremes. In addition, a sense of well being and increased self-esteem enabled more frequentsocial interactions. An eighteen percent weight gain was associated with increased appetite
and relative increase in lean body mass and decrease in total body fat as measured using a
DEXA scan.

Discussion
We have used an epidurally implanted electrode array to modulate the physiological state of
the spinal circuitry to enable full weight-bearing standing in a human with a chronicclinically motor complete SCI. This phenomenon was observed with the first attempt atstanding. The epidural stimulation did not induce standing by directly activating motor
pools, but enabled motor function by stimulating afferent fibers in the dorsal root andengaging populations of interneurons that integrated load-bearing related proprioceptive
input to coordinate motor pool activity. Although motor pool activity in the presence of
epidural stimulation could occur during sitting in some cases, the activity needed for
effective standing required the proprioceptive information associated with load-bearing
positional changes. Dynamic changes in position during standing were accompanied by
motor patterns needed to maintain upright posture without changes in the epidural
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stimulation parameters. Intensive task specific training combined with epidural stimulation
extended the duration of periods of full weight-bearing standing that could be initiated by
the subject.
Robust, consistent rhythmic stepping-like activity emerged during manually facilitatedstepping only when tonic epidural stimulation and stepping-associated proprioception(alternating weight-bearing and flexion and extension of the legs) was present. Whenstanding, the same stimulation parameters elicited primarily tonic bilateral activity;
however, when stepping, the parameters evoked rhythmic alternating activity. Presumably,
the epidural stimulation activates the dorsal root afferent fibers and, more likely at higher
intensities, dorsal columns and additional spinal structures. The continuous stimulation
modulated the physiological state of the spinal cord which enabled sensory information
processing that was closely linked to the functional task. This is of great clinical importance,
because the intended task can be driven and controlled via the spinal sensorimotor circuitry
rather than by an external control system.

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Previous studies have shown that epidural stimulation can induce rhythmic activity inclinically complete subjects lying supine.18–21 Also, different sources of sensory input, e.g.
hip extension and pinching of skin, can elicit rhythmic activity in the trunk and legs insubjects with clinically complete SCI.18,22–24 Manually facilitated standing17 andstepping15,16,27 can elicit bilateral tonic EMG and rhythmic oscillatory EMG, respectively,in many individuals with clinically complete SCI demonstrating the importance of providing
task specific sensory cues. Our study provides evidence that, when enabled by epidural
stimulation, the sensory input may serve as a spinal circuitry controller during standing andmanually facilitated stepping in the absence of clinically detectable supraspinal input inhumans.

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The individual in this study was eventually able to voluntarily execute toe extension, ankle
dorsi-flexion, and leg flexion in the presence of epidural stimulation. In subjects with amotor incomplete SCI who have some ability to voluntarily move their legs, a common
phenomenon is the loss of specificity of control of selected muscles.27 In this study, theactivated motor pools were appropriate for the intended movement. Two possible
mechanisms are: 1) epidural stimulation provided excitation of lumbosacral interneurons
and motoneurons28 which, combined with the weak excitatory activity of residual
descending axons, achieved a level of excitation that was sufficient to activate motoneurons;
and/or 2) axonal regeneration or sprouting may have been induced via activity-dependent
mechanisms over a period of months. It is highly significant from a neurobiological, as well
as a clinical perspective, that this supraspinal control was manifested only in the presence ofcontinuous tonic epidural stimulation. Seemingly, conscious control was regained byelevating the level of spinal interneuronal excitability with stimulation to a critical, but subthreshold level, allowing control via descending pathways.
These same mechanisms may also explain the improved autonomic function in bladder,sexual and thermoregulatory activity that has been of significant benefit to the subject. The
areas of lumbosacral spinal cord stimulated included at least parts of the neural circuits that
regulate these autonomic functions and may have also resulted in activity-dependentchanges.
The evidence supports the proof of principle that humans have conserved spinal locomotor
circuitry as found in other mammals including the ability to: 1) transition from a low level
activity state to one that can generate active standing in the presence of tonic epidural
stimulation; 2) gate tonic electrically evoked responses to coordinate motor pools to elicit
patterns consistent with the task specific sensory input; 3) control the level and timing ofLancet. Author manuscript; available in PMC 2011 December 4.

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neural excitation sufficient to generate standing and facilitate stepping through the use of
appropriate task specific sensory input; and 4) mediate voluntarily initiated movement of thelegs in the presence of epidural stimulation. These results indicate that epidural stimulation
has potential as a clinical intervention in combination with task specific training for therecovery of function after SCI and other neurologic disorders.30 Improvements in the arrayand stimulation technology will be needed for practical application, and the addition ofpharmacological agents may result in greater degrees of functional recovery.
PANEL: Research in Context

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Systematic Review—The search strategy for evidence that epidural stimulation of the
spinal cord could be used to improve motor function in humans consisted of identifying all
published literature listed in PubMed that related to electrical, pharmacological andelectromagnetic stimulation of the spinal cord. This search included studies ranging from insitu isolated spinal cord of the lamprey to humans with implanted epidural electrodes. Eachlisted publication was assessed relative to the animal species, whether the spinal injury was
motor complete or incomplete, details of the stimulation parameters relative to the motor
responses, the specific experimental model used in the study, i.e. in vivo versus in situ, andutilization of proprioceptive input. In addition, our research team sponsored an international
2-day workshop consisting of scientists and clinicians with knowledge of electricalstimulation of the spinal cord and the neural control of posture and locomotion. Study designfor implantation and training of a spinal motor complete human subject was discussed andevaluated extensively. In the most closely related studies, it was shown that epidural
stimulation of the lumbosacral spinal cord of spinally complete (AIS A) subjects could
induce an oscillatory movement in the legs, and the pattern of movement changed withdifferent stimulation parameters.20–21

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Interpretation—While it has been clear that the human spinal cord circuitry can be
induced to generate cyclic movements of the legs without supraspinal input in response to
tonic stimulation of peripheral afferents or directly stimulating the spinal cord, thesignificance of these observations have been uniformly interpreted as providing evidence forcentral pattern generation i.e. oscillations induced without input from the brain or fromperipheral afferents. The present data demonstrate three new concepts regarding the spinalcontrol of movement. First, that the human spinal cord circuitry for posture and locomotion
can be “controlled” by the peripheral sensory input, thus, emphasizing this key role ofsensory input in posture and locomotion rather than its independence from sensory input.
Secondly, we show the “enabling” phenomenon of epidural stimulation whereby modest
levels of stimulation do not “induce” stepping or standing, but when stimulated with theappropriate parameters the sensory input can serve as the “controller”, as occurs in cats andrats. And most dramatically, after months of stimulation and training, voluntary control ofleg movement emerged, but only when enabled by modest levels of epidural stimulation.
None of these observations have been demonstrated previously in a human with chronic(more than 3 years post lesion) paralysis. These observations open the possibility of aparadigm shift in the perception of possible interventions that could be used to improvefunction for a range of neuromotor disorders.

Supplementary Material
Refer to Web version on PubMed Central for supplementary material.

Acknowledgments
We would like to express our appreciation to Milan Dimitrijevic, Karen Minassian, Frank Rattay, and Antonio
Buccalo in the conceptual and technical formulation of the present experiments. We thank Michael Sofroniew,

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Page 9David Magnusson and Jeff Petruska for their feedback on the manuscript. We also gratefully acknowledge theresearch team members who conducted experiments and provided intense training. We are indebted to the research
participant whose dedication, motivation and perseverance made these findings possible.

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Reference List

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1. Grillner S. Neurobiological bases of rhythmic motor acts in vertebrates. Science. 1985; 228:143–9.
[PubMed: 3975635]
2. Gerasimenko Y, Roy RR, Edgerton VR. Epidural stimulation: comparison of the spinal circuits thatgenerate and control locomotion in rats, cats and humans. Exp Neurol. 2008; 209(2):417–25.
[PubMed: 17850791]
3. Rossignol S, Barriere G, Frigon A, et al. Plasticity of locomotor sensorimotor interactions after
peripheral and/or spinal lesions. Brain Res Rev. 2008; 57(1):228–40. [PubMed: 17822774]
4. Grillner S, Wallén P. Central pattern generators for locomotion, with special reference tovertebrates. Ann Rev Neurosci. 1985; 8:233–61. [PubMed: 2984978]
5. Grillner S. The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci.
2003; 4(7):573–86. [PubMed: 12838332]
6. Grillner S, Zangger P. On the central generation of locomotion in the low spinal cat. Exp Brain Res.
1979; 34:241–61. [PubMed: 421750]
7. de Leon RD, Hodgson JA, Roy RR, Edgerton VR. Locomotor capacity attributable to step training
versus spontaneous recovery after spinalization in adult cats. J Neurophysiol. 1998; 79:1329–40.
[PubMed: 9497414]
8. de Leon RD, Hodgson JA, Roy RR, Edgerton VR. Full weight-bearing hindlimb standing following
stand training in the adult spinal cat. J Neurophysiol. 1998; 80:83–91. [PubMed: 9658030]
9. Barbeau H, Rossignol S. Recovery of locomotion after chronic spinalization in the adult cat. Brain
Res. 1987; 412:84–95. [PubMed: 3607464]
10. Courtine G, Gerasimenko Y, van den BR, et al. Transformation of nonfunctional spinal circuits
into functional states after the loss of brain input. Nat Neurosci. 2009; 12(10):1333–42. [PubMed:
19767747]
11. Ichiyama RM, Courtine G, Gerasimenko YP, et al. Step training reinforces specific spinal
locomotor circuitry in adult spinal rats. J Neurosci. 2008; 28(29):7370–5. [PubMed: 18632941]
12. Wernig A, Müller S. Laufband locomotion with body weight support improved walking in persons
with severe spinal cord injuries. Para. 1992; 30:229–38.
13. Wernig A, Nanassy A, Müller S. Maintenance of locomotor abilities following Laufband(treadmill) therapy in para- and tetraplegic persons: follow-up studies. Spinal Cord. 1998; 36:744–
9. [PubMed: 9848480]
14. Harkema S, Schmidt-Read M, Lorenz D, Edgerton VR, Behrman A. Functional recovery inindividuals with chronic incomplete spinal cord injury with intensive activity-based rehabilitation.
Arch Phys Med Rehab. In Press.
15. Dietz V, Colombo G, Jensen L. Locomotor activity in spinal man. The Lancet. 1994; 344:1260–3.
16. Harkema SJ, Hurley SL, Patel UK, Requejo PS, Dobkin BH, Edgerton VR. Human lumbosacral
spinal cord interprets loading during stepping. J Neurophysiol. 1997; 77(2):797–811. [PubMed:
9065851]
17. Harkema SJ. Plasticity of interneuronal networks of the functionally isolated human spinal cord.
Brain Res Rev. 2008; 57(1):255–64. [PubMed: 18042493]
18. Dimitrijevic MR, Gerasimenko Y, Pinter MM. Evidence for a spinal central pattern generator inhumans. Ann N Y Acad Sci. 1998; 860:360–76. [PubMed: 9928325]
19. Gerasimenko, Y.; Daniel, O.; Regnaux, J.; Combeaud, M.; Bussel, B. Mechanisms of locomotor
activity generation under epidural spinal cord stimulation. Dengler, R.; Kossev, A., editors.
Washington, DC: IOS Press; 2001. p. 164-71.
20. Minassian K, Jilge B, Rattay F, et al. Stepping-like movements in humans with complete spinal
cord injury induced by epidural stimulation of the lumbar cord: electromyographic study ofcompound muscle action potentials. Spinal Cord. 2004; 42(7):401–16. [PubMed: 15124000]

Lancet. Author manuscript; available in PMC 2011 December 4.

Harkema et al.

Page 10

NIH-PA Author Manuscript
NIH-PA Author Manuscript

21. Minassian K, Persy I, Rattay F, et al. Human lumbar cord circuitries can be activated by extrinsic
tonic input to generate locomotor-like activity. Hum Mov Sci. 2007; 26:275–95. [PubMed:
17343947]
22. Jilge B, Minassian K, Rattay F, et al. Initiating extension of the lower limbs in subjects withcomplete spinal cord injury by epidural lumbar cord stimulation. Exp Brain Res. 2004; 154(3):308–26. [PubMed: 14586532]
23. Kuhn RA. Functional capacity of the isolated human spinal cord. Brain. 1950; 73(1):1–51.
[PubMed: 15420313]
24. Nadeau S, Jacquemin G, Fournier C, Lamarre Y, Rossignol S. Spontaneous motor rhythms of theback and legs in a patient with a complete spinal cord transection. Neurorehabil Neural Repair.
2010; 24(4):377–83. [PubMed: 20019383]
25. Calancie B. Spinal myoclonus after spinal cord injury. J Spinal Cord Med. 2006; 29:413–24.
[PubMed: 17044393]
26. Marino RJ, Barros T, Biering-Sorensen F, et al. International standards for neurologicalclassification of spinal cord injury. J Spinal Cord Med. 2003; 26 (Suppl 1):S50–S56. [PubMed:
16296564]
27. Beres-Jones JA, Johnson TD, Harkema SJ. Clonus after human spinal cord injury cannot be
attributed solely to recurrent muscle-tendon stretch. Exp Brain Res. 2003; 149(2):222–36.
[PubMed: 12610691]
28. Maegele M, Muller S, Wernig A, Edgerton VR, Harkema SJ. Recruitment of spinal motor pools
during voluntary movements versus stepping after human spinal cord injury. J Neurotrauma. 2002;
19(10):1217–29. [PubMed: 12427330]
29. Jankowska E. Spinal interneuronal systems: identification, multifunctional character andreconfigurations in mammals. J Physiol. 2001; 533:31–40. [PubMed: 11351010]
30. Fuentes R, Petersson P, Siesser WB, Caron MG, Nicolelis MA. Spinal cord stimulation restores
locomotion in animal models of Parkinson’s disease. Science. 2009; 323(5921):1578–82.
[PubMed: 19299613]

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Figure 1. Lower extremity EMG activity during standing and stepping with body weight support
prior to implantation

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These data demonstrate that intensive training did not result in significant changes in
efferent motor patterns. (a) Standing and (b) stepping with body weight support and manual
facilitation on a treadmill prior to implantation. (c) Mean EMG amplitude for standing (solid
symbols) and stepping (open symbols) across three different time points (0, 66, and 170 step
training sessions). Left (L) and right (R) side muscles: rectus femoris (RF), vastus lateralis(VL), medial hamstrings (MH), tibialis anterior (TA), soleus (Sol), and medial
gastrocnemius (MG). FSCAN is ground reaction force data.

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Figure 2. Lower extremity EMG activity with epidural stimulation of the lumbosacral segments
during standing

These data demonstrate that the output of the spinal circuitry is modulated by the
proprioceptive input during standing without manual facilitation when sufficient epidural
stimulation is present. (a) EMG activity increases in amplitude and becomes more constantbilaterally in most muscles as stimulation is increased in strength from 1–8V (15Hz) with aconstant level of body weight support (65% BWS; 585/900N BWS). (b) Reducing bodyweight support from 45% to 5% (405/900 N to 45/900N) and with constant stimulation (8V,
15Hz) changed the EMG amplitudes and oscillatory patterns differently among muscles.
Array diagram illustrates the stimulation configuration; anode electrodes are black andcathode electrodes are gray. Left (L) and right (R) side muscles: rectus femoris (RF), medial
hamstrings (MH), tibialis anterior (TA), and medial gastrocnemius (MG). Stim indicates thestimulation intensity. Interpulse interval depicting stimulation frequency is shown at thebottom of graph a. Refer to Supplementary Video 1.

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Figure 3. Lower extremity EMG activity during sitting and standing with and without epidural
stimulation

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There was little or no EMG activity without stimulation during sitting or standing. With
increasing levels of epidural stimulation, EMG amplitudes were modulated in a tonic pattern
while the subject remained sitting. During the transition from sitting to standing, amplitudes
and patterns of EMG were modulated in all recorded muscles. Transition (white) fromsitting (gray) to standing (yellow) with (a) no stimulation, (b) rostral (spinal segments L1L2) stimulation (4–7.5V, 15Hz), and (c) caudal (spinal segments L4-S1) stimulation (4–7.5V,
15Hz). (d) Averaged mean EMG amplitude responses on the right side during sitting andstanding with no stimulation (ż), and rostral ( ) and caudal ( ) stimulation at 7.5V, 15Hz.
(e) Kinematic representation of sitting to standing transition with caudal stimulation(illustration at 10 frames per sec) (Supplementary Video 2). Array diagram illustrates thestimulation configuration; anode electrodes are black and cathode electrodes are gray. Right(R) side muscles: fine wire: iliopsoas (IL); surface EMG: vastus lateralis (VL), medial
hamstrings (MH), tibialis anterior (TA), soleus (Sol), and medial gastrocnemius (MG). Stim
indicates the stimulation intensity. Interpulse interval depicting stimulation frequency isshown at the bottom of graphs b and c.

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Figure 4. Lower extremity EMG activity with epidural stimulation during continuous fullweight-bearing standing(a) EMG activity with epidural stimulation (7.5V, 15Hz) of the lumbosacral segments
during weight shifting. Center of gravity displacement in the sagittal plane depicting
backward (B) and forward (F) shifts shown under the schematic diagram of the movement.
(b) EMG activity with epidural stimulation (9V, 25Hz) during the transition from manuallyfacilitated weight-bearing standing (gray) to full weight-bearing standing without manual
facilitation (white). Red line indicates 3 second count down by the subject to initiation ofstanding without manual facilitation (Supplementary Video 3). Left (L) and right (R) side
muscles: vastus lateralis (VL), medial hamstrings (MH), tibialis anterior (TA), soleus (Sol),

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and medial gastrocnemius (MG). Array diagram illustrates the stimulation configuration;
anode electrodes are black and cathode electrodes are gray. Stim indicates the stimulation
intensity. Interpulse interval depicting stimulation frequency is shown at the bottom of eachgraph.

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Figure 5. Lower extremity EMG activity during standing and stepping with body weight supportand manual facilitation with and without epidural stimulation of lumbosacral segments

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The EMG patterns were modified by stimulation and by different patterns of sensory input.
EMG activity during (a) manually facilitated stepping (50% BWS, 450/900N, 1.07 m/s)
without stimulation, (b) standing with 25% BWS (225/900N) and with epidural stimulation(7.5 V, 30 Hz) and (c) manually facilitated stepping (50% BWS, 450/900N, 1.07 m/s) with
epidural stimulation (7.5V, 30 Hz). Shaded area indicates one full step of the right leg. (d)Mean EMG activity for the medial hamstrings (MH) during stepping without stimulation( ) and with stimulation ( ) (a and c respectively) and stepping after 170 step training
sessions prior to implantation ( ) (Figure 1b). The horizontal lines represent the baselinevariation in the noise of each signal. Left (L) and right (R) side muscles: vastus lateralis(VL), medial hamstrings (MH), tibialis anterior (TA), and medial gastrocnemius (MG).
Load is load cell reading in Newtons (N). Sagittal joint angles for the left (L Hip) and right(R Hip) hip joint. Stance phase represented by left (L FS) and right (R FS) footswitches.
Array diagram illustrates the stimulation configuration; anode electrodes are black andcathode electrodes are gray. Stim indicates the stimulation intensity. Interpulse interval
depicting stimulation frequency is shown at the bottom of graph c.

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Figure 6. EMG activity during voluntary leg movements in a supine position

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Supraspinal control of leg movements only occurred during epidural stimulation. EMG andkinematics are shown for three different movement commands with (4V, 30Hz) and without
stimulation. At the bottom of each graph the black bar (and gray shading within graph)indicates the “up” command for (a) left leg flexion, (b) left toe extension, and (c) left ankle
dorsiflexion. The white bar (and no shading within graph) indicates the command to relax.
Left and right EMG are shown to emphasize the isolated control of the left side following
the command. There was a delay observed between the onset of the EMG activation in somemuscles relative to the “up” command, while the termination of the activation often occurredprior to the command to relax. Intercostal (IC) EMG activation occurred as the subject
inhaled during the performance of the voluntary leg movement. (d) Kinematic
representation of leg movement (graph a) with and without epidural stimulation (illustrated
at 10 frames per second). Left (L) and right (R) side muscles: fine wire: extensor hallucis
longus (EHL), extensor digitorum longus (EDL), iliopsoas (IL); surface EMG: soleus (Sol),tibialis anterior (TA), peroneus longus (PL), vastus lateralis (VL), medial hamstrings (MH),adductor magnus (AD), gluteus maximus (GL), erector spinae (ES), rectus abdominus (AB),and intercostals (IC). Sagittal joint angles for the toe (1st metatarsal relative to foot), ankle,
knee and hip joints. Array diagram illustrates the stimulation configuration; anode electrodes
are black and cathode electrodes are gray. Stim indicates the stimulation intensity. Interpulseinterval depicting stimulation frequency is shown at the bottom of graph a. Supplementary
Videos 4 and 5 show voluntary control attempts with and without stimulation, respectively.

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