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doi: 10.1152/jn.00688.2011
109:580-590, 2013. First published 17 October 2012;J Neurophysiol
Jason H. Ko, Sonya P. Agnew, Lee E. Miller and Gregory A. Clark
Noah M. Ledbetter, Christian Ethier, Emily R. Oby, Scott D. Hiatt, Andrew M. Wilder,
coordinated grasp and sensory responses
Intrafascicular stimulation of monkey arm nerves evokes
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Innovative Methodology
Intrafascicular stimulation of monkey arm nerves evokes coordinated grasp
and sensory responses
Noah M. Ledbetter,
1
Christian Ethier,
2
Emily R. Oby,
2
Scott D. Hiatt,
3
Andrew M. Wilder,
4
Jason H. Ko,
5
Sonya P. Agnew,
5
Lee E. Miller,
2,6,7
and Gregory A. Clark
1,4
1
Department of Bioengineering, University of Utah, Salt Lake City, Utah;
2
Department of Physiology, Feinberg School of
Medicine, Northwestern University, Chicago, Illinois;
3
Department of Electrical and Computer Engineering, University of
Utah, Salt Lake City, Utah;
4
School of Computing, University of Utah, Salt Lake City, Utah;
5
Division of Plastic and
Reconstructive Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois;
6
Department of Physical
Medicine and Rehabilitation, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; and
7
Department of
Biomedical Engineering, Northwestern University, Evanston, Illinois
Submitted 4 August 2011; accepted in final form 13 October 2012
Ledbetter NM, Ethier C, Oby ER, Hiatt SD, Wilder AM, Ko
JH, Agnew SP, Miller LE, Clark GA. Intrafascicular stimulation of
monkey arm nerves evokes coordinated grasp and sensory responses.
J Neurophysiol 109: 580 –590, 2013. First published October 17,
2012; doi:10.1152/jn.00688.2011.—High-count microelectrode ar-
rays implanted in peripheral nerves could restore motor function after
spinal cord injury or sensory function after limb loss. In this study, we
implanted Utah Slanted Electrode Arrays (USEAs) intrafascicularly at
the elbow or shoulder in arm nerves of rhesus monkeys (n⫽4) under
isoflurane anesthesia. Input-output curves indicated that pulse-width-
modulated single-electrode stimulation in each arm nerve could re-
cruit single muscles with little or no recruitment of other muscles.
Stimulus trains evoked specific, natural, hand movements, which
could be combined via multielectrode stimulation to elicit coordinated
power or pinch grasp. Stimulation also elicited short-latency evoked
potentials (EPs) in primary somatosensory cortex, which might be
used to provide sensory feedback from a prosthetic limb. These results
demonstrate a high-resolution, high-channel-count interface to the
peripheral nervous system for restoring hand function after neural
injury or disruption or for examining nerve structure.
functional electrical stimulation; hand; prosthesis; spinal cord injury;
limb loss
DISRUPTIONS OF NEURAL TRANSMISSION resulting in paralysis—
primarily from spinal cord injury (SCI) but also from lesions,
stroke, head injuries, and acute nerve injury—leave the pa-
tients’ limbs and other affected body parts intact but partially
or totally unable to move. One emerging treatment for para-
lyzed individuals is functional electrical stimulation (FES)
(e.g., ParaStep I, Freehand, Vocare, and IST-12) (Brissot et al.
2000; Fromm et al. 2001; Kilgore et al. 2008; Martens and
Heesakkers 2011). FES-based prostheses can enable paralyzed
individuals to grasp objects with a few simple grips, or even
enable paraplegic individuals to walk a short distance in
conjunction with external support. However, FES systems can
be fatiguing and relatively difficult to use because they typi-
cally activate near-maximal contractions, preferentially acti-
vate fatigable motor units, and provide no somatosensory or
proprioceptive sensory feedback (Popovic et al. 1993; Spadone
et al. 2003).
The 100-electrode Utah Slanted Electrode Array (USEA)
provides a prime candidate for restoring hand function in
paralyzed patients by activating motor fibers, and may amelio-
rate some of the challenges associated with full-muscle FES or
extraneural stimulation. The USEA electrodes are arranged in
a10⫻10 configuration, spaced at 400-
m intervals, with
electrode lengths ranging from 0.5 to 1.5 mm (Branner and
Normann 2000), thereby providing relatively complete cover-
age of a nerve. Because the electrodes penetrate directly into
the nerve fascicles, their tips closely abut different populations
of motor or sensory axons, allowing multiple, selective sites for
stimulation or recording. The USEA has been used previously
to activate cat hindlimb muscles selectively, independently,
and in a fatigue-resistant manner via interleaved activation of
multiple different motor units for a single muscle, each at a
relatively low frequency (Frankel et al. 2011; McDonnall et al.
2004). Thus intrafascicular nerve stimulation with USEAs may
also provide an improved level of hand movements, compared
with conventional FES. Among other advantages, a USEA may
access multiple muscles with a single implant site and inde-
pendent access to multiple different motor units within the
same muscle, thereby also allowing more graded force control
and more fatigue-resistant movements via interleaved stimula-
tion (Normann et al. 2012). It may also allow access to intrinsic
hand muscles, which is difficult to achieve with conventional
extraneural nerve stimulation. Finally, intrafascicular elec-
trodes, such as those of the USEA, can also record single-unit
action potentials, opening the possibility of detecting afferent
signals from sensory receptors in intact limbs distal to the
neural disruption (Branner et al. 2004).
Similarly, amputees also could benefit from the selective
stimulation and recording capabilities of intrafascicular elec-
trodes, which would allow the patients’ nervous system to
communicate with computer-controlled prostheses such as ro-
botic hands or knees. In this instance, implanted electrodes
would be used to record from efferent motor fibers to obtain
motor command signals and to activate small populations of
sensory afferents in order to restore discrete sensations. How-
ever, the electrodes’ functionality with respect to selective
stimulation and recording would remain the same.
Previous studies have shown that, at a gross level, motor
fibers do cluster according to their function (Gustafson et al.
2009), and some motor fibers may be part of more than one
Address for reprint requests and other correspondence: G. A. Clark, Bioen-
gineering Dept., Univ. of Utah, 20 South 2030 East, Salt Lake City, UT 84112
(e-mail: greg.clark@utah.edu).
J Neurophysiol 109: 580 –590, 2013.
First published October 17, 2012; doi:10.1152/jn.00688.2011.
580 0022-3077/13 Copyright © 2013 the American Physiological Society www.jn.org
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nerve (Badia et al. 2010). However, these studies do not
address the relationship between the sensory and motor fibers
within a single fascicle, and it remains unclear whether fibers
innervating a given body region tend to cluster together, or
whether the nerve fibers organize separately into sensory and
motor bundles within the fascicle.
The human hand is a complex mechanical system with 27
degrees of freedom that is difficult to emulate. Monkeys have
opposable thumbs, independent finger control (Schieber 1991),
and intrinsic and extrinsic muscles controlling the hand and
arm similar in number to those in humans (Liu et al. 1996).
Monkeys thus provide an attractive model for testing the ability
of the USEA to restore human hand function. The muscles
used for generating power grip and precision grip are inner-
vated by the median, ulnar, and radial nerves in both humans
and monkeys. Selective activation of monkey hand muscles
has also been reported with the use of flat interface nerve
electrodes (FINEs) (Brill et al. 2009).
In the present study, we examined the feasibility and poten-
tial advantages of USEAs for activation of motor and sensory
fibers in the median, radial, and ulnar nerves of nonhuman
primates, using acute, anesthetized preparations. Although the
commercial version of a single Utah Electrode Array (UEA)
(with equal-length electrodes) has been previously implanted
in the median nerve of one human subject with success (War-
wick et al. 2003), the data set from that study was limited.
Aside from that somewhat anecdotal report, there have been no
previous investigations of USEAs in nonhuman primates, or in
any of the forelimb nerves of any species. Here we examined
the ability of different USEA electrodes to provide access to
different extrinsic and intrinsic hand muscles and the selectiv-
ity of that activation. We also examined the ability to activate
multiple motor groups via multiple nerves so as to achieve
coordinated gripping sequences that could restore clinically
useful hand movements after paralysis. In addition to motor
responses, we examined stimulation-evoked responses cen-
tered around primary somatosensory cortex that could be
useful for restoration of cutaneous and proprioceptive sensa-
tion in amputees. Finally, the combination of sensory and
motor responses was examined to determine whether fibers
from a single body region lie together, or whether the nerve
fibers organize separately into sensory and motor regions
within the fascicle.
MATERIALS AND METHODS
Surgery
These experiments were performed in nonrecovery surgical
procedures on four monkeys that were being euthanized after a
series of unrelated studies. All procedures were performed under
deep surgical levels of anesthesia, with isoflurane gas anesthetic
after premedication with buprenorphine, as approved by the Insti-
tutional Animal Care and Use Committee of Northwestern Univer-
sity. Experiments lasted ⬃30 h. Differences in procedures across
animals are summarized in Table 1.
Skull Screws and Electrocorticography Electrode Grid
The anesthetized monkey was placed in a stereotaxic frame. In
three monkeys, skull screws were placed according to steretotaxic
coordinates and skull landmarks so as to lie primarily over postcentral
cortex for cortical monitoring. The skull screws’ positions in relation
to the cortex were confirmed posthumously. In the fourth monkey, a
craniotomy was performed, and an electrocorticography (ECoG) grid
was placed over somatosensory cortex and adjacent cortices.
Electromyography Recording
Fine-wire electromyography (EMG) electrodes were placed in
forearm, finger, and wrist muscles, and electrical potentials were
recorded on a Cerebus recording system (Blackrock, Salt Lake City,
UT) at 10,000 samples/s with a low-pass filter at 7.5 kHz. Bipolar
recordings were made with intramuscular electrodes inserted into each
muscle, including, in some cases, separate compartments in a single
muscle. In all experiments, the main muscles used in grasp were
monitored, including flexor carpi radialis (FCR), flexor digitorum
superficialis (FDS), flexor carpi ulnaris (FCU), medial head of flexor
digitorum profundus (FDPm), ulnar head of flexor digitorum profun-
dus (FDPu), flexor pollicis brevis (FPB), brachioradialis, extensor
carpi radialis (ECR), extensor digitorum communis (EDC), extensor
carpi ulnaris (ECU), pronator teres (PrT), flexor digitorum profundus
(FDP), the dorsal interossicles, and lumbricals. In some monkeys
additional electrodes were inserted in triceps lateralis, triceps longus,
abductor pollicis brevis (AdP), and palmaris longus. Additionally,
separate compartments in EDC and ECR were monitored in two
monkeys.
Nerve Exposure
Nerves in the arm were exposed at the elbow and shoulder for
subsequent implantation of USEAs. The median nerve was exposed
through a longitudinal incision from midhumeral level to beyond the
antecubital fossa. The PrT muscle and the brachioradialis muscle were
reflected in order to dissect the median nerve free just proximal to its
branch point in the proximal forearm. To gain access to the ulnar
nerve the medial antebrachial cutaneous nerve was transected at the
elbow, and the ulnar nerve was dissected free just proximal to the
elbow. The radial nerve was exposed from the volar side of the arm
by continuing the dissection of the muscles deep to median and ulnar
nerves. Alternatively, the radial nerve was exposed via a second
incision on the dorsal aspect of the arm between the brachioradialis
and extensor carpi radialis longus (ECRL) muscles, exposing the
radial nerve just proximal to its branch points to the brachioradialis
and forearm extensor muscles.
All three nerves were also exposed at the brachial plexus to allow
implantation of USEAs at a second location in each nerve and to
examine the effectiveness of different implant locations. The incision
in the arm was extended proximally, and, in order to fully expose the
nerves of the brachial plexus, the pectoralis minor and pectoralis
major muscles were incised and retracted.
USEA Implantation
USEAs were implanted in nerves just distal to the brachial plexus
(Fig. 1A) and near the elbow (Fig. 1B) by means of a high-speed
insertion system (Rousche and Normann 1992). Arrays were con-
nected to stimulation and recording systems via a modified Integrated
Cable Systems (ICS Mfg., Longmont, CO) or a Tucker-Davis Tech-
nologies (TDT, Alachua, FL) 96-pin connector and adapter board.
Table 1. Procedures performed on each monkey
Name I/O Curves Pulse Train ECoG Skull Screw
NHP1 x x x (lesion)
NHP2 xx
NHP3 xx x
NHP4 xxx
I/O, input-output; ECoG, electrocorticography.
Innovative Methodology
581GRASP AND SENSORY RESPONSES EVOKED BY ARM NERVE STIMULATION
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USEA-Evoked Motor Responses
Electrical stimulation was delivered through the USEA electrode
tips via either a Grass SD-88 stimulator or a custom-built, 300-
channel “UINTA” stimulation system (Wilder et al. 2009). We gen-
erated EMG stimulus-response curves individually for all 96 elec-
trodes on each of 11 USEAs, using pulse-width-modulated (0.1–1,026
s), single-pulse, constant-voltage (3 ⫾2 V) stimuli controlled by
custom software. Stimulation thresholds, plateaus, and intermediate
stimulus-response functions were determined through a closed-loop
binary search using the evoked EMG signals for feedback.
Individual muscle responses were analyzed to determine which
electrodes provided access to appropriate hand muscles. After muscle
access had been determined by the delivery of single-pulse stimula-
tion, pulse trains were delivered in an attempt to generate prolonged,
useful movements of the hand and wrist. Frequency of stimulation for
pulse trains was between 30 and 50 Hz. Cortical activation was
monitored during all nerve stimulation. Somatosensory evoked poten-
tials (SSEPs) were computed using 64 averaged trials for each pulse
on each electrode.
Before inferential statistical analyses of evoked EMG activity were
conducted, EMG values were normalized to the largest response from
the maximum of either bipolar stimulation through nerve cuffs or
single- or multi-electrode stimulation through the USEA. The EMG
values for each run were divided by the maximum evoked EMG to
produce a normalized EMG value (nEMG).
A muscle stimulation selectivity index (SI) was calculated for each
electrode at a specific nEMG value, by use of the following formula
(Dowden et al. 2009):
Largest EMG ⫺2nd Largest EMG
Largest EMG
We analyzed SI values statistically with an overall analysis of
variance (ANOVA) with monkey number, nerve implanted (median,
radial, or ulnar), and level of implant (elbow or shoulder) as factors,
using a hierarchical sum of squares, followed by multiple-comparison
tests with a Scheffé correction as appropriate. Unequal group sizes
were adjusted via weighted means. Multiple-factor interactions with
incomplete terms were not analyzed.
Recording of Cortical Somatosensory Evoked Potentials
Electrical potentials from each screw or grid contact were recorded
in relation to a distant reference by a Cerebus recording system as
described above.
We also compared selectivity of cortical activation for USEA
implants at the elbow and shoulder. Biologically, it is unknown
whether the degree of musculotopic organization of motor nerve fibers
(i.e., their anatomical arrangement, corresponding to their target
muscles) remains constant throughout the nerve length. Thus, from a
practical perspective, it was unclear whether both implant sites would
work equally well, which was particularly important given that only
relatively proximal nerve sites would be available after high-level
transhumeral amputations. To address the relationship of motor and
sensory fibers within the nerve, we investigated whether different
USEA electrodes that activated a given muscle would also evoke
responses on a given ECoG electrode, which would imply that sensory
and motor fibers travel in the same fascicle in a mixed nerve. We first
examined whether the amplitude of the SSEP recorded on a given
ECoG electrode was statistically correlated with the pulse width of the
stimuli delivered through a given USEA electrode during the recruit-
ment curve that had also been used for muscle activation. For USEA
electrodes that could drive cortical activity, we then determined which
muscle responded most strongly to that electrode. Finally, for each
ECoG electrode, we averaged the correlations across different USEA
electrodes that had activated each muscle to determine the mean
correlation between muscles activated by USEA electrodes and so-
matosensory cortical response location.
RESULTS
General Results
Implants in all nerves across all implant levels were capable of
evoking muscle contractions in nerve-appropriate muscles that
were detectable through EMG or visual inspection. Currents to
evoke these contractions were not directly measured (given the
use of constant-voltage stimulation at 3 V) but lie below levels
that could damage tissue with short-term stimulation sessions,
between 5 and 50
A, as documented in the cat, including for
short-term stimulation across multiple sessions (Branner et al.
2004; Frankel et al. 2011; Normann et al. 2012).
Single-Pulse, Single-Electrode Stimulation: Muscle
Activation and Selectivity
Recruitment curves. We first examined the ability to recruit
responses in individual muscles by delivering single-pulse
stimulation through individual USEA electrodes (typically us-
ing a series of varying stimulus-pulse durations) while mea-
suring the evoked EMG responses. As in previous work, the
muscle responses to USEA stimulation were graded across the
range of pulse widths; perithreshold pulse widths had a mean
of 15.4 ⫾0.5
s. Calculated SI values indicated that single-
electrode, single-pulse intrafascicular nerve stimulation could
often activate individual extrinsic muscles to functionally use-
ful levels without activating other muscles (Fig. 2A) and that
Fig. 1. Utah Slanted Electrode Arrays (USEAs)
implanted in arm nerves. Surgical access to all 3
target nerves was achieved through a single surgical
site at either the elbow or the shoulder. In both
images, the more proximal limb is at top and the
more distal limb at the bottom, and the volar (palm
side) surface of the arm is depicted. R, radial nerve;
M, median nerve; U, ulnar nerve; *, olecranon
process at the elbow. A: left shoulder-level radial,
median, and ulnar nerves, each shown implanted
with a 100-electrode USEA. Insertion support (sub-
sequently removed) is seen below the median nerve.
B: right elbow-level arm nerves, just proximal to the
elbow. USEA implants are shown protected by a
custom containment system composed of metal
mesh and Kwik-Cast silicone (World Precision
Instruments).
Innovative Methodology
582 GRASP AND SENSORY RESPONSES EVOKED BY ARM NERVE STIMULATION
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different muscles could be recruited selectively by different
USEA electrodes (Fig. 2B). Intrinsic muscles could also be
activated by USEA stimulation, although they were usually
coactivated with other intrinsic muscles.
Of a possible 1,056 electrodes across 11 implants, 462
(43%) evoked at least low-level responses (defined as 0.2
nEMG) at pulse widths ⬍512
s. Many electrodes presumably
ended in extrafascicular, nonneuronal tissue, and hence would
not have evoked responses except at very strong stimulus
levels. In the three monkeys in which input-output curves were
generated, the mean SI across all implants at 0.2 nEMG was
0.44 ⫾0.01 (mean ⫾SE reported for all selectivity measures).
The mean number of electrodes per array that activated mus-
cles at 0.2 nEMG was 42, and it dropped to 34 at 0.5 nEMG
and 18 at 0.9 nEMG. However, some selectivity was main-
tained at the stronger activation values, 0.5 nEMG (0.43 ⫾
0.01) and 0.9 nEMG (0.31 ⫾0.02). A single USEA thus
provided selective activation of multiple muscles innervated by
a single nerve, at a variety of activation levels. At the elbow
(672 total electrodes, 7 implants) and the shoulder (384 total
electrodes, 4 implants) in all three nerves, 382 of the electrodes
(36% of all electrodes) elicited strong EMG responses (defined
as 0.5 nEMG) in the same muscles in which they elicited
weaker responses. At the elbow all implants could reach 0.9
nEMG in some muscles (178 electrodes, 26.5% of elbow
electrodes), whereas at the shoulder only the median nerve
implants were capable of evoking contractions at 0.9 nEMG
(23 electrodes, 5.9%). Because data for values above 0.2
nEMG are incomplete, the selectivity analysis was confined to
0.2 nEMG (Fig. 3); data are summarized for selectivity at
higher nEMG values in Table 2.
Muscle selectivity across nerves and implant levels. An
ANOVA of the SI calculated at 0.2 nEMG for the factors of
nerve, primate, and implant level indicated that the implant
level (elbow or shoulder) was not a significant factor, whereas
the individual animal and nerve implanted were significant
factors (Table 3). The mean SI calculated at 0.2 nEMG of all
elbow implants tended to be lower than the mean of all
shoulder implants (0.42 ⫾0.01 vs. 0.52 ⫾0.03; elbow: 356
electrodes, 7 arrays, shoulder: 106 electrodes, 4 arrays), pri-
marily because of results from the ulnar nerve; however, in the
median and radial nerves, this trend was reversed. Specific
comparisons regarding implant level for the different nerves
were not analyzed for statistical significance because only a
single shoulder-level implant was done in the radial and ulnar
nerves and because the implant level was not a statistically
significant factor. Descriptively, however, within-nerve com-
parisons of elbow- and shoulder-level SIs in the median nerve
(0.54 ⫾0.02 vs. 0.47 ⫾0.03; 153 and 73 electrodes, 3 and 2
arrays, respectively) and radial nerve (0.32 ⫾0.02 vs. 0.26 ⫾
0.06; 120 and 13 electrodes, 2 and 1 arrays, respectively) showed
that selectivity tended to be higher at the elbow than at the
shoulder, whereas in the ulnar nerve selectivity at the elbow
tended to be lower than at the shoulder (0.26 ⫾0.02 vs. 0.78 ⫾
0.05; 84 and 20 electrodes, 2 and 1 arrays, respectively). Multiple-
comparison tests with a Scheffé correction indicated that SI was
statistically different across all nerve pairings (all P⬍0.05), with
population-normalized-mean values as follows: median 0.56 ⫾
0.02, ulnar 0.44 ⫾0.03, and radial 0.36 ⫾0.02.
Musculotopic arrangement of nerve fibers. To evaluate the
musculotopic arrangement of motor fibers within a nerve, we
examined the extent to which neighboring USEA electrodes
evoked responses in a common muscle. For all implants,
electrode sites that recruited the same muscle or close synergist
muscles were usually in close proximity to one another, sug-
gesting a musculotopic arrangement (Fig. 2B). To quantify
musculotopy, for each USEA electrode we first calculated the
expected number of neighboring (adjacent) electrodes that
would activate the same muscle if nerve fibers were randomly
distributed, based on the number of responses evoked in each
muscle for each given USEA. We then compared the number
expected from chance with the number of neighboring elec-
trodes that had actually recruited the same response as the
given test electrode at threshold. Significantly more neighbor-
ing electrodes recruited the same motor response than expected
from chance alone (mean ⫽0.98 ⫾0.07 electrodes, P⬍0.05)
(Fig. 4), indicating that motor fibers were organized musculo-
topically within all nerves.
Single-Electrode Pulse Trains Also Recruited
Selective Movements
Functionally useful movements require stimulus trains,
rather than single-pulse activation of motor nerve fibers. To
test our ability to generate individuated and coordinated move-
ments with the USEA, we applied pulse trains (30 –50 Hz,
1.8 –3 V) to particular electrodes. Pulse widths used in the
functional muscle contraction sequences were higher than
perithreshold values. We monitored movements at the hand,
elbow, and shoulder, as well as rotation of the forearm. Mo-
tions were observed and categorized in terms of the joint at
which the movement occurred and its direction, together
with the muscles that showed EMG activity. Across all
subjects, median nerve stimulation generated six to nine
visually different movements across different combinations
of joints (Fig. 5 and Supplemental Movie S1).
1
These
1
Supplemental Material for this article is available online at the Journal
website.
Fig. 2. Muscle activation shows selectivity and musculotopy. A: selectivity.
Stimuli of increasing pulse width evoked successively larger responses in
flexor digitorum superficialis (FDS), with little or no activation of other
muscles. This electrode showed a selectivity of 0.85. B: musculotopy. Each tile
in the 10-by-10 grid represents an electrode on the USEA, the symbol
indicating the muscle most strongly activated by that electrode. Electrodes are
shown as in a cross section of the nerve with the most superficial aspect of the
nerve at top. Responses in a given muscle tend to be recruited by adjacent
USEA electrodes, whereas responses in other muscles are recruited by other
USEA electrodes, indicating a musculotopic arrangement of nerve fibers. ABP,
abductor pollicis brevis; FDPm, medial head of flexor digitorum profundus
(FDP); FCR, flexor carpi radialis; PaL, palmaris longus; PrT, pronator teres;
Lu1, 1st lumbrical; Lu2, 2nd lumbrical; OpP, opponens pollicis; FPB, flexor
pollicis brevis; ADP, abductor pollicis brevis.
Innovative Methodology
583GRASP AND SENSORY RESPONSES EVOKED BY ARM NERVE STIMULATION
J Neurophysiol •doi:10.1152/jn.00688.2011 •www.jn.org
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movements approximately corresponded to the activation of
individual muscles associated with each movement in vari-
ous combinations (e.g., FCR for wrist flexion; FDS and FDP
for finger flexion; the intrinsic muscles and FPB for small
finger and thumb movements; and PrT for arm pronation).
The ability of the different USEA electrodes to elicit distinct
movements and different EMG responses indicates that
selective stimulation was partially maintained during pulse
train delivery, such that even with the low-level activation
of additional muscles the motions evoked were clearly
related to the muscle that was selectively activated through
single-pulse stimulation.
Ulnar nerve Across all nerves
Ulnar nerve
Radial nerve
Radial nerve
Number of electrodesNumber of electrodes
Number of electrodes
0 0.2 0.4 0.6 0.8 1 0 0.2 0.4 0.6 0.8 1
0
5
10
15
20
0 0.2 0.4 0.6 0.8 1
0
5
10
15
20
0 0.2 0.4 0.6 0.8 1
0
5
10
15
20
0 0.2 0.4 0.6 0.8 1
0
5
10
15
20
00.20.40.60.81
0
5
10
15
20
0
5
10
15
20
Median nerve
Elbow implants Shoulder implants
Number of electrodes
Uln Rad Med
Uln Rad Med
0
5
10
15
20
25
00.2 0.4 0.6 0.8 1
0
5
10
15
20
25
30
Elbow Shoulder
Elbow Shoulder
Elbow Shoulder
00.20.40.60.81
0
5
10
15
20
25
30
0 0.2 0.4 0.6 0.8 1
0
5
10
15
20
25
30
00.2 0.4 0.6 0.8 1
0
5
10
15
20
25
30
35
40
Elbow implants Shoulder implants
Selectivity Index Selectivity Index Selectivity Index
U-S
R-S
M-S
U-E
R-E
M-E
Median nerve
0 0.2 0.4 0.6 0.8 1
Both levels
Across all electrodes
SI at shoulder
0
5
10
15
20
25
0 0.2 0.4 0.6 0.8 1
14 5
1 6
13
14
6
13
20 20
3
7
)522 ,5()18 ,2()751,3(
)331,3()31 ,1()711,2(
)401,3()02 ,1()58,2(
)264 ,11()601 ,4()653,7(
Fig. 3. Selectivity of muscle activation for all
USEA electrodes and implant sites. The num-
ber of electrodes that recruited responses at a
given level of selectivity is depicted across all
levels and nerves. Left: results for USEA im-
plants near the elbow for median nerve (top),
radial nerve (2nd row), and ulnar nerve (3rd
row) and across all nerves (bottom). Center:
results for USEA implants in nerves near the
shoulder. Right: results summated for USEAs
at both the elbow and the shoulder. Bottom
right: group results across all nerves at both
levels. For each panel, the large number at top
right indicates how many different muscles
could be preferentially activated at that partic-
ular level-implant combination across all se-
lectivity indexes (SIs). The smaller numbers in
parentheses below the number of muscles in-
dicate the number of implants and the number
of electrodes used in the analyses, respec-
tively.
Table 2. Selectivity of muscle responses at multiple strength levels
nEMG Mean SI SE Arrays (of 11) Elbow Electrodes Shoulder Electrodes Total (of 1,056) Mean Pulse Width,
s
0.2 0.44 0.01 11 356 106 462 16.7
0.5 0.43 0.01 11 296 86 382 17.0
0.9 0.31 0.02 6 178 23* 201 19.0
Mean selectivity decreased as muscle activation level increased. At each level of activation [normalized electromyography value (nEMG) 0.2– 0.9], the mean
selectivity index (SI), SE of the mean SI, and total number of electrodes at each location are shown. Few individual electrodes were capable of eliciting 0.9 nEMG
responses, particularly at the shoulder. *Median nerve only.
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Multielectrode, Multi-USEA Pulse Trains Evoked
Coordinated Grasp
To produce a coordinated grasp, muscles not only must be
selectively activated but also must contract and relax in specific
patterns (Long et al. 1970; Maier and Hepp-Reymond 1995).
To test the ability to evoke these more complex types of
movements, between three and nine electrodes across all arrays
were selected that activated the muscles necessary for power
grip through the UINTA stimulation system custom software.
A 2-s movement sequence was programmed consisting of
finger extension to open the hand, finger flexion to grasp an
object, and, finally, finger extension to release the object.
Activation of extrinsic finger flexors that span the wrist typi-
cally caused undesired wrist flexion along with flexion of the
fingers. In these cases, wrist extensors were also activated to
counteract the flexion force, a combination that is necessary
under normal conditions as well. A 50-g ball was placed in the
animal’s palm as it was initially opened. When the hand closed,
the ball was held within the hand until the program instructed
the fingers to extend (Fig. 6 and Supplemental Movie S2). The
shown movement was evoked with six electrodes with pulse
widths of 10, 100, 10, 50, 100, and 500
s (average 128
s).
Once programmed, the control sequence reliably produced the
desired movement sequence for the duration of the experiment.
Via this technique, the anesthetized monkey’s hand also
engaged a variation of power grip sometimes called bucket
grip. In addition, electrodes associated with intrinsic hand
muscles were combined with the extrinsic muscles to gen-
erate a pinch grip between the thumb and forefinger (Sup-
plemental Movie S3).
USEA Activation of Sensory Fibers
To examine our ability to evoke sensory signals, as would be
necessary in a limb-loss prosthesis that restores sensation, we
monitored SSEPs, using either skull screws (n⫽3) or an
ECoG grid (n⫽1) during USEA stimulation. Stimulation
produced short-latency (⬃5 ms to onset) SSEPs in and around
primary somatosensory cortex on 52% of tested stimulating
electrodes. To avoid the possibility of indirect sensory activa-
tion (e.g., H or F reflexes), the analysis of SSEP data was
limited to the first 20 ms after stimulation (Fig. 7). The short
latency of these responses indicates that they are likely due to
direct afferent fiber activation, not indirect sensory responses
due to movement caused by concurrent muscle activation. In
the monkey with the ECoG grid, low-level stimulation applied
to USEAs (n⫽3 USEAs) recruited cortical responses at a
pulse duration that did not activate muscles in 32% of elec-
trodes, providing further evidence that direct sensory fiber
activation was achieved.
Relationship Between Somatotopic and
Musculotopic Organizations
We next examined whether afferent nerve fibers were orga-
nized somatotopically and the relationship between somato-
topic and musculotopic organizations.
Different USEA electrodes evoked different cortical responses.
Consistent with a somatotopic organization, different elec-
trodes on the same USEA, or on different USEAs, evoked
responses recorded through different cortical electrodes in
three monkeys. (Upon postmortem dissection, one primate was
found to have a lesion within the somatosensory cortex from
previous work that precluded cortical analyses for the present
work.) For monkeys with skull screws (n⫽2) rather than the
ECoG electrode grid, different patterns of cortical activation
were discernible only with stimulation via USEAs on different
nerves, presumably because of the relatively coarse spatial
resolution provided by skull screw recordings. For example,
the maximal responses to median nerve stimulation were re-
corded on electrodes different from the electrodes showing the
maximal responses evoked by radial nerve stimulation. Addi-
tionally, for the one monkey with the ECoG grid, different
USEA electrodes on a single USEA in a given nerve evoked
responses in discernibly different cortical regions (i.e., differ-
ent ECoG electrodes).
Somatotopic and musculotopic maps covary. Results showed
that the amplitude of the SSEP on some cortical electrodes was
significantly correlated with stimulation strength on USEA elec-
Fig. 4. Quantification of musculotopic arrangement of motor fibers. We
assessed the musculotopic organization of nerve fibers by comparing the
muscle activated by each USEA electrode with the muscles activated by
neighboring USEA electrodes. For each electrode capable of activating a
muscle, we calculated the probability that a neighboring electrode would
activate the same muscle from chance alone. The actual number of neighboring
electrodes that preferentially activated the same muscle was consistently
higher than the number expected from chance (i.e., the actual ⫺expected
difference was ⬎0), indicating a musculotopic arrangement in which motor
fibers to a given muscle were close together within the nerve. This pattern held
for muscles of all types and each nerve individually.
Table 3. Selectivity of muscle responses at multiple
strength levels
Factor Sum Sq. d.f. Mean Sq. FProbability ⬎F
Implant level 0.04 1 0.04 0.76 3.83E-01
Animal no. 2.02 2 1.01 17.30 5.71E-08
Nerve 3.15 2 1.58 27.07 7.79E-12
Error 26.57 456 0.06
Total 32.17 461
Analysis of variance (ANOVA) of SI, linear model, hierarchical sum of
squares. Individual animal and nerve implanted were significant factors. All
electrodes capable of eliciting a 0.2 nEMG response or greater were included
in the analysis.
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trodes that activated muscles with similar function (Fig. 8). In
addition, adjacent cortical electrodes showed similar corre-
lations, whereas cortical electrodes distant to one another
did not. Instead, responses on distal cortical electrodes were
correlated with stimulus strength on USEA electrodes that
activated other muscles. For example, stimulation strengths
on USEA electrodes implanted in the median nerve that
activated wrist flexor muscles were correlated (r0.45 or
greater, P⬍0.05) with response magnitudes on ECoG
electrode 18, whereas stimulus strengths on USEA elec-
trodes that activated finger flexor muscles were correlated (r
0.45 or greater) with response magnitudes on ECoG elec-
trodes 1 and 2(Fig. 8).
These results imply that somatosensory fibers and motor
fibers for a given body region travel closely together within the
nerve. Given that USEA-evoked motor selectivity appears to
hold even at the subfascicular level, it is plausible that the
motor-sensory coorganization occurs at the subfascicular level
as well. These findings complement earlier work demonstrat-
ing that somatosensory fibers of the same submodality and
receptive field region cluster together within the nerve (Eke-
dahl et al. 1997; Hallin 1990).
DISCUSSION
General
Here we report the first USEA implantation in the peripheral
nerves of a nonhuman primate, the first attempt to quantify the
efficacy and selectivity of the USEA in activating extrinsic and
intrinsic hand muscles, and the first recordings of cortical
sensory responses evoked through USEA stimulation of arm
nerves. The results here demonstrate that intrafascicular elec-
trodes can provide excellent access to multiple muscles, in-
cluding intrinsic hand muscles not typically accessed in con-
ventional FES. The different electrodes of a single USEA
could activate multiple different muscles, and the combination
of just three USEAs in the median, radial, and ulnar nerves
could access nearly all forearm and hand muscles. Although
the procedure to implant USEAs for clinical applications
Fig. 5. USEA single-electrode pulse-train stimulation of me-
dian nerve recruits specific digit and wrist movements (prona-
tion not shown). White arrows indicate fingers/joints in motion.
Different USEA electrodes evoked different movements. A: rest.
B: wrist flexion. C:digits 3–5, flexion (in shadow). D:digit 2, tip
flexion; note the different fingers engaged in Cand D.E:digits
2–5, flexion at metacarpophalangeal (MCP) joints. F:digits 2–5,
tip extension, with flexion at MCP joints. Note the relative
straightening of the fingertips in Fcompared with the extent of
finger flexion in E, demarcated by white lines in Eand F.
Fig. 6. Coordinated, sequential grasp-and-release movements
produced by multielectrode, multi-USEA stimulation. USEA
stimulation generated grip sufficient to hold a ball. Bottom:
electrodes used in the grip sequence for the 3 implanted nerves;
filled dots indicate electrodes active at the time of the picture.
A: rest position. B: wrist extension. C: 1-s hand opening and
forearm supination to accept the ball. The experimenter intro-
duces the ball to the anesthetized primate’s hand. D: 1-s power
grip. E: wrist and fingers extend again, releasing the ball.
F: wrist flexes and forearm pronates to drop the ball.
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would be invasive, it is less invasive and would require less
recovery time than, for example, targeted reinnervation ap-
proaches presently used successfully for control of prosthetic
limbs (Kuiken et al. 2009).
Recruitment of Motor Responses via USEA Stimulation of
Motor Fibers
Activation of motor fibers provided fine-resolution control
of forearm movements. Selective activation of the muscles
used to grip objects was achieved with both the elbow-level
and shoulder-level implants, indicating that both locations have
potential uses for peripheral nervous system (PNS)-based pros-
theses. Although shoulder-level implants had a mean SI com-
parable to elbow-level implants, the small sample size makes
determination of the strength of that trend difficult. However,
the greater number of usable electrodes suggests that the elbow
may be a more desirable implant location when available.
Nonetheless, shoulder-level implants would be useful in cases
of high-humeral amputation, or for recruiting muscles of the
Fig. 7. Primary somatosensory cortex was activated through USEA peripheral nerve stimulation of sensory nerve fibers. Anterior to left, medial on top in all
panels. Stimuli were delivered at the beginning of each trace. A: electrocorticography (ECoG) electrode positions shown in relation to the cortex. Band C: cortical
recording pattern associated with electrodes in the median nerve that activated thumb and index finger intrinsic muscles (B) or electrodes in the radial nerve that
activated brachioradialis (C), an elbow flexor. Cs, central sulcus; Ips, intraparietal sulcus.
Fig. 8. Coregistration of musculotopic and somatotopic maps. Different USEA electrodes that evoked responses in a given muscle via activation of motor nerve
fibers also evoked responses on the same cortical ECoG electrodes, via activation of sensory nerve fibers. Each grid displays a color map for the 32 ECoG
electrodes for a given muscle, indicated by the label above the grid [e.g, brachioradialis (Brd), extensor carpi radialis (ECR), etc.]. Each electrode was categorized
by muscle, requiring an SI of ⬎0.25 calculated at normalized EMG value (nEMG) of 0.2. Colors correspond to the mean Pearson’s correlation coefficient (r)
between the stimulus pulse width and the amplitude of the evoked cortical response across all electrodes that could activate each muscle (n⫽692, P⬍0.01
shown). ECoG electrodes within each grid are arbitrarily numbered from 1to 8from left to right at bottom, extending through 25–32 at top. USEA electrodes
that evoked responses in a given muscle or similar muscles, e.g., wrist extensors, also evoked responses in a similar set of cortical electrodes, whereas USEA
electrodes that evoked responses in other muscles activated other cortical areas. For example, USEA electrodes that activated extensor muscles extensor carpi
ulnaris (ECU) and ECR also evoked responses on ECoG electrodes 10 and 11, as indicated by the high correlation between the stimulus pulse width and the
amplitude of the evoked somatosensory evoked potential (SSEP) on those ECoG electrodes. In contrast, USEA electrodes that activated the flexor muscle FDS
evoked responses in more anterior-lateral cortical regions (ECoG electrodes 1 and 2). Muscles are grouped according to their dominant innervation, e.g., radial
nerve (top), median nerve (middle 2 rows), and ulnar nerve (bottom).
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upper arm after SCI, given that some electrodes at the shoulder
level were selective (40 electrodes with an SI ⬎0.5).
Single-pulse activation of individual muscles was often
selective, particularly for extrinsic hand muscles. Although the
intrinsic muscles with similar functions (such as the lumbri-
cals) were usually recruited together, the intrinsic muscles in
different groups (thenar, interossi, and lumbrical) were often
recruited separately. On some electrodes (in elbow-level im-
plants in the median nerve), the index lumbrical was recruited
alone, without activity on the other lumbricals, further indicat-
ing the specificity of muscle stimulation possible through
intrafascicular electrodes. From previous work with intrafas-
cicular electrodes, it is known that it is possible to evoke a
response from only a portion of a fascicle. In the present study,
it was not directly demonstrated whether the selectivity seen is
principally due to a similar level of subfascicular selectivity or
a more segregated set of fascicular bundles; however, the high
impedance of the epineurium surrounding each fascicle sub-
stantially limits current spread from one fascicle to another. In
either case, under the assumption that the nerve is musculoto-
pically and somatotopically organized, current spread would
cause physically close muscles and sensory areas to be acti-
vated together. Moreover, current spread cannot fully account
for the musculotopy (or somatopy) observed here. Current
spread from a given electrode to the neural tissue at an adjacent
electrode might indeed active some fibers there, but such
current spread could not fully explain why the dominant nEMG
response at the given electrode was the same as that at the
adjacent electrode. The strongest activation at the given site
will reflect activation of the greatest number of nerve fibers,
which probabilistically would occur in close proximity to the
given electrode tip. Our data indicate that the selectivity of
muscle activation was highly variable among different nerves
and individuals. However, the overall musculotopic arrange-
ment of fibers across the broad distribution of SIs likely
indicates that, independent of the degree to which the selec-
tivity seen in this study is due to fasciculation or instead to
subfascicular organization, there is a strong tendency for axons
to particular muscles to group together, in agreement with
other recent studies of nerve organization (Badia et al. 2010;
Brill et al. 2009).
Pulse-train stimulation of selective electrodes generated
smooth and distinct movements. Furthermore, different move-
ments evoked by pulse-train stimulation were combined into
functional grip-and-release sequences by activating several
electrodes simultaneously or in sequence, and multiple types of
grip (power, bucket, and pinch) could be reliably generated.
These results all indicate the feasibility of using a penetrating
electrode in the PNS as a prosthesis for limb reanimation in
paralyzed patients. In the cat hindlimb, contractions produced
by stimulation through multiple USEA electrodes that activate
different motor units of the same muscles can be combined and
interleaved to produce fatigue-resistant movements and stable
static positions (Normann et al. 2005). So long as stimulation
through the USEA electrodes can evoke responses in indepen-
dent, nonoverlapping motor units, the same approach may
work for monkey arm nerves, and presumably for human
nerves as well. However, the time constraints of the present
acute studies precluded systematic investigations of the overlap
of USEA electrode responses and the effects of interleaved
stimulation on fatigue resistance (see Normann et al. 2012 for
details of the overlap and fatigability tests).
Studies of precision grip indicate that the intrinsic hand
muscles, particularly the first dorsal interosseous and the mus-
cles in the thenar group, are important for stabilizing the thumb
and finger metacarpophalangeal (MCP) joints (Maier and
Hepp-Reymond 1995). Unfortunately, present FES-based so-
lutions do not fully access the hand muscles required for grasp,
particularly the intrinsic hand muscles. Although direct stim-
ulation of extrinsic hand muscles does provide functional
power grip, the same intramuscular electrodes cannot easily be
used for control of intrinsic hand muscles, largely because of
their small size and the difficulty of surgical access. Because of
these limitations, additional surgeries such as tendon transfers
are sometimes necessary to achieve strong, stable grip force
(Kilgore et al. 2008). In contrast, our three implanted USEAs
allowed access to all the instrumented hand muscles, including
all extrinsic and intrinsic muscles implicated in grip (Maier and
Hepp-Reymond 1995; Schieber 1995). The activation of in-
trinsic and extrinsic hand muscles in a coordinated fashion
allows for versatile hand posturing and gripping. Thus, for
example, we were able to encode a stimulation sequence with
four electrodes that brought the thumb and forefinger together
(Supplemental Movie S3).
Stimulation of Sensory Fibers
Lack of sensory feedback is also a major challenge for users
of a limb-replacement prosthesis. Without normal somatosen-
sory feedback, many patients complain that their prosthetic
limb is unwieldy and difficult to use (Biddiss and Chau 2007;
Pezzin et al. 2004). Intrafascicular electrode arrays, such as the
USEA, should be capable of selectively activating multiple,
independent subsets of sensory fibers, just as they can for
motor fibers. Motor and sensory nerves remain functional long
after limb amputation, and stimulation of sensory fibers can
elicit sensation (Anani et al. 1977; Dhillon et al. 2004; Dhillon
and Horch 2005; Rossini et al. 2010; Warwick 2005). Hence,
it may be possible to stimulate sensory fibers through USEAs
and thereby evoke graded and varied sensory responses, in-
cluding proprioception and pressure, to aid in gripping and
reaching tasks.
Here, stimulation through individual USEA electrodes gen-
erated a variety of patterns of somatosensory cortical activa-
tion. In principle, such differentiable sensory signals could be
used to provide cutaneous and proprioceptive sensory feedback
from a neuroprosthetic artificial limb. Furthermore, the re-
sponses on a given cortical electrode were associated with
stimulation on USEA electrodes that were also associated with
specific muscles or classes of muscles (e.g., finger flexors).
Because motor axons are organized musculotopically, and
USEA electrodes that stimulate muscles with similar function
are often near one another (e.g., Fig. 2B, FDP and FDS or FCR
and PrT), we can conclude that the somatotopic and musculo-
topic maps in the nerve are in approximate register with one
another. Because muscle activity could often be evoked on an
electrode that also evoked sensory responses, it is likely that
individual fascicles are mixed sensory-motor, consistent with
previous studies (Chaudhuri et al. 2011; Schady et al. 1983).
The modality of sensory responses is difficult to determine
from recordings from the cortical surface with the electrodes
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used in this study, especially given that there is some overlap
in the representation of body space in the cortex. However,
activity from stretch receptors in a given muscle would be
expected to lie in close proximity to motor fibers associated
with the same muscle, indicating a high likelihood that the
evoked potentials could convey some proprioceptive feedback
for use in a prosthetic application. Such feedback might pro-
vide both intuitive, closed-loop prosthetic control and en-
hanced integration of the artificial limb with the user’s own
internal body image.
Considerations for Long-Term Intrafascicular
Electrode Implants
In SCI patients, the lower motoneurons remain mostly intact
within the spinal cord. However, their chronic deinnervation
can cause secondary degeneration, disassembly, or disorgani-
zation of the neuromuscular junction, changes in muscle ex-
citability, and muscle atrophy. Thus, in a chronic implantation
in a paralyzed individual, the initial conditions of the muscle
and neuromuscular junction might be quite different from those
in the intact animals in the present study. However, the initial
peripheral changes that occur after SCI are largely reversible
through FES, which, over time, can restore the neuromuscular
junction’s natural arborization and can improve the efficacy of
muscle activation (Baldi et al. 1998). Indeed, the ability to
return the neuromuscular system toward its normal preinjury
conditions may constitute an additional benefit of intrafascic-
ular electrode technology. However, without early intervention
SCI-induced hypertonia and spasticity can cause permanent
changes to the functionality of muscles. All potential therapies,
including the proposed USEA, PNS-based prosthesis, thus give
the most benefit when provided immediately after injury.
Neurons may undergo important changes at the sites of
chronic electrode implants that could affect electrode function-
ality. Fibrosis around electrodes and a continuing foreign body
response can push axons away from the electrode tips, ham-
pering their ability to record and stimulate neurons selectively
(Biran et al. 2005). Although all neural implants face the
problems associated with tissue response, central nervous sys-
tem (CNS) implants of UEAs are subjected to less motion than
nerve implants, and traditionally have been more reliable
(Simeral et al. 2011) than long-term USEA implants in initial
studies (Branner et al. 2004). However, recent and ongoing
research has demonstrated substantive improvements in both
long-term recording and stimulating capabilities of USEAs in
cat sciatic nerve (Clark et al. 2011; Frankel et al. 2011;
Ledbetter et al. 2011; Normann et al. 2012), which may
translate to comparable success for USEAs in monkey arm
nerves, and ultimately for clinical applications.
Issues of Muscle Control for the Design of the
Motor Program
Strategies for motor restoration that are based on nerve
stimulation explicitly involve the activation of lower motor
neurons, which can engage spinal reflexes that can operate
independently of the brain. For example, Renshaw reflexes
involve negative feedback circuits in which a motoneuron
inhibits itself (through a Renshaw interneuron). However,
synaptic inhibition that occurs at the motoneuron soma many
space constants away will have almost no effect on the direct
activation of motor fiber axons at the USEA stimulation site.
Because sensory and motor fibers are mixed within the
nerve, activation of proprioceptive, cutaneous, or even nocice-
ptive reflex pathways might be engaged coincidently with
motor fiber stimulation in the awake animal. In principle, these
effects might need to be incorporated into our artificial motor
program. However, such considerations have not proven to be
problematic in other clinical FES applications with extraneural
stimulation. Given the high selectivity and relatively low
currents (5–50
A) associated with intrafascicular stimulation,
these concerns also seem unlikely for USEAs.
Brain-Controlled Activation of Motor Nerve Fibers
and Behavior
In a closely related project, we have demonstrated that
recordings from similar UEAs implanted in the primary motor
cortex of monkeys can provide accurate information about muscle
activity during normal or intended movement (Pohlmeyer et al.
2007). The information can be used to restore simple voluntary
movement to monkeys during peripheral nerve block, used as a
temporary paralysis model of SCI.
During this nerve-block paralysis, stimulation through intra-
muscular electrodes is used to evoke the intended movement,
as inferred from the cortical recordings in real time (Ethier et
al. 2012; Moritz et al. 2008; Pohlmeyer et al. 2009). Poten-
tially, in future work, USEA-based stimulation of motor fibers
could be controlled in a similar manner, providing the mon-
key—and, ultimately, a paralyzed person—volitional control
of more dexterous and coordinated hand movements than can
be achieved with intramuscular or extraneural electrodes.
GRANTS
This work was supported by U.S. Army Medical Research and Materiel
Command Grant W81XWH-10-1-0931, National Institute of Neurological
Disorders and Stroke Grant 01-NS-053603, Northwestern University, and the
University of Utah.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the author(s).
AUTHOR CONTRIBUTIONS
Author contributions: N.M.L., C.E., L.E.M., and G.A.C. conception and
design of research; N.M.L., C.E., E.R.O., S.D.H., A.M.W., J.H.K., S.P.A.,
L.E.M., and G.A.C. performed experiments; N.M.L. analyzed data; N.M.L.,
C.E., E.R.O., L.E.M., and G.A.C. interpreted results of experiments; N.M.L.
prepared figures; N.M.L. and G.A.C. drafted manuscript; N.M.L., C.E., J.H.K.,
S.P.A., L.E.M., and G.A.C. edited and revised manuscript; N.M.L. and G.A.C.
approved final version of manuscript.
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Innovative Methodology
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