Brain Advance Access published April 8, 2014
doi:10.1093/brain/awu038

Brain 2014: Page 1 of 16

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BRAIN
A JOURNAL OF NEUROLOGY

Altering spinal cord excitability enables
voluntary movements after chronic complete
paralysis in humans
Claudia A. Angeli,1,2 V. Reggie Edgerton,3,4 Yury P. Gerasimenko3,5 and Susan J. Harkema1,2

Correspondence to: Susan Harkema, Ph.D.,
220 Abraham Flexner Way,Louisville, KY40202, USA
E-mail: susanharkema@KentuckyOneHealth.org

Previously, we reported that one individual who had a motor complete, but sensory incomplete spinal cord injury regained
voluntary movement after 7 months of epidural stimulation and stand training. We presumed that the residual sensory pathways
were critical in this recovery. However, we now report in three more individuals voluntary movement occurred with epidural
stimulation immediately after implant even in two who were diagnosed with a motor and sensory complete lesion. We demonstrate that neuromodulating the spinal circuitry with epidural stimulation, enables completely paralysed individuals to processconceptual, auditory and visual input to regain relatively fine voluntary control of paralysed muscles. We show that neuromodulation of the sub-threshold motor state of excitability of the lumbosacral spinal networks was the key to recovery of intentional movement in four of four individuals diagnosed as having complete paralysis of the legs. We have uncovereda fundamentally new intervention strategy that can dramatically affect recovery of voluntary movement in individuals withcomplete paralysis even years after injury.

Keywords: human spinal cord injury; epidural stimulation; voluntary movement
Abbreviations: AIS = American Spinal Injury Association Impairment Scale

Introduction
The clinical diagnosis of having a motor complete lesion commonlyclassified by the American Spinal Injury Association Impairment
Scale (AIS) as grade A or B (Marino et al., 2003; Waring et al.,2010) is when there is no clinical evidence of volitional activationof any muscle below the lesion. Presently, the prognosis of recovery of any intentional control of movement below the injury level
after clinically defined complete paralysis for over 2 years is
negligible. This diagnosis has immediate and severe implications

for the patient often limiting the rehabilitation and interventional
strategies provided that are targeted for recovery (Waters et al.,
1992, 1998; Ditunno, 1999; Burns et al., 2003; Calancie et al.,2004b). There is not currently an effective treatment thatwould result in regaining voluntary motor function for these
individuals. The presumed solution ultimately has been thought
to be to promote regeneration of axons across the lesion withthe hope that functionally beneficial connections can be formed(Richardson et al., 1980; David and Aguayo, 1981; Zhao et al.,2013).

Received September 18, 2013. Revised January 14, 2014. Accepted January 20, 2014
ß The Author (2014). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
For Permissions, please email: journals.permissions@oup.com

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1 Frazier Rehab Institute, Kentucky One Health, Louisville, KY, USA
2 Department of Neurological Surgery, Kentucky Spinal Cord Research Centre, University of Louisville, KY, USA
3 Department of Integrative Biology and Comparative Physiology, University of California, Los Angeles, CA, USA
4 Department of Neurobiology and Brain Research Institute, University of California, Los Angeles, CA, USA
5 Pavlov Institute of Physiology, St. Petersburg, Russia

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C. Angeli et al.

Table 1 Clinical characteristics of four research participants
Subject

B07
A45
B13
A53

Age (years)

23.8
24
32.8
27

Gender

Male
Male
Male
Male

Time since
injury (years)

Injury level

3.4
2.2
4.2
2.3

C7
T5–T6
C6–C7
T5

Neuro level

T2
T4
C7
T5

AIS grade

B
A
B
A

SSEP

TMS

Upper

Lower

NormalNormalNormalNormal

BD
NP
BD
NP

NR
NR
Not tested
NR

SSEP = somatosensory evoked potential; TMS = transcranial magnetic stimulation; C = cervical; T = thoracic; BD = bilateral delay; NP = not present; NR = no response.

Materials and methods
Characteristics of subjects
Anepiduralspinalcord
stimulation
unit(Medtronics,
RestoreADVANCED) and a 16-electrode array was implanted at vertebrae T11–T12 over spinal cord segments L1–S1 (Harkema et al.,2011a) in four individuals with motor complete spinal cord injury(Table 1 and Supplementary Fig. 1) using the following inclusion criteria: (i) stable medical condition without cardiopulmonary disease ordysautonomia that would contraindicate standing or stepping withbody weight support training; (ii) no painful musculoskeletal dysfunction, unhealed fracture, contracture, pressure sore, or urinary tract
infection that might interfere with stand or step training; (iii) no clinically significant depression or ongoing drug abuse; (iv) no current
anti-spasticity medication regimen; (v) non-progressive spinal cord

injury above T10; (vi) AIS A or B; (vii) no motor response present inleg muscles during transmagnetic stimulation; (viii) not present or bilateral delay of sensory evoked potentials; (ix) no volitional control
during voluntary movement attempts in leg muscles as measured by
EMG activity; (x) segmental reflexes remain functional below thelesion; (xi) brain influence on spinal reflexes is not observed as measured by EMG activity; (xii) must not have received BotoxÕ injectionsin the previous 6 months; (xiii) be unable to stand or step independently; (xiv) at least 1-year post-injury; and (xv) must be at least
18 years of age
All four individuals implanted were male, at least 2 years post-dateof injury and ranged in neurological level from C7–T5. The averageage of all individuals was 26.9 (  4) years at the time of implant. All
individuals were unable to stand or walk independently or voluntarily
move their lower extremities despite standard-of-care rehabilitation
and additional intensive locomotor training (Harkema et al., 2011b).
The research participants signed an informed consent for electrodeimplantation, stimulation, stand and stepping training interventions
and physiological monitoring studies approved by the University ofLouisville and the University of California, Los Angeles Institutional
Review Boards.

Clinical and physiological status
Standard of care clinical evaluations were performed to characterize
the injury. Two clinicians independently performed a physical exam
and used the AIS to classify the injury clinically (Marino et al., 2003;
Waring et al., 2010). Two individuals were classified and confirmed as
AIS-B and two individuals were classified and confirmed as AIS-A
before implantation and at the time of initial lumbosacral spinal cord
epidural stimulation (Supplementary Fig. 1).
Upper and lower extremity somatosensory evoked potentials wereassessed clinically before implantation and at multiple time points following implant in all participants (Perot and Vera, 1982; Dimitrijevic
et al., 1983b) (Supplementary Fig. 1). All participants had normal
somatosensory evoked potentials from upper extremity median nerve
stimulation at the wrist. Both AIS-B individuals had bilateral corticaldelays present from lower extremity stimulation at the posterior tibial
nerve and ankle, whereas both AIS-A individuals had no response(Supplementary Fig. 1). Transcranial magnetic stimulation was usedclinically to assess the functional integrity of the cortico-spinal tracts(Dimitrijevic et al., 1992a; McKay et al., 1997, 2005). No motor
evoked potentials in the leg muscles were detected during transcranial
magnetic stimulation of the motor cortex in tested individuals. A single
pulse was delivered through a dual-cone coil placed slightly off centre
from the scalp vertex to optimize left and right hemispheres. Pulses of
100-ms duration were delivered starting at 30% intensity increasing by
5% until 85% of maximum intensity was reached. Data for Patients
A45 (post step training with epidural stimulation) and A53 (before

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However, we previously reported the return of control of movement in one individual with motor complete, but sensory incomplete spinal cord injury 42 years after complete paralysis after
7 months of intense stand training using epidural stimulation(Harkema et al., 2011a). These unexpected results led us to theorize that the residual sensory pathways were critical in mediating
the voluntary movements elicited with epidural stimulation andspecific intent by the individual. The intense stand training andrepetitive stimulation may have driven neural plasticity that eventually resulted in the ability to voluntarily move the legs. In thisstudy, we include three additional individuals with chronic spinal
cord injury; one was AIS B (sensory incomplete) and two AIS A(sensory complete), who were also classified as motor complete
using all currently available clinical and neurophysiological testing(Dimitrijevic et al., 1992a; McKay et al., 1997, 2005). We tested
their ability to move voluntarily with epidural stimulation after
implantation (before any training with stimulation) and thenagain after the intense stand training using epidural stimulationintervention (see Supplementary material for description of standtraining) and after intense step training in combination with epidural stimulation. We hypothesized that the individuals with AIS A
spinal cord injury would not elicit any voluntary movement using
epidural stimulation even after training and that the individualwith AIS B spinal cord injury would develop the ability to voluntarily move the legs only after training. These experiments wereconducted as part of a larger ongoing study of stand and step
training in combination with epidural stimulation in individuals
with chronic motor complete spinal cord injury.

Voluntary movements after paralysis

Brain 2014: Page 3 of 16| 3

implantation) are shown in Fig. 1A and C, respectively. Individuals
were asked to attempt a sustained dorsiflexion during which transcranial magnetic stimulation was delivered following the same procedures
described above. No motor evoked responses in leg muscles weredetected during the combined voluntary attempt and transcranial
magnetic stimulation and no movement resulted from the attempted
action (Fig. 1B and D). Patient B13 was not tested before implantation.
Patients A45 and A53 were classified as motor and sensory complete
and Patients B07 and B13 as motor complete and sensory incomplete
based on all clinical and neurophysiological measures described above.
Before electrode implantation, participants received a minimum of
80 locomotor training sessions (Harkema et al., 2012b) using bodyweight support on a treadmill with manual facilitation. Average bodyweight support throughout all sessions for all participants was 43.6%( 4.5) walking at an average speed of 1.07 m/s (  0.04). Patients
B07 and A45 had no significant EMG activity during stepping.
Patients B13 and A53 had significant muscle activity during stepping.

There were no significant changes in the EMG activity during stepping
following the stepping intervention before implantation in any of thefour research participants (Harkema et al., 2012a). Some neurophysiological measures can be used to detect residual descending input tothe spinal circuitry even when there is no ability to voluntarily executemovement below the level of lesion and these observations have beenused to reach a diagnosis of ‘discomplete’ (Dimitrijevic et al., 1984;
Sherwood et al., 1992; Dimitrijevic, 1994; Calancie et al., 2004a;
McKay et al., 2004). A functional neurophysiological assessment was
performed at multiple time points before and after implantation(Fig. 2) to assess residual motor output present during various manoeuvres (Dimitrijevic, 1988; Dimitrijevic et al., 1992b; McKay et al.,2004, 2011; Li et al., 2012). Supplementary Fig. 2 illustrates motor
activity observed during 5-min relaxation, a reinforcement manoeuvre(Dimitrijevic et al., 1983a, 1984) and attempts to actively move theankle joint and hip joint at different time points before and after implantation. EMG activity during attempts to move the legs or during

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Figure 1 Transmagnetic stimulation motor evoked potentials of the soleus (SOL) and tibialis anterior (TA) for two subjects (Patients A45
and A53) performed during multiple stimulation intensities without active dorsiflexion (A and C) and during active dorsiflexion (B and D).
No responses were seen for either subject at the recorded intensities.

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C. Angeli et al.

reinforcement manoeuvres was similar to the EMG seen during 5 minof relaxation in all individuals. In Patients B13 and A53 mean EMG
amplitudes were higher during attempted relaxation compared with
Patients B07 and A45 because of higher levels of resting excitability.
In Patient A45 relaxation excitability increased post-stand training with
epidural stimulation; however, no changes were seen in the ability toactivate motor neurons below the level of the injury during active
voluntary attempts. No functional connectivity between the supraspinal and spinal centres below the level of injury was detected withclinical or neurophysiological assessments in any of the four subjects.

Assessment of voluntary movement
Patient B07 was the first research participant to be implanted and we
did not discover his ability to perform voluntary movements of the legswith epidural stimulation until the conclusion of the stand training
intervention using epidural stimulation. We then designed and conducted the initial experiments to assess this individual’s voluntaryfunction. Subsequently, the three additional research participants
were implanted and before beginning any training interventions we
conducted the experiments assessing voluntary movement (T1; see
Fig. 2). As a result we have different time points for voluntary experiments in relation to training interventions for the first participant compared to the other three participants. Refer to the Supplementary
Table 1 for a list of experimental sessions and testing time point
used on each figure for each research participant.
We collected EMG, joint angles, and tensile force data at 2000 Hz
using a 24-channel hard-wired AD board and custom-written acquisition software (LabView, National Instruments). Bilateral EMG (Motion
Lab Systems) from the soleus, tibialis anterior, medial hamstrings,
vastus lateralis, adductor magnus, gluteus maximus, and intercostal(sixth rib) muscles was recorded using bipolar surface electrodes with
fixed inter-electrode distance (Harkema et al., 1997). Bilateral EMG
from the iliopsoas, extensor hallucis longus and extensor digitorum
longus was recorded with fine wire electrodes. Two surface electrodes
placed symmetrically lateral to the electrode array incision site over the

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Figure 2 Timeline of implantation and experimental sessions for all participants. All individuals underwent a screening phase with at least
80 sessions of locomotor training before implantation. Patient B07 was the first subject implanted and voluntary activity was not founduntil the end of stand with epidural stimulation (ES). He was tested with EMG at this time point, however, T1 represents the firstexperimental session with force and fine motor control testing. Patients A45, B13 and A53 were tested with the same protocol post
implantation and before the beginning of stand training with epidural stimulation. All participants initiated a home training programme forvoluntary activity after the initial finding of their ability to move with epidural stimulation. Clinical evaluations including transcranial
magnetic stimulation, Functional Neurophysiological Assessment, somatosensory evoked potentials and ASIA (American Spinal Injury
Association) exams were performed before and after the 80 sessions of locomotor training during the screening phase and at theconclusion of stand and step training with epidural stimulation. Blue arrows show time points where clinical evaluations took place. Patient
A53 is currently undergoing step training with epidural stimulation. See Supplementary Tables 1 and 2 for further details.

Voluntary movements after paralysis| 5

Voluntary movement training
programme
A home-based stimulation protocol was developed to allow the individuals to stimulate for 1 h while practicing intentional movement in
the supine position. This protocol started immediately after the firstassessment of successful voluntary movement was obtained (Fig. 2).
All research participants were asked to practice daily (7 days a week)
for 1 h. The stimulation protocol for the home-based programme wasdetermined in the laboratory. The individuals modulated the voltage
needed to optimize each movement after the stimulation configurations were selected for each individual to optimize the voluntary
movement of the whole leg, ankle and toe (Supplementary videos 1-3).

Results
Four individuals diagnosed with clinically motor complete paralysis
and implanted with a lumbrosacral spinal cord stimulator at least
2.2 years post injury (3.0  0.95 years) were able to execute intentional movements of the legs in response to a verbal command.
No motor activity was present when attempting to move without
epidural stimulation following a verbal command (Patient B07) ora visual cue (Patients B13, A45 and A53) (Fig. 3A). However, allfour individuals were able to generate EMG activity and movement during ankle dorsiflexion in the presence of epidural stimulation (Fig. 3B) during their first experimental session [T1 (before
stand training): Patients A45, B13, A53 and post stand training:
Patient B07, see Fig.2].
Appropriate activation and movement of ankle and toe muscles
was achieved by all individuals when performing ankle dorsiflexion
with epidural stimulation (Fig. 3B). In one subject (Patient B13)
clonic-like activity in the toe extensors was present during the
movement and sustained clonic activity remained when commanded to relax (Beres-Jones et al., 2003). However, this clonicactivity did not prevent the movement. Patients A45 and A53 hadtonic activity in the soleus before the attempt, showing a reduction in amplitude during the dorsiflexion effort. Reciprocal inhibition of antagonist muscles was also present in the execution ofother movements such as leg flexion. These results demonstratethat humans diagnosed with complete motor paralysis can recover
volitional motor drive which can drive coordinated, task-specificmovements in the presence of lumbosacral spinal cord epidural
stimulation.

Force and rate of modulation
Having observed some recovery of the ability to move intentionally by each of the four individuals, we began to assess the motor
control fidelity. Graded levels of force were generated on command by three of four individuals (Fig. 4A and B). Three subjects(Patients B07, A45 and A53) generated forces that proportionately
matched the percent of effort requested in flexing the entire leg(Fig. 4B). The level of activation of the iliopsoas muscle reflected
the relative magnitude of force generated during leg flexion. The
activation of the intercostal muscles (sixth rib), was closely synchronized with the initiation of force generation, generally reflecting the percent effort in stabilizing the rib cage (Fig. 4A).

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paraspinal muscles were used to record the stimulation artefact. Hip,knee, ankle and first toe joint angles were acquired using a high-speed
optical motion capture system (Motion Analysis). EMG data wererectified and high-pass filtered at 32 Hz using Labview software customized by our laboratory. Tensile force was measured using a piezoelectric load cell (Kistler) mounted on a frame placed around the mattable.
Stimulation parameters were optimized for each leg and joint movement. Cathodes and anodes were selected to target primary motor
pool activation areas that were key in the movement. Stimulation
was constant and all participants achieved movement at optimal
frequencies of either 25 Hz or 30 Hz. Voltage was typically tested
through a wide range from sub-movement threshold to above optimal.
Although initially configuration parameters were specific to a single
joint movement and right or left leg, after training, participants wereable to perform multiple movements on left and right legs using thesame configuration (Supplementary Table 2).
The participants were in a supine position throughout all recordings.
To measure force during extension of the first toe a ring was secured
over the toe and attached to a force transducer by way of a nonelastic cable. Similarly the ring and cable were secured around the
distal portion of the foot when recording force during ankle dorsiflexion. To record force during flexion of the knee and hip combined thecable was secured to the ankle. The cable had sufficient complianceto allow the leg to move from full extension to a position in which theknee and hip could reach a 530 angle. The resistance to the movement was equivalent to the weight of the cable (0.16 N) and thefriction force of the foot with the table in the early phase of the leg
flexion. A computer monitor displayed a real time sine wave withfrequency of 0.25 Hz as well as the force measured by the load cellas the research participants performed the requested action. Both signals were used to determine the degree to which the individual could
translate the timing of the visual appearance of the sine wave to ananalogous change in force. Although the sine wave was continuously
displayed to the participants, they were instructed to initiate eacheffort with the rising phase of a sine wave of their choosing. There
was no instruction to match the amplitude of force generation withthe peak of the sine wave, and there was no verbal command given
before the attempts.
To assess the ability to translate an auditory signal to an analogouschange in force a signal from a tone generator (300 Hz tone frequency), modulated at 0.25 Hz was sent through headphones. Threedifferent volumes (60, 70 and 80 dB) were presented in a random
order. The research participant was instructed to modulate the force
based on the modulation frequency of the sound and the given amplitude. A trial period was conducted so the participant could listen at
the three different volumes and learn to discriminate between them.
Full leg flexion was the only action tested with the auditory cues.
Stimulation parameters used during these trials were matched tothose found as optimal during the visual cue assessment for thesame leg.
During experimental sessions continuous stimulation was provided
with optimal parameters during all attempts. Stimulation was shut
down only to change configurations and to assess the ability tomove with no stimulation at the beginning of trials for each joint
and side. Experimental sessions lasted for 2 h and left/rightleg, ankle and toe were tested starting by assessing threshold andoptimal stimulation parameters using visual cues. Each joint wasalso assessed for fine motor control and accuracy including the modulation of three levels of force generation, fast oscillations and sustained
force.

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Figure 3 Lower extremity EMG activity during voluntary movement occurred only with epidural stimulation in four individuals with motor
complete spinal cord injury. EMG activity during attempts of ankle dorsiflexion (A) without stimulation and (B) with stimulation. Force was
not collected for Patient B07. Electrode representation for each subject denotes the stimulation configuration used. Although stimulation
was applied throughout the time shown in B, in all four subjects EMG bursts were synchronized with the intent to move. Grey boxes arecathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency varied from 25 to 30 Hz. Muscles,
surface EMG: intercostal sixth rib (IC), tibialis anterior (TA), soleus (SOL); fine wire EMG: iliopsoas (IL), extensor digitorum longus (EDL),
extensor hallucis longus (EHL). Black bars represent flexion as determined by peak force generation and white bars represent passive
extension (from peak force to return to resting position). Although the subjects were instructed to flex and extend, they were unable toactively extend before training. Grey highlighted indicates the active ‘flexion/extension’ period.

Reciprocity in the EMG activity of extensors and flexors when
flexing and extending the leg further indicates that the neuralactivation specificity to the lumbosacral motor pools was sufficientto generate a functionally coordinated movement (Fig. 4A and C).

When Patient A45 was asked to generate a sustained contractionfor ‘as long as possible’ the effort could be maintained for a few
seconds followed by several oscillatory movements (Fig. 4C).
There was alternating activity in the iliopsoas and vastus lateralis,Voluntary movements after paralysis

Brain 2014: Page 7 of 16| 7with the vastus lateralis only becoming activated after flexor activity ended. Patients B07 and A53 were also able to performsustained leg flexion. In all cases, the integrated force was closely
linked to the iliopsoas EMG amplitude (Fig. 4D). Patient A53
demonstrated a similar pattern of alternating activity between
the iliopsoas and vastus lateralis as shown by the other AIS-A
individual (Patient A45). Patient B13 was unable to generate

graded levels of force or a sustained effort before training andcould not consistently discriminate low and medium efforts following training.
To further assess the level of control of the newly acquired
ability to move in the presence of epidural stimulation the individuals were then asked to oscillate as rapidly as possible. The cycle
rate for the toe was 1 Hz for Patient B07 (Fig. 5A–C) andDownloaded from http://brain.oxfordjournals.org/ by guest on April 9, 2014

Figure 4 Force level and endurance of voluntary movements. (A) Left leg force and left iliopsoas, vastus lateralis and intercostals EMG
activity generated during a low (20%), medium (60%) and high (100%) effort of hip/knee flexion with epidural stimulation from PatientA45. Grey shading indicates force duration. (B) Integrated leg force (left y-axis) and iliospsoas EMG activity (right y-axis) from Patients
A45 (red), B07 (black) and A53 (blue) during hip/knee flexion with epidural stimulation. Solid symbols (with solid line) represent the
integrated force for each attempt and open symbols (with dash line) represent the integrated EMG of the iliopsoas muscle for eachattempt. (C) Left leg force and iliopsoas, vastus lateralis and intercostals EMG activity generated during a request to sustain voluntary
flexion as long as possible from Patient A45. Shaded grey indicates duration of sustained force. (D) Integrated force (solid bar) andiliopsoas EMG (open bar) during sustained contraction from Patients A45, B07 and A53 as shown in C. Electrode representation denotes
the stimulation configuration used by Patient A45. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive
electrodes. Stimulation frequency was 25 Hz. Muscles, surface EMG: intercostal sixth rib (IC), vastus lateralis (VL); fine wire EMG: iliopsoas(IL). Stimulation artefact recorded over paraspinal muscles at T12 [epidural stimulation (ES) = blue trace]. FRC = force measured throughload cell and non-elastic wire.

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Figure 5 Rate of voluntary movements controlled by three individuals with motor complete spinal cord injury. (A) Force and extensor
hallucis longus (EHL) EMG activity during fast voluntary first toe flexion/extension against a compliant resistance from Patient B07 from asingle attempt. (B) A 1-s sweep from A before initiation of force generation encompassed by the first dashed vertical box. Ten 10 ms tracesof EHL are overlaid every 0.1 s (bottom panel). The red crosses represent the timing of the stimulation artefact. (C) A 1-s period (A) during
one cycle of force generation encompassed by the second dashed vertical box. Traces of EHL are shown as an overlay of 31 responses
marked relative to the stimulation stimulus (bottom panel). (D and F) Force (black line) and iliopsoas and vastus lateralis EMG activity(continued)

Voluntary movements after paralysis

Visual and auditory processing
We also assessed whether volitional control could modulate thelevel of activation of the appropriate motor pools based on visual
and/or auditory input. All individuals could modulate the motor
tasks according to visual and auditory cues. The individuals wereasked to synchronize the flexion of the leg, dorsiflexion of theankle and extension of the toe according to the rise and fall ofa sine wave displayed on a computer screen. The individuals wereable to consistently activate the appropriate muscles for the specified action with temporally synchronized force generation (datanot shown). We compared the ability of the four individuals tomodulate the flexion of the leg to a visual cue during optimal
stimulation to three volume levels (60, 70 and 80 dB) of a similar
auditory cue (Fig. 6). Individuals were asked to generate leg flexion in response to the onset of a 0.25 Hz auditory signal with thelevel of force to be generated to correspond to the amplitude of
the tone. Data shown in Fig. 6 are for the following time points,
T3: Patients B07 and A45; T2: Patient B13; and T1: Patient A53(Supplementary Table 1 and Fig. 2). Three of four individuals wereable to discriminate between sound amplitudes, although the| 9differentiation between low and medium forces was not consistentin Patients B13 and B07. For Patients A45 and B07, EMG amplitude of the iliopsoas and the adductor for the high volume wascomparable with the EMG amplitudes generated when the force
was modulated by a visual cue using the same stimulation parameters. The results demonstrate that auditory and visual cues
were processed by the sensorimotor cortex so that the appropriate
spinal interneuronal systems below the level of injury enabling the
subject to titrate the desired level of excitability of the correct
motor pools for the intended movement.

Effects of repetitive training on
voluntary performance
Daily training using epidural stimulation with stand training andhome-based voluntary training with epidural stimulation resulted
in the generation of voluntary efforts with higher forces and lower
stimulation voltages to reach the thresholds that enabled voluntary
motor responses in two individuals (Patients B07 and B13). After
28 weeks of home-based stand and voluntary training with epidural stimulation in Patient B07, the stimulation threshold for force
generation was lower. The threshold intensity was further reduced
after an additional 12 weeks of training (Fig. 7A). Similar results
were observed in both legs and during toe extension for Patient
B07 (data not shown). Following stand training and home-based
voluntary training (Fig. 2), Patient B13 showed a similar trend oflower threshold for force generation even achieving movementwith no stimulation. With continued home-based voluntary training and at the conclusion of step training, Patient B13 maintained
the ability to perform leg flexion with no stimulation. The peakforce to stimulation strength relationship for Patient B13 post step
training was characteristic of a parabolic function. Stimulation
amplitudes between 0.5 V and 1.5 V resulted in force values
lower than those obtained when moving with no stimulation.
From 1.5 V to 2.5 V, force increased linearly with increased intensity. In the case of Patient A45, although a force increase was notobserved at lower stimulation voltages following training, improvements in the accuracy to match the oscilloscope signal
were observed (Fig. 7B).
Figure 7B compares the ability of all subjects to match force
generation during leg flexion to a visual cue at T1 (top panel),
T2 (middle panel) and T3 (bottom panel). Patient A45 showed thegreatest accuracy improvement matching the force generation to
the visual cue (Fig. 7B). This accuracy was demonstrated bothwhile responding to a visual cue, as well as to an auditory cue.
Patient A53 is currently undergoing step training, therefore T3
data have not been collected. These results demonstrate the ability

Figure 5 Continued
during fast voluntary whole leg flexion/extension against a compliant resistance from Patients A45 and A53, respectively. The linear
envelope of the EMG signals (purple line, filter: second-order Butterworth 500–100 Hz) is shown over the raw signal. (E and G) Plot of
linear envelope of the vastus lateralis versus iliopsoas from D and F. Red over the linear envelopes represents the flexion phase while green
represents the extension phase of one cycle of the movement. Electrode representation for each subject denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes. Stimulation frequency varied
from 25 to 30Hz. Muscles, surface EMG: vastus lateralis (VL); *fine wire EMG: iliopsoas (IL), extensor hallucis longus (EHL). Stimulation
artefact recorded over paraspinal muscles at T12 [epidural stimulation (ES) = blue trace].

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0.4 Hz for Patient A45 and 0.85 Hz for Patient A53 when oscillating the whole leg (Fig. 5D–G, Supplementary Video 4). Clonicactivity (6.5 Hz) of the extensor hallicus longus was not linked tothe stimulation frequency (30 Hz) and occurred throughout thetest in Patient B07 (Fig. 5B). EMG responses were initiated justbefore there was a rise in force (Fig. 5C). There was no periodic
bursting of EMG activity within the timeframe of a single force
effort (Fig. 5C). As noted earlier Patients A45 and A53 had reciprocity in the modulation of the EMG of the iliopsoas and thevastus lateralis during leg flexion and extension (Fig. 5D–G). In
Fig. 5D, one of the oscillatory cycles has been marked in red
and green, which denote the modulation of the amplitude of
the EMG of the iliopsoas and vastus lateralis. Figure 5E shows
the relative modulation of the hip flexor and knee extensor, andalso highlights the one oscillation with flexion in red and extension
in green (Patient A45). Patient A53 showed a similar modulationof the iliopsoas and vastus lateralis during multiple oscillatory
cycles of leg flexion (Fig. 5F–G). After home-based training
Patient B07 was able to generate similar reciprocal activation of
flexors and extensors between the iliopsoas and vastus lateralis,but only during single attempts. Patient B13 was not able to generate different levels of force, oscillations or sustain the contractions upon request at his initial testing. His level of clonus andspasticity throughout the day was markedly higher than theother individuals.

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of the spinal networks to learn with task-specific training and improve motor pool recruitment to promote force generation andaccuracy. Another representation of the volitional contributions
in a more task-specific activity was demonstrated by Patients
A45 and A53 while stepping on the treadmill with body weightsupport and manual assistance, in the presence of epidural stimulation (Fig. 8). During stepping, Patient A45 was able to modulate
the amount and pattern of EMG activity of lower extremity muscles when consciously thinking about stepping and moving thelegs through the step cycle (Fig. 8A). Amplitude and burst duration of the flexors and extensors (bilaterally) were increased, extensors of the left knee and bilateral ankles were also modulatedby the intent. Linear envelope plots of flexors and extensors show

a general increase in amplitude although the coordination was notchanged (Fig. 8B). Similarly, Patient A53 was able to modulate theamplitude of EMG of flexors and extensors during the step cycle(Fig. 8C). Both participants were able to have a greater modulation of the flexor groups as compared to the extensors. This isconsistent with their voluntary activity practice as all participantsregained the ability to perform flexion tasks with a greater difficulty performing active extension. This ability to modulate EMG
with intent during stepping was only seen in two of three individuals. Because of the fact that this observation was performed after
the completion of all laboratory training for Patient B07, we nevertested his ability to modulate motor output during stepping.
Patient B13 was not able to show this ability during stepping;

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Figure 6 Voluntary movement with epidural stimulation performed in response to visual and auditory cues in four individuals with motor
complete spinal cord injury. Averaged linear envelopes (filter: Winter Butterworth low-pass 2 Hz) of EMG activity and force (FORCE)
generated from three trials. The left panel of each participant represents whole leg flexion/extension in response to a visual cue during
optimal stimulation. Black line represents the mean signal and grey line indicates 1 SD (standard deviation) about the mean. The red line
represents the oscilloscope signal which served as the visual cue. The right panel of each participant represents whole leg flexion in
response three different volumes of an auditory cue during optimal stimulation. Black line represents the mean signal and grey line
indicates one standard deviation about the mean. The red line represents the oscilloscope signal that matched the auditory volume cue.
Stimulation parameters and voltages for the visual and auditory attempts were the same for each subject. Electrode representation foreach subject denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive
electrodes. Stimulation frequency varied from 25 to 30 Hz. Muscles, surface EMG:intercostal sixth rib (IC), adductor magnus (AD); finewire EMG: iliopsoas (IL).

Brain 2014: Page 11 of 16

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Figure 7 Stimulation voltage to force relationship during voluntary movement with epidural stimulation in three individuals with motor complete spinal cord injury. (A) Relationshipbetween stimulation strength (V) and peak force (N) during hip/knee flexion for three time points in Patients B07, A45, B13 and A53 (only two time points tested). Cubic line of best fit isshown. Electrode representation for each subject denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes, white boxes are inactive electrodes.
Stimulation frequency varied from 25 to 30Hz. (B) Top: overlap of linear envelopes for IL (filter: Winter Butterworth low-pass 2 Hz) (green), force generation (red) and oscilloscope signal(dark blue) for first time point (T1 = red) performed at optimal voltage. Middle: overlap of linear envelopes (filter: Winter Butterworth low-pass 2 Hz) (green), force generation (black) andoscilloscope signal (dark blue) for post stand training (T2 = blue) performed at optimal voltage. Bottom: overlap of linear envelopes (filter: Winter Butterworth low-pass 2 Hz) (green), force
generation (black) and oscilloscope signal (dark blue) for last time point (T3 = black) performed at optimal voltage. Attempts show improvements in accuracy of force generation during
hip/knee flexion following a visual cue.

Voluntary movements after paralysis| 11

| Brain 2014: Page 12 of 16

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Figure 8 Modulation in EMG activity during volitional assistance during stepping with epidural stimulation by an individual with motor complete spinal cord. Coordination and amplitudeof EMG was modified by the intent to step. (A) Left and right activity during continuous stepping (40% body weight support, 1.07 m/s) with epidural stimulation and manual assistance.
Initial steps show EMG pattern while the subject (Patient A45) is not thinking about stepping. Section within the red dashed lines show the period of steps while the subject is consciously
thinking about stepping and facilitating each step (with voluntary intent). (B) Plot of linear envelope of the EMG signals of the soleus (SOL) versus tibialis anterior (TA, top) and rectus
femoris (RF) medial hamstrings (MH, bottom) (filter: second-order Butterworth 500–100 Hz). Black plots represent both the steps before and after the voluntary intent to assist; red plots
represent all steps within the dashed lines during voluntary intent to assist from A. (C) Similar data from Patient A53 during continuous stepping (40% body weight support, 0.36 m/s) with
epidural stimulation and manual assistance. Plot of linear envelope of the EMG signals of the soleus versus tibialis anterior (top) and rectus femoris versus medial hamstrings (bottom)(filter: second-order Butterworth 500–100 Hz). Black plots represent both the steps before and after the voluntary intent to assist, while red plots represent steps in which Patient A53 is
consciously thinking about stepping and facilitating each step. Electrode representation denotes the stimulation configuration used. Grey boxes are cathodes and black boxes are anodes,
white boxes are inactive electrodes. Stimulation frequency was 40 Hz for Patient A45 and 30 Hz for Patient A53. Note Patient A53 was using three interleaved configurations. Muscles:
soleus (SOL), medial gastrocnemius (MG), tibialis anterior (TA), medial hamstrings (MH), vastus lateralis (VL), and rectus femoris (RF). EMG data are presented in mV. Hip, knee and ankle
are sagittal joint angles (degrees). The break in kinematic data is the result of a brief interruption in the recording. Ground reaction forces (FSCAN) reflect stance and swing phase (N).

12
C. Angeli et al.

Voluntary movements after paralysis
this might be the result of the higher sensitivity to stimulation andgreater difficulty in performing multiple repetitions of volitional
activity.

Discussion| 13

The resting general excitability state of the spinal circuitry wasdifferent among the four individuals that participated in this study(Supplementary Fig. 2). There were differences in stimulation intensity thresholds seen across individuals for the generation of
movement (Fig. 7). Patients B07 and A45 required higher levelsof stimulation to initiate movement and had relatively low levels of
clonus and spasticity throughout the day. In contrast, Patients B13
and A53, the more spontaneously active individuals who reported
more clonus and spasticity, could initiate movement at lower
thresholds of stimulation. We propose that the functional stateof spinal network excitability of interneurons (Bannatyne et al.,2009) and motor neurons was modulated by the epidural stimulation, presumably driving them closer to their appropriate activation threshold, enabling intentional movement (Quevedo et al.,2005; Berg et al., 2007; Yarom and Hounsgaard, 2011). Thus,
loss of voluntary control of movement may be attributed to not
only a physical disruption of descending connections, but also to aphysiological alteration of the central state of excitability of the
spinal circuitry (Edgerton et al., 1997; de Leon et al., 1999;
Tillakaratne et al., 2002). These findings have important implications regarding the significance of sub-motor threshold modulationof spinal circuitry as an important factor in motor control in theuninjured as well as injured spinal cord.
The recovery of the volitional motor drive in four individuals
diagnosed with complete motor paralysis (Fig. 3) could havebeen facilitated by lumbosacral spinal cord epidural stimulation
through transmission of rostro-caudal signal propagation throughthe propriospinal interneuronal projections (Zaporozhets et al.,2006, 2011; Courtine et al., 2008; Cowley et al., 2008; Flynn
et al., 2011). We assessed the individuals’ ability to execute a
movement on command by comparing the EMG and force patterns with a sine wave pattern on a computer screen (Fig. 7B). In
general, at the first time point tested, all individuals demonstrated
a delay in the initiation of the force relative to the rise of the sine
wave and the force decline was earlier than the decline of theposition cursor. Regardless of these time differences in initiationand termination of the effort, the patients could clearly executethe movements on command. The delay in the motor response
related to the intention to move observed in each individual could
be consistent with the voluntarily controlled motor commands
being mediated more indirectly through descending propriospinal
pathways. Although we cannot rule out a delay of processing theauditory and visual cues, there is precedence in the rat model that
tonic intraspinal stimulation immediately caudal to the injury resulted in functional improvements comparable with those seen
following long-distance axon regeneration (Yakovenko et al.,2007). Cowley et al. (2010) showed that even in the absence oflong direct transmission, propriospinal pathways through commissural projections can transmit a locomotor command to the lumbrosacral spinal cord with 27% success. Thus, the stimulation may
facilitate excitation of propriospinal neurons which supports propagation of the voluntary command to the lumbosacral spinal cord.
It is also possible that reticulospinal neurons may mediate ipsilateral corticospinal tract relay through commissural interneurons.
Studies have shown that commissural interneurons activated byreticulospinal neurons have direct contacts with interneurons mediating reflex actions from Group Ib tendon organ afferents andDownloaded from http://brain.oxfordjournals.org/ by guest on April 9, 2014

This study demonstrates the ability of four individuals with chronic
complete motor paralysis to execute voluntary tasks with selectivity of appropriate motor pools in the presence of epidural stimulation. High fidelity sensorimotor translation of visual and auditory
signals were processed to control the timing and amount of force
generated during the movements. In three of four individuals, weobserved the recovery of voluntary movement with epidural
stimulation soon after implantation, two of whom had complete
loss of both motor and sensory function (Supplementary Videos
1–3). This shows that by neuromodulating the spinal circuitry at
sub-threshold motor levels with epidural stimulation, chronicallycomplete paralysed individuals can process conceptual, auditory,
and visual input to regain specific voluntary control of paralysedmuscles. We have uncovered a fundamentally new intervention
strategy that can dramatically affect recovery of voluntary movement in individuals with complete paralysis even years after injury.
The results in the three individuals who were tested after implantation, but before repetitive training, suggests that descending
connections to the spinal cord circuitry may have existed since thetime of injury. Patient B07 did not show voluntary ability until
after 7 months of epidural stimulation and stand training, froman attempt he initiated. The initial study protocol did not include
attempted voluntary movements so we cannot verify whether
movement was possible before training. However, Patients A45,
B13 and A53 were able to voluntarily execute movements after
11, 4 and 7 days of epidural stimulation, respectively(Supplementary Table 1). Anatomical connections may have persisted after the injury that were previously ‘silent’ because of lossof conduction as a result of disruption of myelin or the ionic channels of the neurons (Waxman, 1989; Fehlings and Nashmi, 1996;
Shi and Blight, 1997; Sinha et al., 2006; Coggan et al., 2011). In
our study, these individuals initially were able to elicit these intentional movements only with the epidural stimulation indicatingthat the limited influence of the available supraspinal connections
was not sufficient to activate motor pools. As demonstrated in Fig.
1B and D, transcranial magnetic stimulation did not show anychanges in excitation even when the individuals were requested
to attempt to actively dorsiflex the ankle at the time the transcranial magnetic stimulation pulse was delivered. This suggests thatthe alteration of the spinal cord circuitry with epidural stimulation
was enhancing the central excitatory drive to the motor neurons.
Conceivable through activated lumbosacral interneurons, since
before the intent of the movement the motor pools were notactive (Angel et al., 1996, 2005; Djouhri and Jankowska, 1998;
Edgley et al., 2004; Cabaj et al., 2006; Bannatyne et al., 2009).
The somatosensory evoked potentials results in the two AIS-B individuals showing a shorter latency of responses after training may
suggest improved somatosensory transmission promoted by repetitive epidural stimulation.

Brain 2014: Page 13 of 16

14| Brain 2014: Page 14 of 16

activities to guide the design of the control algorithms and patientinterfaces. Future experiments with improved technology areneeded expediently to take the most advantage functionally ofthese neurophysiological findings in people after severe spinal
cord injury.

Acknowledgements
We would like to express our appreciation to Rebekah Morton,
Matthew Green and Paul Criscola for their invaluable support of
the research volunteers. We are indebted to our research participants whose dedication, motivation and perseverance made thesefindings possible.

Funding
US National Institutes of Health, NIBIB, under the award number
R01EB007615, and NIGMS P30 GM103507, Christopher andDana Reeve Foundation, the Leona M. and Harry B. Helmsley
Charitable Trust, Kessler Foundation, University of LouisvilleFoundation, and Jewish Hospital and St. Mary’s Foundation,
Frazier Rehab Institute and University of Louisville Hospital.

Supplementary material
Supplementary material is available at Brain online.

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