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Electrical Stimulation In Muscle Reinnervation
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Updated
June 23, 2003
Al Majed A.A., Neumann C.M.,
Brushart T.M., and Gordon T. (2000) Brief electrical stimulation promotes the
speed and accuracy of motor axonal regeneration. J. Neurosci. 20, 2602-2608.
Abstract: Functional recovery is often poor despite the capacity for axonal
regeneration in the peripheral nervous system and advances in microsurgical
technique. Regeneration of axons in mixed nerve into inappropriate pathways is a
major contributing factor to this failure. In this study, we use the rat femoral
nerve model of transection and surgical repair to evaluate (1) the effect of
nerve transection on the speed of regeneration and the generation of
motor-sensory specificity, (2) the efficacy of electrical stimulation in
accelerating axonal regeneration and promoting the reinnervation of appropriate
muscle pathways by femoral motor nerves, and (3) the mechanism of action of
electrical stimulation. Using the retrograde neurotracers fluorogold and
fluororuby to backlabel motoneurons that regenerate axons into muscle and
cutaneous pathways, we found the following. (1) There is a very protracted
period (10 weeks) of axonal outgrowth that adds substantially to the delay in
axonal regeneration (staggered regeneration). This process of staggered
regeneration is associated with preferential motor reinnervation (PMR). (2) One
hour to 2 weeks of 20 Hz continuous electrical stimulation of the parent axons
proximal to the repair site dramatically reduces this period (to 3 weeks) and
accelerates PMR. (3) The positive effect of short-term electrical stimulation is
mediated via the cell body, implicating an enhanced growth program. The
effectiveness of such a short-period low-frequency electrical stimulation
suggests a new therapeutic approach to accelerate nerve regeneration after
injury and, in turn, improve functional recovery
Andreose J.S., Xu R., Lomo
T., Salpeter M.M., and Fumagalli G. (1993) Degradation of two AChR populations
at rat neuromuscular junctions: regulation in vivo by electrical stimulation. J.
Neurosci. 13, 3433-3438.
Abstract: The effect of electrical stimulation on the stability of junctional
ACh receptors (AChR) on soleus muscles of Wistar rats was compared to that of
denervation and reinnervation. Denervation causes the degradation rate of the
slowly degrading AChRs (Rs) at the neuromuscular junction to accelerate and be
replaced by rapidly degrading AChRs (Rr), while reinnervation restabilizes the
accelerated Rs. Electrical stimulation initiated at the time of denervation
prevented the acceleration of the Rs. It could not, however, reverse the effect
of denervation if initiated after the AChRs became destabilized, nor could it
slow the degradation rate of the Rr. We conclude that electrical stimulation of
denervated muscle downregulates the expression of the Rr and prevents the
destabilization of Rs
Angaut-Petit D. and Mallart
A. (1985) Electrical activity of mouse motor endings during muscle
reinnervation. Neuroscience 16, 1047-1056.
Abstract: An in vitro study of electrical activity of regenerating motor endings
was performed 11-15 days after the crushing of one motor nerve supplying the
triangularis sterni muscle in the adult mouse. For this purpose, presynaptic
membrane currents elicited by electrical stimulation of the regenerating nerve
were recorded by external electrodes. Ionic channel distribution along the
length of the endings was deduced from wave form configuration in normal
perfusing fluid together with changes produced by application of specific
channel blocking agents. The sharp negative deflection which was shown to
correspond to inward Na+ current by its sensitivity to tetrodotoxin application
could be recorded along most of the length of the endings indicating a
widespread distribution of Na channels. Frequent absence of the late wave form
component which signals K+ current was taken to indicate an even K+ current
density in the few last nodes, the heminode and the distal part of the endings.
Therefore, it appears that regenerating motor endings are characterized by an
overlap of Na and K conductances all along their length. In the course of
regeneration, the heminode loses the sensitivity to K channel blocking agents
and the remainder of the terminal becomes insensitive to tetrodotoxin, the
former change occurring usually earlier than the latter
Anonsen C.K., Patterson H.C.,
Trachy R.E., Gordon A.M., and Cummings C.W. (1985) Reinnervation of skeletal
muscle with a neuromuscular pedicle. Otolaryngol. Head Neck Surg. 93, 48-57.
Abstract: In the past decade the otolaryngologist has become interested in the
problem of muscle reinnervation as it relates to laryngeal and facial paralysis.
Although reinnervation by neuromuscular pedicle transfer has shown promising
results in the laboratory and clinic, some investigators have had difficulty in
achieving reliable results with this procedure. To further assess the
technique's validity, we investigated the neuromuscular pedicle. This study
utilized a strap muscle neuromuscular pedicle transfer to a contralateral strap
muscle in the rabbit. The results were analyzed by the use of a number of
independent measures, including electrical stimulation of the nerve, muscle
contractibility, electromyography, enzyme histochemistry, reduced-silver
staining for normal fibers, and the retrograde transport of the enzyme marker
horseradish peroxidase. The physiologic and anatomic results demonstrated that
morphologic and functional reinnervation of the experimentally isolated muscle
by the transferred neuromuscular pedicle occurred. The most convincing data were
produced by gross electrical stimulation, twitch and tetanic contraction, and
horseradish peroxidase labeling. Electromyographic activity and other histologic
findings supported the above conclusions
Bacou F., Rouanet P., Barjot
C., Janmot C., Vigneron P., and d'Albis A. (1996) Expression of myosin isoforms
in denervated, cross-reinnervated, and electrically stimulated rabbit muscles.
Eur. J. Biochem. 236, 539-547.
Abstract: The expression of myosin heavy (MyHC) and light (MyLC) chain isoforms
was analyzed after denervation and cross-reinnervation by a fast nerve of the
slow-twitch Semimembranosus proprius (SMp) muscle, and after denervation and
electrical stimulation at low frequency of the fast- twitch Semimembranous
accessorius (SMa) muscle of the rabbit. The control SMp (100% type I fibers)
expressed 100% type I MyHC and 100% slow-type (1S', 1S and 2S) MyLC isoforms.
Five month denervation did not alter significantly the MyHC expression of the
muscle, but induced the expression of a new type 1 MyLC corresponding most
probably to an embryonic MyLC. Five-month cross-reinnervation of the SMp by the
fast SMa nerve induced a large change of its fiber type properties. As shown by
immunocytochemistry, almost all fibers were stained by fast myosin antibody, but
a high proportion of them co-expressed slow myosin. This result was in agreement
with biochemical data showing that fast MyHC and MyLC isoforms became
predominant. The control SMa (nearly 100% type II fibers) expressed almost 100%
type II MyHC (70% type IIb and 22% IIx/d) and 100% fast-type (1F, 2F and 3F)
MyLC isoforms. Five month denervation of the SMa induced a shift in its MyHC,
with 98% type IIx/d and 2% type IIb isoforms, and no change in the proportions
of its MyLC. Three month electrical stimulation at 10 Hz of the SMa transformed
its fiber type composition. All fibers reacted with the slow myosin antibody and
a minor proportion of them were stained by the fast myosin antibody. These
observations were in agreement with the biochemical analysis showing a large
predominance of the slow-type MyHC and MyLC isoforms. Taken together, these
results obtained from rabbit muscles which are normally homogeneous in either
fast-twitch or slow-twitch fiber types, further support the idea that the
different myosin isoforms, particularly the MyHC, are differentially regulated
by motor innervation. Type I MyHC is maintained in denervated SMp muscle, but is
not expressed in denervated SMa. Type IIb isoform is the most sensitive to
neural influence, as it disappears rapidly in denervated and electrically
stimulated fast-twitch SMa muscle, and is barely expressed in cross-reinnervated
slow-twitch SMp muscle. In contrast, type IIa and type IIx/d are less dependent
upon motor innervation. In addition to the previous studies of d'Albis et al.
analysis of these results leads us to conclude that, in the rabbit, sensitivity
to motor innervation increases from the glycolytic to the oxydative types of
fibers, in the order IIB > IIX/IID > IIA > I
Badke A., Irintchev A.P.,
Wernig A. (1989) Maturation of Transmission in Reinnervated Mouse Soleus Muscle.
Muscle & Nerve
12:580-586. Abstract: After the
tibial nerve of the mouse was cut unilaterally and immediately re-sutuared,
reinnervation of soleus muscle proceeded rapidly and muscle isometric
contraction characteristics reached normal values within 2 months. In contrast,
synaptic transmission remained immature since resistance to pre-synaptic
(magnesium) or post-synaptic (curare) blocking solutions remained reduced.
Results suggest that release probability and transmitter stores were smaller
than normal. To study the effect of training, animals were allowed to run in
wheels. Running caused a delay in reinnervation at 18-20 days, which was,
however, abolished by 4 weeks. On the other hand, exercise counteracted
development of denervation atrophy. The safety margin of transmission in runners
was higher than in nonrunners at 4 weeks, indicating enhanced maturation, but
was lower at 2 months of reinnervation. These results suggest that recovery of
muscle precedes maturation of synaptic transmission.
Becker M.H., Lassner F.,
Dagtekin F.Z., Walter G.F., and Berger A. (1995) Morphometric changes in free
neurovascular latissimus dorsi flaps: an experimental study. Microsurgery 16,
786-792.
Abstract: This study was designed to investigate regeneration of reinnervated,
free transplanted muscles. We used a rat model, consisting of eight rats per
group, in which the latissimus dorsi muscle was transplanted orthotopically and
then harvested and evaluated after 2 and 12 weeks. Age-matched control animals
were used to oppose non-operated muscles. At date of removal the patency of the
vascular anastomoses was checked clinically and histologically.
Electrophysiological measurements were also performed and conventional and
enzyme histochemical histological slides manufactured. Two weeks after the free
neurovascular flap transfer the muscle was not yet innervated, and
histologically a dissolved pattern of type 1 and type IIA muscle fibres was
found. The muscle fibres demonstrated a decrease of more than 50%
cross-sectional area. After 12 weeks the muscles were reinnervated again; muscle
contraction was positive with electrical stimulation and the cross- sectional
area had regained 80% of the activity of normal muscle fibres. With enzyme
histochemical staining the typical type grouping of reinnervated muscles could
be demonstrated
Becker M.H., Lassner F.,
Dagtekin F., Walter G.F., and Berger A. (1995) [Muscle-specific changes in free
latissimus dorsi transplantation in the rat model]. Handchir. Mikrochir. Plast.
Chir 27, 93-97.
Abstract: The aim of this study is to gain further knowledge concerning the
regeneration of reinnervated, freely transplanted muscles. Therefore, we used a
rat model, consisting of eight rats per group, in which the latissimus dorsi
muscle was transplanted orthotopically, after a period of time of two and twelve
weeks harvested, then evaluated histologically and enzyme-histochemically. As
controls we used a group of non-operated muscles. At date of removal, the
patency of the vascular anastomoses was checked clinically and histologically.
Additionally, electrophysiological measurements and conventional and enzyme-histochemical
histologies were performed. Two weeks after the free neurovascular flap
transplantation, the muscle was not innervated yet, histologically a dissolved
pattern of type 1 and type 2 muscle fibers was found. After twelve weeks of
time, the muscles were reinnervated again, muscle contraction was positive
Bennett R.L., Knowlton G.C.
(1958) Overwork weakness in partially denervated skeletal muscle. Clin Orthop
12, 22-29.
Bensman A. (1970) Strenuous
exercise may impair muscle function in Guillain-Barre patients. JAMA
214:468-469.
Blaskey J, Broder C,
Montgoamery J, Parker K, Pohl P (1986) Therapeutic Management of Patients
with Guillain-Barre Syndrome. Professional Staff Association of Rancho Los
Amigos Medical Center, Inc., Downey, CA.
Bowen J.M. (1977)
Denervation in the Canine Pectineus Muscle: Quantitative EMG Analysis of Its
Time Course. Arch Phys Med Rehabil 58, 339-344.
Chamberlain L.J., Yannas
I.V., Hsu H.P., Strichartz G.R., and Spector M. (2000) Near-terminus axonal
structure and function following rat sciatic nerve regeneration through a
collagen-GAG matrix in a ten-millimeter gap. J. Neurosci. Res. 60, 666-677.
Abstract: The objectives of this study were to evaluate the regenerated axon
structure at near-terminal locations in the peroneal and tibial branches 1 year
following implantation of several tubular devices in a 10-mm gap in the adult
rat sciatic nerve and to determine the extent of recovery of selected sensory
and motor functions. The devices were collagen and silicone tubes implanted
alone or filled with a porous collagen-glycosaminoglycan matrix. Intact
contralateral nerves and autografts were used as controls. Nerves were retrieved
at 30 and 60 weeks postoperatively for histological evaluation of the number and
diameter of regenerated axons proximal and distal to the gap and in the tibial
and peroneal nerve branches, near the termination point. Several functional
evaluation methods were employed: gait analysis, pinch test, muscle
circumference, and response to electrical stimulation. A notable finding was
that the matrix-filled collagen tube group had a significantly greater number of
large-diameter myelinated axons (> or =6 microm in diameter) in the distal nerve
branches than any other group, including the autograft group. These results were
consistent with previously reported electrophysiological measurements that
showed that the action potential amplitude for the A fibers in the matrix-
filled collagen tube group was greater than for the autograft control group.
Functional testing revealed the existence of both sensory and motor recovery
following peripheral nerve regeneration through all devices; however, the tests
employed in this study did not show differences among the groups with
regeneration. Electrical stimulation in vivo showed that threshold parameters to
elicit muscle twitch were the same for reinnervating and control nerves. The
investigation is of importance in showing for the first time the superiority of
a specific fully resorbable off-the-shelf device over an autograft for bridging
gaps in peripheral nerve, with respect to the near-terminus axonal structure
Cole B.G. and Gardiner P.F.
(1984) Does electrical stimulation of denervated muscle, continued after
reinnervation, influence recovery of contractile function? Exp. Neurol. 85,
52-62.
Abstract: The study was conducted to determine if daily electrical stimulation
of denervated muscle, initiated the day following crush denervation and
continued for 8 weeks (i.e., 5 weeks after presumptive reinnervation), would
influence denervation-associated alterations in muscle size and in situ
contractile properties of rat gastrocnemius. A stimulation protocol of brief,
strong, isometric contractions was designed to maximize the beneficial effects
as described by previous authors. By 8 weeks after crush, unstimulated muscles
were still significantly lighter in wet weight, were tetanically weaker, and
showed slower isometric contractile responses in situ than controls. Denervated
muscles which had been stimulated daily were heavier and tetanically stronger
(the latter not different from controls) than those in the nonstimulated group.
Muscle weights from groups of animals killed at 2 or 4 weeks after nerve crush
indicated the major benefit of stimulation occurred during this initial 4-week
period. In situ fatigue properties were unaffected by denervation or
stimulation. A protocol of electrical stimulation-evoked strong contractions,
initiated soon after denervation and continued after reinnervation, was
effective in attenuating the strength-related, but not speed-related, changes in
neuromuscular function resulting from denervation. These latter changes are
presumably the result of loss of "neurotrophic influence" and/or continuous
low-tension muscle activity lost as a result of denervation
Cope T.C., Bonasera S.J.,
and Nichols T.R. (1994) Reinnervated muscles fail to produce stretch reflexes.
J. Neurophysiol. 71, 817-820.
Abstract: 1. We studied the stretch-evoked reflex organization of hind limb
muscles in two decerebrate cats 36 mo after unilateral section and immediate
surgical repair of the common nerve supplying the lateral gastrocnemius (LG) and
soleus (S) muscles. 2. The production of considerable reflex force by
reinnervated muscles in response to electrical stimulation of uninjured nerves
indicated substantial functional recovery of motor units. However, reduction in
the responsiveness of reinnervated muscles to stretch of the untreated medial
gastrocnemius (MG) muscle indicated some deficit in recovery of normal synaptic
integration. 3. Stretch failed to elicit autogenic excitation of the
reinnervated S and LG. This failure was observed whether the reinnervated
muscles were quiescent or contracting in other reflexes. 4. The heterogenic
reflex organization of reinnervated muscles was abnormal. Stretch of the
reinnervated S failed to evoke heterogenic reflexes both in the untreated MG and
in the reinnervated LG. Stretch of the reinnervated LG failed to produce
excitation of MG. 5. These findings demonstrate deficiencies in proprioceptive
feedback from reinnervated muscles and lead us to expect incomplete recovery of
motor function after nerve section
Cossu G., Valls-Sole J.,
Valldeoriola F., Munoz E., Benitez P., and Aguilar F. (1999) Reflex excitability
of facial motoneurons at onset of muscle reinnervation after facial nerve palsy.
Muscle Nerve 22, 614-620.
Abstract: We studied 18 patients with complete unilateral denervation of the
facial muscles after idiopathic facial nerve palsy to determine whether
motoneuronal excitability is enhanced in the few motor units that are active at
onset of muscle reinnervation. The study was carried out between 75 and 90 days
after the facial nerve lesion. We used two needle electrodes to record
simultaneously the spontaneous and voluntary activity of the orbicularis oris (OOris)
and orbicularis oculi (OOculi) muscles, as well as the responses to ipsilateral
and contralateral facial and supraorbital nerve stimuli. All patients showed
involuntary firing of motor unit action potentials (MUAPs) in at least one of
the muscles. Synkinetic activation of motor units in the OOris was induced by
spontaneous blinking in all patients, and by inhalation and swallowing in some.
Electrical stimulation of the ipsilateral facial nerve induced a direct M
response in only 4 patients. In contrast, long-latency reflex responses were
induced in both muscles by electrical stimulation of ipsilateral and
contralateral facial and supraorbital nerves in all patients, at latencies
ranging between 44 and 132 ms. The shape of such MUAP reflex responses was the
same as that of the MUAPs seen to fire at rest. These findings provide evidence
of enhanced excitability of facial motoneurons in our patients. Such
hyperexcitability may be partly responsible for the postparalytic motor
dysfunction syndrome that occurs after facial palsy with severe axonal damage
Daniel R.K., Egerszegi E.P.,
Samulack D.D., Skanes S.E., Dykes R.W., and Rennie W.R. (1986) Tissue
transplants in primates for upper extremity reconstruction: a preliminary
report. J. Hand Surg. [Am. ] 11, 1-8.
Abstract: Recent advances in clinical transplantation surgery suggest that hand
transplantation is no longer an unrealistic expectation. However, two questions
must be answered. Can composite tissue transplants survive in a primate species?
Does the required neural reinnervation occur under immunosuppression? Four hand
transplants and seven neurovascular free flap transplants were done in baboons
immunosuppressed with Cyclosporin A and steroids (methylprednisolone). Long-term
survival occurred in nine. Electrophysiologic tests of sensory axons revealed
reinnervation of transplanted skin as evidenced by well-defined, low threshold
receptive fields in the donor tissue. Reinnervation of donor muscle was
demonstrated by motor unit recruitment in stepwise fashion after electrical
stimulation of the recipient's median and ulnar nerves. Afferent fibers serving
the donor's joints and muscle spindles were also observed
de Bisschop G. (1983)
[Strategy for the prevention and treatment of post-paralytic facial syncinesis].
Ann. Otolaryngol. Chir Cervicofac. 100, 581-586.
Abstract: The existence of facial heimspasm and post-paralytic syncinesia is in
general interpreted as the result of aberrant reinnervation following a Bell's
palsy. In a certain number of cases, electrophysiological tests reveal synaptic
abnormalities in the facial nucleus. These findings must be taken into
consideration, together with the possibility of ephapsic stimulation of the
proximal part of the facial nerve, when explaining the regression of syncinesia
which is found in certain patients during the reinnervation phase. Prevension is
based principally upon the quality of treatment and the rapidity with which both
electrophysiological testing is undertaken and treatment started. It is
important to avoid treatment aimed at accelerating reinnervation (neuronotrophic
factors, dielectrolysis, etc . . . The process should take place naturally.
Electrical stimulation, administered under conditions of choice of current on
the basis of the lesion, experimentally prevents dissemination of reinnervation.
Repeated evaluation of possible diffusion of the blink reflex can be used to
detect sub-clinical stages of progression to syncinesia. It would seem necessary
to review from a particular standpoint the organised programming of
physiotherapy and its association with biofeedback-EMG techniques. If signs of
syncinesia develop, appropriate physiotherapy, biofeedback-EMG techniques and
contralateral strio-motor electrotherapy combined with sedative and
anti-paroxysmal therapy should be started
Eberstein A. and Pachter B.R.
(1986) The effect of electrical stimulation on reinnervation of rat muscle:
contractile properties and endplate morphometry. Brain Res. 384, 304-310.
Abstract: Denervated extensor digitorum longus muscles of Wistar rats were
electrically stimulated in vivo for 4 days (2h per day) after peroneal nerve
crush 1 cm from the muscle. Isometric contractile properties and endplate
ultrastructure were measured on days 11 and 18. On day 11, the time to peak
(116% of control) and 1/2-relaxation time (136% of control) for the twitch
tensions of stimulated muscles measured in vivo were significantly less than
those (127% and 157% of controls, respectively) of non-stimulated muscles. Peak
twitch and tetanic tensions were not significantly different. The postsynaptic
area of endplates for stimulated muscles were closer in size to controls than
those for the non-stimulated ones. On day 18, no difference was found in the
contractile responses between stimulated and non-stimulated groups. Similarly,
the postsynaptic areas were the same for both groups. These results demonstrate
that denervated muscle stimulated electrically for 4 days prior to reinnervation
can preserve the structure of the endplate as well as accelerate recovery of
normal function in reinnervated muscle fibers after 11 days of denervation
Erb D.E., Mora R.J., and
Bunge R.P. (1993) Reinnervation of adult rat gastrocnemius muscle by embryonic
motoneurons transplanted into the axotomized tibial nerve. Exp. Neurol. 124,
372-376.
Abstract: In some cases of spinal cord injury and in certain motoneuron
diseases, such as amyotrophic lateral sclerosis and spinal muscular atrophies,
lower motoneurons are destroyed and muscle function cannot be restored except by
reinnervation from alternate motoneuron sources. We have tested the feasibility
of employing local transplantation of embryonic motoneurons to restore
innervation to denervated somatic muscle as a first step in salvaging muscle
function and enabling use of functional electric stimulation. Dissociated
ventral spinal cord cells from Embryonic Days 14 and 15 rats were transplanted
into the distal stump of axotomized tibial nerves of adult rats. Animals were
killed 3-18 weeks after transplantation. After 3 weeks large multipolar cells,
resembling alpha motoneurons, were observed within the transplant site
surrounded by myelinated and unmyelinated axons and dendrites. Axons emanating
from these transplanted motoneurons were identified within the nerve stump and
within the previously denervated gastrocnemius muscle, forming neuromuscular
junctions. Transplanted motoneurons survived up to 18 weeks and were labeled
after intramuscular injection of fast blue. This study demonstrates that
embryonic spinal motoneurons, transplanted into the distal adult peripheral
nerve stump, are able to survive and reinnervate the denervated target muscle.
We are now exploring the possibility of using this experimental approach to
retard the atrophy of denervated skeletal muscle, thus providing a muscle
capable of useful response to functional electrical stimulation
Gaillard S. and Horvat J.C.
(1993) [Model of "bridge" graft between the cervical spinal cord and biceps
muscle using a peripheral nerve autograft. Study in adult rats]. Chirurgie 119,
649-656.
Abstract: The authors present, in the adult rat, a model of reconnection between
an injured cervical spinal cord (C5) and the biceps brachii muscle (BB)
previously denervated, by means of an autologous peripheral nerve segment (PNG).
The study includes 30 rats shared into 4 principal groups: A) the denervation of
BB by transection and ligature of the musculocutaneous nerve (MCN); B)
transection and immediate suture of the MCN; C) transection/ligature of the MCN
and insertion of a PNG both into the cervical spinal cord and into the BB; D)
transection of the MCN, ligature of its proximal tip, insertion of one end of a
PNG into the cervical spinal cord and suture of the other end with the distal
stump of the MCN. Assessment of the following parameters were performed, in all
animals, three months after the grafting procedure: 1) the muscle strength by
using the toilet test; 2) the weight of the experimental BB in comparison to the
contralateral BB; 3) the response (contraction) of the BB under electrical
stimulation of either the MCN or the PNG; 4) the histological appearance of the
BB; 5) the presence of retrogradely labelled neuronal somata in the cervical
spinal cord following application of horseradish peroxidase (HRP) to the MCN or
to the GNP. These parameters of evaluation have at first been validated in two
cases already known: the chronic denervation of the BB (group A), and the
peripheral nerve lesion (group B). Once these cases validated, they have been
used to appreciate the muscular reinnervation by axonal growth from the spinal
cord.(ABSTRACT TRUNCATED AT 250 WORDS)
Gordon T. and Mao J. (1994)
Muscle atrophy and procedures for training after spinal cord injury. Phys. Ther.
74, 50-60.
Abstract: Functional electrical stimulation (FES) of paralyzed muscles holds
promise as a strategy to assist patients in executing functional movements after
spinal cord injuries. Muscle atrophy is one of the major problems that must be
addressed for this approach to be successful. Loss of muscle mass may occur as a
result of lesions to motoneurons in either the spinal cord or the central
command pathway, or a combination of the two. For injuries to spinal motoneurons,
muscle fibers undergo denervation atrophy. Damage to the central command
pathway, on the other hand, results in disuse atrophy. In association with
atrophy, the low contractile forces and inability of the muscles to sustain
contractions are of direct therapeutic concern. In this review, methods aimed at
recovery of function of paralyzed limbs by reducing susceptibility to fatigue
and atrophy of paralyzed muscles are discussed. One is related to promoting
nerve sprouting in partially denervated muscles to reinnervate muscle fibers and
reverse denervation atrophy. The other regards training of paralyzed muscles to
increase strength (muscle force) and endurance (fatigue resistance) by means of
FES. Most training regimens with low-frequency FES increase muscle endurance.
Efforts to design optimal regimens for increasing both muscle strength and
endurance must involve consideration of several factors that are still
controversial. These factors, which include muscle properties (such as fiber
type composition and physiological type) and conditions imposed on the muscle
(such as loading) during contractions elicited by FES, are discussed in detail
Gordon T. (1995) Fatigue in
adapted systems. Overuse and underuse paradigms. Adv. Exp. Med. Biol. 384,
429-456.
Abstract: Alterations in structural and biochemical properties of muscles that
underlie physiological parameters of contractile force, speed and fatigability
are described under conditions of 1) overuse: imposed electrical stimulation,
natural exercise and functional overload; 2) reinnervation of denervated
muscles; and 3) underusage: conditions of restricted use after spinal cord
injury, weightlessness, immobilization and drug-induced neuromuscular blockade.
These conditions demonstrate the remarkable plasticity of muscle fibers with
obvious implications in health and disease. They also identify that the amount
of neuromuscular activity and loading of muscle contractions are major factors
determining susceptibility to fatigue and muscle strength, respectively
Green D.C., Berke G.S., and
Graves M.C. (1991) A functional evaluation of ansa cervicalis nerve transfer for
unilateral vocal cord paralysis: future directions for laryngeal reinnervation.
Otolaryngol. Head Neck Surg. 104, 453-466.
Abstract: There are a variety of methods for treating unilateral vocal cord
paralysis, but to date there are few objective studies that evaluate the
functional results of nerve transfer from the ansa cervicalis. Six dogs
underwent unilateral recurrent laryngeal nerve section with immediate
reanastamosis to the sternothyroid branch of the ansa cervicalis. After 5 to 6
months, measurements of vocal efficiency and acoustic parameters,
videolaryngoscopy, videostroboscopy, and evoked electromyography were performed.
Identical measurements were made in eight control dogs during normal
electrically induced phonation and a simulated unilateral recurrent laryngeal
nerve paralysis. Histologic analysis of both vocalis muscles, recurrent
laryngeal nerves, ansa cervicalis, and the ansa-recurrent laryngeal nerve
anastamosis site was performed. Evidence of reinnervation was found in all of
the animals that underwent nerve transfer. The vocal efficiency and acoustic
quality after ansa cervicalis nerve transfer were dependent on the degree of
electrical stimulation from the transferred nerve to the reinnervated cord
during phonation. In the absence of electrical stimulation to the nerve
transfer, physiologic vocal cord motion could not be elicited from the
reinnervated cord
Gurney M.E. (1984)
Suppression of sprouting at the neuromuscular junction by immune sera. Nature
307, 546-548.
Abstract: Injury of afferent motor axons or pathological loss of motoneurones
from the spinal cord causes the remaining axons within a muscle to sprout and to
reinnervate the denervated muscle fibres. Sprouting occurs at two sites along
intramuscular axons, at nodes of Ranvier (nodal sprouting) and at the
neuromuscular junction (terminal sprouting). Terminal sprouting is also produced
by treatment with botulinum toxin and by other agents that render muscle
inactive. The muscle probably provides a signal for terminal sprouting as
restoration of muscle activity by direct electrical stimulation prevents
sprouting. Such a signal might be a local change on the muscle fibre surface or
a 'soluble' sprouting factor, although the failure to induce terminal sprouting
in one muscle by denervating adjacent muscles argues against the latter
hypothesis. I now report that rabbit antisera against a 56,000 (56K)-molecular
weight protein secreted by denervated rat muscle suppress botulinum
toxin-induced terminal sprouting in the mouse gluteus muscle. An immune response
against this protein has also been detected in serum of patients with
amyotrophic lateral sclerosis (ALS), a disease in which loss of motoneurones
from the spinal cord is not accompanied by the degree of sprouting and
reinnervation seen in other motoneurone diseases
Herbison G.J., Teng C.S.,
and Gordon E.E. (1973) Electrical stimulation of reinnervating rat muscle. Arch.
Phys. Med. Rehabil. 54, 156-160.
Herbison G.J., Jaweed M.M.,
Ditunno J.F., Scott C.M. (1974) Overwork of Denervated Skeletal Muscle. Arch
Phys Med Rehabil 55, 202-205.
Herbison G.J., Jaweed M.M.,
Ditunno J.F. (1974) Effect of swimming on reinnervation of rat skeletal muscle.
J Neurol, Neurosurg & Psychiat 37, 1247-1251.
Herbison G.J., Jaweed M.M.,
Ditunno J.F. (1980) Effect of activity on reinnervating rat skeletal muscle
contractility. Exp Neurol 70, 498-506.
Herbison G.J., Jaweed M.M.,
Ditunno J.F. (1980) Histochemical Fiber Type Alterations Secondary to Exercise
Training of Reinnervating Adult Rat Muscle. Arch Phys Med Rehabil 61,
255-257.
Herbison G.J., Jaweed M.M.,
Ditunno J.F. (1981) Contractile Properties of Reinnervating Skeletal Muscle in
the Rat. Arch Phys Med Rehabil 62, 35-39.
Herbison G.J., Jaweed M.M.,
Ditunno J.F. (1982) Reinnervating Rat Skeletal Muscle: Effect of 35% Grade
Treadmill Exercise. Arch Phys Med Rehabil 63, 313-316.
Herbison G.J., Jaweed M.M.,
and Ditunno J.F., Jr. (1983) Exercise therapies in peripheral neuropathies.
Arch. Phys. Med. Rehabil. 64, 201-205.
Abstract: The treatment of peripheral neuropathies should be aimed at
maintaining the range of motion of the joints, re-educating the patient in
skilled activities and optimizing the recovery of strength. Many techniques have
been described to substitute for, to strengthen and to improve the function of
residual innervated muscle; however, not all of these techniques are of
unquestioned value. Specifically, electrical stimulation does not appear to
enhance reinnervation of totally denervated muscle. Similarly, overstretching
weakened muscle may impair the use of paretic muscle. Because overwork may
damage partially denervated muscle, brief isometric or isotonic contractions may
be more beneficial for increasing strength than a program of habitual exhausting
activities
Herbison G.J., Jaweed M.M.,
and Ditunno J.F., Jr. (1983) Acetylcholine sensitivity and fibrillation
potentials in electrically stimulated crush-denervated rat skeletal muscle.
Arch. Phys. Med. Rehabil. 64, 217-220.
Abstract: Juxtamuscular electrodes were implanted unilaterally in six groups of
adult female Wistar rats to evaluate the effect of chronic electrical
stimulation (ES) during denervation and reinnervation of the rat soleus muscle.
Two weeks later, the animals underwent bilateral crush- denervation of the
sciatic nerve at the sciatic notch. Six additional groups served as normal
controls. The soleus muscles in the crush denervated and control groups were
stimulated unilaterally with a 4mA, 4msec duration current given at 10Hz
continuously 8 hours each day for 5, 10, 15, 20, 25 or 30 days. At the end of
each period, the soleus muscles were evaluated for the muscle weights,
acetylcholine (ACh) sensitivity and fibrillation potentials (FPs). The normal
muscles were unaffected by the stimulation. The denervated-stimulated soleus
muscles were heavier at 10 days (p less than 0.05) and had fewer FPs after 5 to
15 days (p less than 0.01) of electrical stimulation than their matched
denervated controls. The ACh sensitivity throughout the experimental period and
the fibrillatory activity from 20 to 30 days post-crush were similar in the
denervated and the denervated-stimulated muscles. In conclusion, ES reduced the
degree of atrophy and the number of fibrillations of the soleus muscle in the
denervation stage. However, it neither enhanced nor impaired the reinnervation
of muscle
Herbison G.J., Jaweed M.M.,
Ditunno J.F. (1986) Electrical Stimulation of Sciatic Nerve of Rats After
Partial Denervation of Soleus Muscle. Arch Phys Med Rehabil 67, 79-83.
Herrmann V. and Bergmann K.
(1987) [Long-term experimental electric stimulation of denervated laryngeal
muscles in dogs. Myopathologic findings]. Zentralbl. Allg. Pathol. 133, 337-350.
Abstract: The recurrent laryngeal nerve was transsected unilaterally and a
device for electrical stimulation of the denervated muscles was implanted in 6
dogs. After 3 to 11 months the laryngeal muscles were obtained and
histopathologically demonstrated a striking neurogenic pattern. In place of
homogeneous muscle fiber atrophy, a patchwork of grouped fibre atrophy,
compensational hypertrophy, fibre regeneration and reinnervation as well as
muscle fibre type grouping were observed. Muscle fibre type distribution in the
m. cricoarytenoideus posterior, m. vocalis and m. cricothyroideus was determined
and compared between the normal and denervated sites. All muscles showed some
changes in the fibre type distribution, including type grouping, but these were
most pronounced in m. vocalis. The average fibre diameter decreased whereas
fibre size variability increased. Mixed muscle fibre atrophy with compensatory
hypertrophy of a single fibre type predominated. There was no evidence of disuse
atrophy. The electrically stimulated muscles could be maintained at a reduced
functional level throughout the study period
Jaweed M.M., Herbison G.J.,
and Ditunno J.F. (1982) Direct electrical stimulation of rat soleus during
denervation- reinnervation. Exp. Neurol. 75, 589-599.
Kinney C.L., Jaweed M.M.,
Herbison G.J., Ditunno J.F. (1986) Overwork effect on partially denervated rat
soleus muscle. Arch Phys Med Rehabil 67:286-289.
Koerber H.R. and Mirnics K.
(1996) Plasticity of dorsal horn cell receptive fields after peripheral nerve
regeneration. J. Neurophysiol. 75, 2255-2267.
Abstract: 1. The tibial and sural nerves were transected and repaired in nine
adult cats. The receptive field (RF) properties of dorsal horn neurons were
examined at three different intervals (5-6, 9, or 12 mo) after axotomy. The
properties examined included RF location, area, and modality convergence. In
some cases, discrete areas of the cell's RF were stimulated electrically while
the evoked cord dorsum potentials (CDPs) and any intracellularly recorded
responses were simultaneously recorded. 2. At the shortest interval following
reinnervation, the somatotopic organization in the affected areas of the dorsal
horn was lost. Dorsal horn cells that received input primarily from regenerated
fibers had large, low-threshold excitatory RFs that contained much of the
reinnervated skin. Those cells with RFs restricted to a fraction of the
reinnervated skin had significant components of their RFs on the foot dorsum
supplied by intact fibers (i.e., superficial peroneal nerve). 3. At longer
intervals the somatotopic organization remained scrambled. Dorsal horn cell
low-threshold RFs were significantly reduced in size. Many cells exhibited large
areas of excitatory subliminal fringe and concise inhibitory RFs. In addition,
those cells that responded to peripheral stimuli across a wide range of stimulus
intensities (wide-dynamic-range cells) also exhibited plasticity in the relative
sizes of their low- and high-threshold RFs. 4. At the shortest recovery time,
focal electrical stimulation of the skin within the RF of an impaled cell and
simultaneous recordings of the evoked CDPs and postsynaptic potentials revealed
that at numerous locations within the initial large RFs, single fibers or small
groups of fibers could be electrically activated that were not connected to the
dorsal horn cell. At the longer recovery times there was a much higher incidence
of connectivity. 5. These results suggest that mechanisms affecting both
synaptic efficacy of afferent fiber connections and/or the establishment of
afferent-driven inhibitory inputs may effect the reshaping of dorsal horn cell
RFs after reinnervation. These results are discussed in relation to their
potential contribution to previously observed cortical plasticity and functional
recovery following similar lesions
Koller R., Happak W., Frey
M., Neumayer C., Girsch W., Liegl C., and Gruber H. (1997) [Comparative studies
of morphometric and functional results following reconstruction of motor
nerves]. Handchir. Mikrochir. Plast. Chir 29, 330-334.
Abstract: In order to determine the value of a reconstructive procedure in the
peripheral nerve, experimental studies often evaluate the number and the
diameter of myelinated nerve fibers as a parameter for the quality of
regeneration. This study addresses the correlation between the number of fibers
in a peripheral motor nerve after microsurgical reconstruction and the
functional result, expressed as the force of the reinnervated muscle. In a total
number of 24 sheep, the motor branch to the rectus femoris muscle was severed.
The muscle was reinnervated either by direct neurorrhaphy or by nerve grafting,
performed in three different ways (free grafting to the ipsilateral muscle, free
grafting to the contralateral muscle, vascularized grafting to the ipsilateral
muscle). In the final experiments, the muscle force in the reinnervated muscle
was determined by supramaximal electrical stimulation. Number and diameter of
myelinated nerve fibers were evaluated by computer- assisted morphometric
analysis. Regression analysis of morphometric data and the muscle forces was
calculated. No correlation was found between fiber numbers in the nerve graft
and the maximal force. However, a positive correlation between the number of
myelinated fibers in the motor branch distal to the site of coaptation and the
functional result was observed in some cases. The diameter of myelinated fibers
had no influence on the functional outcome
Lewis D.M., al Amood W.S.,
and Schmalbruch H. (1997) Effects of long-term phasic electrical stimulation on
denervated soleus muscle: guinea-pig contrasted with rat. J. Muscle Res. Cell
Motil. 18, 573-586.
Abstract: Guinea-pig soleus muscles were denervated and electrically stimulated
for periods of 43 to 66 days. Stimuli were in 1 s bursts of 40 Hz pulses,
repeated every 5 min. Other guinea-pigs were denervated for 82 days without
stimulation and, in a third group, the soleus muscle was necrotized and allowed
to regenerate without reinnervation for 13-15 days. Isometric and isotonic
recordings were made in vivo. Denervated guinea-pig muscles were embedded in
epoxy resin for light and electron microscopy. Chronic stimulation of denervated
guinea-pig soleus had no effects on the prolonged twitch or on reduced maximal
shortening velocity, maximal rate of rise of tension and tetanic force. This
contrasts with the slow-to-fast conversion produced by denervation and
denervation-stimulation of rat soleus. Loss of force was much greater in rat
than guinea-pig after denervation, and chronic stimulation increased force in
rat to the same level as in guinea-pig after denervation (with or without
stimulation). Eighty-day denervated guinea- pig soleus did not reveal those
morphological signs of fibre breakdown and regeneration which are prominent in
denervated rat soleus muscles. Those changes in rat resembled aneurally
regenerated muscles in several aspects, especially the increased incidence of
fibres with internal myo- nuclei which did not appear in guinea-pig soleus after
denervation. Aneurally regenerated guinea-pig soleus became fast like aneurally
regenerated rat muscle. Our data are compatible with the hypothesis that
slow-to-fast transformation of denervated rat soleus is not directly brought
about by chronic stimulation but by de-novo formation of fast-contracting
regenerated fibres. The persistence of fibrillation in guinea-pig but not rat
after denervation may account for the species difference
Lieber R. (2002) Skeletal
Muscle Structure, Function and Plasticity: the Physiological Basis of
Rehabilitation, Ed 2. Philadelphia, Lippincott, Williams & Wilkins, pp
271-274.
Matsushita H. (1989)
[Changes in concentrations of nerve- and muscle-related proteins during
reinnervation of slow and fast muscles]. Aichi. Gakuin. Daigaku Shigakkai. Shi
27, 397-413.
Abstract: The concentration of the nerve-related (gamma-enolase) and muscle-
related (beta-enolase and creatine kinase of B type) proteins was measured in
the rat sciatic nerve and the muscles; soleus (SOL), a typical slow-twitch
muscle, and extensor digitorum longus (EDL), a typical fast-twitch muscle. The
nerves and muscles were subjected to experimental manipulation of their
innervation. 1. Nerve-related protein, gamma-enolase. The concentration of
gamma-enolase in the distal part of the transected sciatic nerve was decreased
in 2 weeks to about 10% of normal. When the sciatic nerve was sutured
immediately after the transection, the concentration of gamma-enolase recovered
in 34 weeks to a level of about 62.8% of normal. 2. Fast muscle-related protein,
beta-enolase. The concentration of the beta-enolase in the SOL and the EDL was
reduced after sciatic nerve transection. When the sciatic nerve was sutured
immediately after complete transection, the concentration of beta-enolase of SOL
and EDL became almost equal on the 34th week. After cross union of the nerves
innervating the SOL and EDL muscles, the concentration of the beta-enolase were
almost equal on the 20th post-operative week in the both muscles, and reversed
on the 34th week. The beta-enolase concentrations in the SOL and EDL muscles
innervated by the TTX-perfused sciatic nerve were reduced to 72.3% and 70.4%,
respectively. Continuous electrical stimulation of the sciatic nerve reduced the
beta-enolase concentration in the EDL to 51.8% of normal, but did not affect the
SOL significantly. 3. Slow muscle- related protein, creatine kinase of B type
(CK-B). After complete severance of the sciatic nerve the CK-B concentration
showed a marked increase in the both muscles. When the sciatic nerve was sutured
immediately after transection, the CK-B concentration on the 34th week was about
35.3% in the SOL and close to normal in the EDL. On the 34th week after cross
union of the nerves innervating the SOL and EDL muscles, the CK-B concentration
was reduced to about 41.1% in the SOL, while it was increased to about 111% in
the EDL. On the 20th week after self re-union of the nerves innervating the SOL
and EDL muscles, the CK- B concentration in the EDL recovered the normal level,
but in the SOL muscle it was increased significantly. 4. It appears that the
measurement of the concentration of gamma-enolase, beta-enolase and CK- B can
provide valuable informations on the recovery course of skeletal muscles after
nerve injury
McCallister W.V., Tang P.,
and Trumble T.E. (1999) Is end-to-side neurorrhaphy effective? A study of axonal
sprouting stimulated from intact nerves. J. Reconstr. Microsurg. 15, 597-603.
Abstract: The purpose of this study was to determine if axonal sprouting across
an end-to-side coaptation could be stimulated and if so, to identify the source
of the regenerating axons. Mechanical trauma, the method used to stimulate
axonal sprouting, was compared to a control group with coaptation only and an
additional non-grafted control group. After a 20-week recovery period,
electrical stimulation revealed that the target muscles had been reinnervated in
all groups except the non- grafted control group. Axonal counting demonstrated a
significant increase for the mechanical trauma group compared to the control
group with coaptation only [ratio of the density of axons/microm2 of the
experimental to the contralateral control side: 2.78+/-0.11 vs. 0.96+/- 0.15,
respectively, p<0.002). Tibialis anterior muscle weights were significantly
increased for both groups vs. the non-grafted control group (ratio of
experimental to the contralateral control side: coaptation-only control,
0.539+/-0.024; mechanical trauma, 0.538+/- 0.036 vs. nongrafted control,
0.220+/-0.003, p<0.002). Of importance, this study provides evidence that the
intact tibial nerve functions as a bridge for regenerating axons derived from
the proximal peroneal stump. This suggests an alternative explanation to
successful end-to- side axonal sprouting, and questions the clinical utility of
end-to- side coaptation
McDevitt L., Fortner P., and
Pomeranz B. (1987) Application of weak electric field to the hindpaw enhances
sciatic motor nerve regeneration in the adult rat. Brain Res. 416, 308-314.
Abstract: Direct current (DC) electrical stimulation of the hindpaw is shown to
enhance sciatic motor nerve regeneration in the adult rat. Cathodal stimulation,
using weak currents (10 microA/cm2; field strength approximately 100 mV/cm)
increased the reinnervation of the hindpaw muscles as measured by evoked
electromyograms. This enhanced regeneration only occurred after cut-and-suture
lesions, but not after crushing injury of the sciatic nerve. This enhancement of
motor nerve regeneration by weak DC fields had been previously described in
amphibians but we are the first to describe this phenomenon in mammals
Montserrat L. and Benito M.
(1990) Motor reflex responses elicited by cutaneous stimulation in the
regenerating nerve of man: axon reflex or ephaptic response? Muscle Nerve 13,
501-507.
Abstract: In 57 of 60 nerves (29 median and 31 ulnar) sutured at the wrist,
forearm and arm, we recorded motor responses in thenar or hypothenar muscles by
electrical stimulation of the corresponding fingers. Recordings were made at
different times during the process of regeneration, ranging from 3 months up to
11 years. The responses showed a constant shape and latency to every stimulation
(simple or repetitive). The latency was shorter the more distal the level of
injury and the greater the elapsed time from the reinnervation. The point of "reflexion"
of the responses is at or very near the line of nerve suture. The
electrophysiological behavior of the responses fits well with either the
criterion of axon reflex or ephaptic response. We discuss both possibilities and
conclude that it is not possible, with the electrophysiological technique that
we used, to distinguish between an axon reflex and an ephaptic response
Nakatsuchi Y., Matsui T.,
and Handa Y. (1980) Funicular orientation by electrical stimulation and internal
neurolysis in peripheral nerve suture. Hand 12, 65-74.
Abstract: Eleven peripheral nerve lacerations around the wrists of ten patients
were treated with funicular suture or nerve graft. In three freshly lacerated
nerves funicular orientation could be made only by electrical stimulation to
both cut ends. The electrophysiological method was also utilised to obtain
funicular orientation of a proximal stump in eight old nerve lacerations.
However, funicular orientation of the distal stump of old lacerations, which was
not responsive to electrical stimulation, was performed anatomically by internal
neurolysis from a terminal branching area up to a distal stump. By six months
after the operation, motor and sensory functions of the patients with funicular
suture had recovered to an excellent degree with rapid reinnervation
Navarro X. and Kennedy W.R.
(1990) Changes in sudomotor nerve territories with aging in the mouse. J. Auton.
Nerv. Syst. 31, 101-107.
Abstract: This study evaluates sudomotor function in the hindpaw of young and
aged mice. Sweating was stimulated by pilocarpine injection and by electrical
stimulation of the sciatic, tibial, peroneal, sural and saphenous nerves. The
number of responsive sweat glands of the paw was determined by the silicon mold
technique. The results obtained provide evidence that the number of functioning
sweat glands of the hindpaw tended to decrease in aged mice. The peripheral
sudomotor territories and the complement of sweat glands for individual nerves
declined slightly with age. Moreover, the number of sweat glands responsive to
cholinergic stimulation was decreased when compared with the number responsive
to electrical stimulation of the sciatic nerve in aged mice. These and previous
observations suggest that the number of sudomotor axons in the peripheral nerve,
as well as their capabilities for compensatory reinnervation of sweat glands by
regeneration and by sprouting, is reduced with aging
Ochi M., Iwasa J., Uchio Y.,
Adachi N., and Sumen Y. (1999) The regeneration of sensory neurones in the
reconstruction of the anterior cruciate ligament. J. Bone Joint Surg. Br. 81,
902-906.
Abstract: We examined whether somatosensory evoked potentials (SEPs) were
detectable after direct electrical stimulation of injured, reconstructed and
normal anterior cruciate ligaments (ACL) during arthroscopy under general
anaesthesia. We investigated the position sense of the knee before and after
reconstruction and the correlation between the SEP and instability. We found
detectable SEPs in all ligaments which had been reconstructed with autogenous
semitendinosus and gracilis tendons over the past 18 months as well as in all
cases of the normal group. The SEP was detectable in only 15 out of 32 cases in
the injured group, although the voltages in the injured group were significantly
lower than those of the controls. This was not the case in the reconstructed
group. The postoperative position sense in 17 knees improved significantly, but
there was no correlation between it and the voltage. The voltage of stable knees
was significantly higher than that of the unstable joints. Our findings showed
that sensory reinnervation occurred in the reconstructed human ACL and was
closely related to the function of the knee
Pachter B.R., Eberstein A.
(1989) Passive Exercise and Reinnervation of the Rat Denervated Extensor
Digitorum Longus Muscle after Nerve Crush. Am J Phys Med Rehabil
68:179-182.
Panenic R. and Gardiner P.F.
(1998) The case for adaptability of the neuromuscular junction to endurance
exercise training. Can. J. Appl. Physiol 23, 339-360.
Abstract: Although the adaptability of the neuromuscular junction (NMJ) has been
demonstrated using the models of denervation/reinnervation, electrical
stimulation, development, aging, and pathological states, relatively little is
known about the effects of increased chronic voluntary use on the morphology and
physiological function of the NMJ. A review of findings relating to adaptations
in the various pre- and postsynaptic components of the NMJ with exercise
training is presented. These findings are discussed as they pertain to NMJ
function during exercise. Other physiological modulators of the NMJ, such as
trophic factors released by nerve terminals and muscles, and circulating
substances are discussed in terms of possible roles they may play in
training-induced adaptations
Reiness C.G., Hogan P.G.,
Marshall J.M., and Hall Z.W. (1977) Factors influencing degradation of
extrajunctional acetylcholine receptors in skeletal muscle. Prog. Clin. Biol.
Res. 15, 207-215.
Abstract: During development and after both denervation and reinnervation in
adult mammalian skeletal muscle, the level of acetylcholine (ACh) receptors in
the extrajunctional membrane undergoes wide variation. We have determined the
rate of extrajunctional receptor degradation in denervated muscles in organ
culture under a variety of conditions by measuring the rate at which alpha-bungarotoxin
bound to the receptors is degraded. Direct electrical stimulation of muscles for
several days dramatically reduced the levels of extrajunctional ACh sensitivity,
and also reduced the rate of receptor degradation. Since the effect of activity
on the rate of receptor degradation is in the opposite direction of the observed
change in receptor levels, we conclude that activity must also decrease the rate
of receptor synthesis. Receptor degradation was also examined in muscles at
various times after denervation. The half-time of degradation increased from
approximately 7 hr at 2-5 days after denervation to approximately 14 hr at 10-14
days. Hypophysectomy, which decreases the average rate of protein degradation in
muscle, also decreased the rate of extrajunctional receptor degradation, but
thyroxine, which restores the normal rate of overall protein breakdown in
hypophysectomized animals, did not affect receptor breakdown. Since
hypophysectomy did not increase the level of extrajunctional ACh receptors, it
must also affect ACh receptor synthesis
Salmons S. and Sreter F.A.
(1976) Significance of impulse activity in the transformation of skeletal muscle
type. Nature 263, 30-34.
Abstract: The changes which follow cross reinnervation of mammalian fast and
slow twitch muscles may reflect a capacity of skeletal muscle to respond
adaptively to different functional requirements. This interpretation is
supported by experiments in which long-term electrical stimulation was used both
to reproduce and to oppose the effects of cross reinnervation
Sanes J.R., Covault J.
(1985) Axon guidance during reinnervation of skeletal muscle. Trends in
Neurosciences 8:523-528.
Sanes J.R., Lichtman J.W.
(1999) Development of the vertebrate neuromuscular junction. Annual Review of
Neuroscience 22:389-442.
Schimrigk K., McLaughlin J.,
and Gruninger W. (1977) The effect of electrical stimulation on the
experimentally denervated rat muscle. Scand. J. Rehabil. Med. 9, 55-60.
Abstract: The m. quadriceps of white rats was electrically stimulated after
nerve crush and after nerve section. Electrically stimulated muscles showed
fewer central nuclei and a greater number of necrotic single fibres. The
demonstration of motor endplates could not give a reliable indication of the
onset of reinnervation. The various results show the importance of the trophic
influence of the nerve and raise the suspicion that electrical stimulation has a
retarding effect on the atrophy but also on regeneration of the fibres. After 7
weeks the unstimulated muscles show a greater degree of regeneration than the
stimulated ones
Smith K.J. and Kodama R.T.
(1991) Reinnervation of denervated skeletal muscle by central neurons
regenerating via ventral roots implanted into the spinal cord. Brain Res. 551,
221-229.
Abstract: The reinnervation of denervated skeletal muscle by central axons
regenerating via a ventral root implanted into the spinal cord was examined in
rats. The 8th thoracic ventral root was severed and its distal end implanted
into the ventro-lateral column of the spinal cord via a stab incision. In
control animals the root was severed, but was not implanted into the stab
incision. After 12-14 months the animals were examined electrophysiologically to
determine the presence or absence of motor units in the 8th intercostal muscle
which were reinnervated by centrally derived axons regenerating via the implant.
Such units were found in implanted animals, but in none of the controls.
Evidence that the motor units were reinnervated by central axons included the
facts that the units could be activated either, (1) reflexly (i.e. trans-synaptically)
by electrical stimulation of the dorsal roots or spinal cord, or (2)
pharmacologically by either the intraspinal injection of glutamate or
acetycholine, or by the systemic administration of strychnine. Great care was
taken to ensure that the only feasible connection between the spinal cord and
the 8th intercostal muscle was via the site of implantation. The EMG signals
from the motor units were of large amplitude, typical of reinnervated muscle,
and their individual activation resulted in discernible contractions of regions
of the T8 intercostal muscle. We conclude that regenerating CNS neurons can be
guided to innervate denervated skeletal muscle by the implantation of severed
ventral roots into the spinal cord. The neuromuscular synapses formed are
functional and persistent. The findings may be relevant to the restoration of
function after nervous injuries, such as the avulsion of ventral roots
Soucy M., Seburn K.,
Gardiner P. (1996) Is increased voluntary motor activity beneficial or
detrimental during the period of motor nerve regeneration/reinnervation? Can
J Appl Physiol
21:218-224.
Abstract: A model
of partial denervation of the rat lateral gastrocnemius was used to investigate
the effects of daily activity (treadmill plus voluntary wheel exercise) on the
regeneration/ reinnervation of motoneurons recovering from nerve crush. It
appears that increased activity has no effect on axon regeneration rate, but may
be detrimental to the reinnervation process.
Stanco A.M. and Werle M.J.
(1998) Agrin and acetylcholine receptor distribution following electrical
stimulation. Muscle Nerve 21, 407-409.
Abstract: Electrical stimulation is a therapeutic modality available for the
preservation of muscle function following peripheral nerve injury. Agrin, a
synaptic basal lamina protein, induces accumulation of acetylcholine receptors (AChRs)
and other molecules at the neuromuscular junction. Electrical stimulation of
denervated muscle does not alter agrin and AChR distribution at abandoned
synaptic sites, supporting the hypothesis that the existing aggregation of
synaptic molecules, which may be necessary for successful reinnervation, is
unaltered by electrical stimulation of denervated muscle
Tam S.L., Archibald V.,
Jassar B., Tyreman N., Gordon T. (2001) Increased neuromuscular activity reduces
sprouting in partially denervated muscles. J Neurosci 21:654-667.
Targan R.S., Alon G., and
Kay S.L. (2000) Effect of long-term electrical stimulation on motor recovery and
improvement of clinical residuals in patients with unresolved facial nerve
palsy. Otolaryngol. Head Neck Surg. 122, 246-252.
Abstract: PURPOSE: This study investigated the efficacy of a pulsatile
electrical current to shorten neuromuscular conduction latencies and minimize
clinical residuals in patients with chronic facial nerve damage caused by Bell's
palsy or acoustic neuroma excision. SUBJECTS: The study group included 12
patients (mean age 50.4 +/- 12. 3 years) with idiopathic Bell's palsy and 5
patients (mean age 45.6 +/- 10.7 years) whose facial nerves were surgically
sacrificed. The mean time since the onset of paresis/paralysis was 3.7 years
(range 1-7 years) and 7.2 years (range 6-9 years) for the Bell's and neuroma
excision groups, respectively.Method And Procedures: Motor nerve conduction
latencies, House-Brackmann facial recovery scores, and a 12-item clinical
assessment of residuals were obtained 3 months before the onset of treatment, at
the beginning of treatment, and after 6 months of stimulation. Patients were
treated at home for periods of up to 6 hours daily for 6 months with a
battery-powered stimulator. Stimulation intensity was kept at a submotor level
throughout the study. Surface electrodes were secured over the most affected
muscles. Groups and time factors were used in the analyses of the 3 outcome
measures. RESULTS: No statistical differences were found between the two
diagnostic groups with respect to any of the 3 outcome measures. Mean motor
nerve latencies decreased by 1.13 ms (analysis of variance test, significant P =
0.0001). House-Brackmann scores were also significantly lower (Wilcoxon signed
rank test, P = 0.0003) after treatment. Collective scores on the 12 clinical
impairment measures decreased 28.7 +/- 8.1 points after 6 months [analysis of
variance test, significant P = 0.0005). Eight patients showed more than 40%
improvement, 4 better than 30%, and 5 less than 10% improvement in residuals
score. CONCLUSION: These data are consistent with the notion that long-term
electrical stimulation may facilitate partial reinnervation in patients with
chronic facial paresis/paralysis. Additionally, residual clinical impairments
are likely to improve even if motor recovery is not evident
Williams H.B. (1996) The
value of continuous electrical muscle stimulation using a completely implantable
system in the preservation of muscle function following motor nerve injury and
repair: an experimental study. Microsurgery 17, 589-596.
Abstract: Functional recovery following motor nerve injury and repair is
directly related to the degree of muscle atrophy that takes place during the
period of nerve regeneration. The extent of this muscle atrophy is related to a
number of factors including the accuracy of nerve repair; the distance through
which the nerve must regenerate; the age of the patient; and the type of nerve
injury and other associated tendon and soft tissue and bony damage. Atrophy of
muscle that is always associated with nerve injury is a combination of disuse
and degeneration. Our hypothesis proposed the following question: "Would
continuous electrical stimulation of the denervated muscle during the period of
nerve regeneration maintain the integrity of the muscle fibers and hence their
potential functional capacity?" We have completed a series of animal studies
(rabbit and canine models) in our laboratory using a completely implantable
system to provide continuous muscle stimulation following nerve injury and
microsurgical repair. In several different experiments, the nerves under study
were cut and repaired at 4 and 12 cm from the muscles to study the effects of
short- and long-term recovery. In all experiments, a beneficial effect was
demonstrated with improved morphology and functional capacity of the
reinnervated stimulated muscles when compared with nonstimulated controls. In
addition, electrical stimulation using this implantable system could be applied
for extended periods without evidence of discomfort in the experimental animals
Wolf S.R. (1998) [Idiopathic
facial paralysis]. HNO 46, 786-798.
Abstract: Although acute idiopathic facial paresis is often labelled "Bell's
palsy", historical studies show that Nicolaus Anton Friedreich (1761- 1836) from
Wurzburg was the first physician to describe the typical symptoms of the
disorder in 1797, approximately 24 years prior to the paper published by Sir
Charles Bell. Diagnostics has now improved to the extent that acute idiopathic
facial palsy can more frequently be assigned to etiologies caused by
inflammatory disorders. Herpes simplex virus type I and Borrelia burgdorferi are
particularly relevant. Underestimation of the degree of paresis is, particularly
in children, a drawback of the clinical examination. "Incomplete eyelid closure"
is not a reliable indicator of remaining nerve function. For this reason
complete electromyography (EMG) is recommended in all cases of severe facial
paresis. Since electroneurography does not reliably reflect the degree of
denervation present, needle EMG is preferred. The therapy of the facial palsy of
unclear etiology is still not well defined. Nevertheless, we recommend that a
combined treatment should be used early, at least in patients with disfiguring
pareses. Combinations may consist of cortisone, virostatic agents and
hemorrheologic substances and possibly antibiotics. Surgical decompression of
the facial nerve remains controversial, since positive surgical results lack
statistical support. Individual instructions for facial exercises, massage and
muscle relaxation can support rehabilitation and possibly reduce the production
of pathological synkinesia. Electrical stimulation should not be used. There are
a number of possibilities available to reduce the effects of misdirected
reinnervation, especially the use of botulinum-A-toxin. However, intensive
diagnosis and therapy in the early phase of paresis are decisive in obtaining a
favorable outcome. Further refinements in rehabilitation and comparative
multicenter controlled studies are still required for future improvements in
affected patients
Zealear D.L., Billante C.L.,
Chongkolwatana C., and Herzon G.D. (2000) The effects of chronic electrical
stimulation on laryngeal muscle reinnervation. ORL J. Otorhinolaryngol. Relat
Spec. 62, 87-95.
Abstract: The present study examined the effects of functional neuromuscular
stimulation (FNS) on reinnervation of the posterior cricoarytenoid (PCA) muscle.
In 4 canines, the recurrent laryngeal nerve (RLN) was sectioned and anastomosed
and a patch electrode array implanted for stimulation and recording at multiple
PCA sites. Following implantation, FNS was applied to 2 canines for a period of
6 weeks. Two additional animals served as nonstimulated controls. In each
animal, histomorphometric analysis of the RLN was used to assess the quality of
nerve regeneration and the potential for muscle reconnection. The magnitude of
reinnervation was monitored by electromyographic (EMG) potentials evoked by RLN
stimulation. The appropriateness of reconnection was determined by the pattern
of spontaneous EMG activity and recovery of vocal fold abduction. Results of
this preliminary study indicated that FNS caused an overall repression of
reinnervation. However, the repression preferentially inhibited reconnection by
foreign nerve fibers, promoting selective reinnervation and preventing
synkinesis
Zhao Q., Dahlin L.B., and
Kanje M. (1992) Reinnervation of muscles in rats after repair of transsected
sciatic nerves with Y-shaped and X-shaped silicone tubes. Muscle reinnervation
after nerve repair. Scand. J. Plast. Reconstr. Surg. Hand Surg. 26, 265-270.
Abstract: Reinnervation of the gastrocnemius and anterior tibial muscles was
assessed by measurements of tetanic force after repair of sciatic nerves with
Y-shaped or X-shaped silicone tubes in rats. The transsected proximal stump of
either the tibial or the peroneal fascicle was introduced into the opening of a
Y-shaped silicone tube, or both fascicles were introduced into an X-shaped tube.
The distal tibial and peroneal fascicles were inserted into the distal outlets
of the tubes leaving a gap of 4 mm between proximal and distal stumps. In the
X-shaped tubes the proximal inserts were placed opposite or adjacent to their
respective distal parts. Sixteen weeks later reinnervation was evaluated by
measurements of tetanic force of the gastrocnemius and anterior tibial muscles
after electrical stimulation of the fascicles. There was preferential
reinnervation in both types of tubes. In Y-shaped tubes about 90% of the tetanic
force could be recorded from both muscles after stimulation of the peroneal and
tibial fascicles, respectively. Recovery was lower in the X-shaped tubes,
amounting to about 75%. Contractions evoked by misrouted fibres were similar
(roughly 40%) in both models. We conclude that motor axons preferentially, but
not exclusively, selected a path to reinnervate their original target muscle
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