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Ectopic generation of impulses and cross-talk in spinal nerve roots of УdystrophicФ mice.

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Ectopic Generation of
Impulses and Cross-Talk in Spinal Nerve
Roots of “Dystrophic” Mice
Michael Rasminsky, MD, PhD
In “dystrophic” mice, many spinal root axons are bare and closely apposed to one another in midroot. T h e direction of
nerve impulse traffic in lumbosacral spinal nerve roots was determined by biphasic recording of spontaneous activity.
In normal mice, impulse traffic in dorsal and ventral roots is directed toward and away from the spinal cord,
respectively. However, in spinal root fibers of dystrophic mice, impulses also originate in midroot and are propagated
toward both the spinal cord and the periphery. Impulses originate in midroot as single isolated events, in bursts at
frequencies of u p to 100 Hz, or as continuous activity persisting for several minutes in single fibers. Ectopically arising
activity in some single fibers is consistently associated with transmission of an impulse i n another fiber past the site of
origin of the ectopically arising impulse. Thus impulses arise in the spinal root axons of dystrophic mice both
spontaneously and as a result of cross-talk between single fibers.
Rasminsky M: Ectopic generation of impulses and crowtalk in spinal nerve roots of “dystrophic” mire.
A n n Neurol 3 351-357, I978
the ectopic activity is d u e to side-to-side communication between adjacent axons within the roots.
In normal nerve fibers, impulses arise at the cell body
o r at a sensory terminal and are conducted to the
opposite end of the fiber. Impulses do not ordinarily
arise in the midportion of nerve fibers. In pathological
situations there are exceptions to this rule. Impulses
arise from limb nerves during and following the ischemia caused by a pneumatic tourniquet [ 2 4 ] . Percussion of a nerve may provoke impulse generation at
the percussion site [22]; demyelinated nerves are particularly susceptible to excitation by percussion 1181.
T h e application of certain toxins to nerve fibers also
provokes spontaneous activity [ 8 , 29,361.
In genetically “dystrophic” mice, most lumbosacral
spinal root axons are thinly myelinated near both the
spinal cord and che exit from the spinal canal, and are
bare in midroot [ 4 , 5 , 3 9 ] .In a study of the physiological properties of motor neurons of dystrophic mice,
Huizar et a1 [ 191 noted that direct iritracellular stimulation of a motor neuron was occasionally followed by
repetitive discharge of the neuron; this repetitive discharge was initiated by impulses invading the motor
neuron antidromically and was therefore thought to
originate in the peripheral nerve.
This paper presents direct evidence that nervous
impulses are ectopically generated in the lumbosacral
spinal root axons of dystrophic mice and that some of
Experiments were performcd o n adult 19 to 37 weeks) cfystrophic mice (strains 120 H 6 FliJ dy/dy anti dy2.’/Jyz.’)and
controls i - t i ? )obtained from Jackson 1-abotdtories, Bar
Harbor, ME. Dystrophic mice weighed 15 to 26 gm and
controls, 25 to 35 gm.
Anesthesia was inrlucecl with sodium pentobarbital, 3 0
mg per kilogram ofbotly weight intraperitoneally, and maintained rhroughout thr experiment with inhalation of
Huothane in oxygen. A lumbosacral laminectomy was performed; the paraffin pool made over the laminectomy site
was usually maintained at 2G“ to 28°C hy radiant heat. Some
experiments were performed with the pool at 37°C; the
lower temperature was preferred since the radiant heat
necessary to maintain the small pool a t 37OC caused some
mice t o die of hyperthermia. Spontaneous activity on undissecteri ventral anti dorsal roots was recorded differentially
between a pair of 1 2 5 pin silver electrodes separated by 0.5
to 1 mm. The recorded ac-tiun potentials were as a rule
biphasic o r monophasic, the initial negativity occurring at
the electroJe first traversed by the advancing impulse. Occasionally, recorded potentials were triphasic, a small, brief
initial positive deflection preceding the major negative
deflection; this is an unavoidable consequence of volume
conductor recording and will not be further discussed. The
From the Division of Neurology, Montreal General Hospital, and
the Departments of Neurology and Neurosurgery, McGill University, Montreal, Que. Canada.
Address reprinr requesrs to L)r Rasrninsky. Division of Neurology,
Montreal General Hospital, 1650 Cedar Ave, Montreal, Que, H 3 G
1A4, Canada.
Materials and Methods
Accepted for publication Nov 2, 1977.
0364-5114/78/0003-0412$01.25 @ 1978 by Michael Rasminsky 351
Fig 1 . Spontaneous activity on a lunibosacral ventral root of a
dystrophic mouse. Downward dejections are impulses traveling
away from the spinal cord (centrifugal);upward dejections are
impulses traveling toward the spinal cord (centripetal). Centripetalactivity is seen near the spinal cord but not near the exit
from the spinal canal.
direction of propagation of each impulse could be inferred
from the polarity of the initial major deflection of the action
potential. Negativity at the more distal electrode is displayed as an upward deflection; thus, an impulse traveling
toward the spinal cord gives rise to an action potential with
an upward deflection, and an impulse traveling away from
the spinal cord gives rise to an impulse with a downward
Permanent records of spontaneous activity were usually
made by photographing single or multiple superimposed
sweeps on the screen of a storage oscilloscope.For display of
lengthy periods of spontaneousactivity, the recorded potentials were digitized after amplification, stored in the memory
of a PDP 11/40computer, and written out by an X-Y plotter
(Figs 1, 2).
Normal Mice
All spontaneous impulse traffic in the lumbosacral
dorsal roots was toward the spinal cord (centripetal),
and all spontaneous impulse traffic in lumbosacral
ventral roots was away from the spinal cord (centrifugal).
Dystrophic Mice
SPONTANEOUS ACTIVITY. Near the exit from the
spinal canal, virtually all impulses inventral roots were
centrifugal; near the spinal cord, a substantial propor-
352 Annals of Neurology Vol 3 No 4 April 1978
10 mscc
Fig 2. Spontaneous activity on a lumbosacralventral root of a
dystrophic mouse recordedproximally ( A ) and more distally (B)
on the same root. ( A 3 Near the spinal cord, both rentrifugal
(downward dejections) and centripetal (upward de$ections) activity is observed. (Ad Application of local anesthetic near the
spinal cordabolishes only the centrrfugalactivity. (B)Centrifugalactivity (originating between recording sites A and B)
persists at the more distal recording site. (VR = ventral root.)
tion of the spontaneous impulse traffic was centripetal
(Fig 1). Since few if any centripetal impulses traversed
the more distal portion of the root, the centripetal
impulses traversing the more proximal portion of the
root must have arisen in midroot. The findings were
similar in dorsal roots: near the spinal cord most impulse traffic was centripetal, but near the exit from the
spinal canal both centripetal and centrifugal impulses
were observed. In most dystrophic mice, a great deal
of spontaneous activity originating in midroot was
found in all roots examined; however, in some mice
little or no spontaneous activity originated in the
roots. This variation in behavior was in no obvious
relationship to age, weight, or level of anesthesia.
Spontaneous activity tended to decrease but did not
disappear as the temperature of the paraffin pool was
raised to 37°C.
Spontaneous activity originating in the midportion
of the ventral root persisted even when normal centrifugal activity was eliminated by application of local
anesthetic to the ventral root at the exit from the
spinal cord (Fig 2) or by cutting the ventral root at the
spinal cord. In some instances, spontaneous activity
originating in midroot was substantially reduced fol-
'10 r n s e c '
Fig .3. Spontaneous actifsity o n a lumbosairaldorsal root of a
dystrophic m0uJ.e simultaneously reiordedfrom proximal
(PROX) and di.ital (DlS)electrodepairs. ( a ) A nimpulie trareli n g toicwd the spinalcord (upward dejections)fivit traz'erses
the distal and then the proximal electrode.i. ( b )Impulse.r arising
between the elertrode.r truijerse the distal eleitr0de.i traveling
away from the cordand the proximal eleitrodes traveling tozrurd
the iovd. Dependinx on the Aite of origin of the spontaneous actiiity. the impulie may arrizie a t the proximal electrodes before
(b,)or after (b2)arri.iZ!ingatthedi.italelectrodes. (c)A n impulje
ari.ring proximal t o the proximal electrode puir and trazding
away from the spinal cord idou~nzi~arddejertions)
first traz8evse.i
the pvo?cimuland then the distal eleitvodes.
lowing local anesthetization or sectioning of the ventral root near the cord.
The site of origin of impulses in single spinal root
fibers could be identified by simultaneous recording
from two pairs of electrodes applied to the same root
(Fig 3 ) . In roots in which there was spontaneous activity in one or only a small number of fibers, it was
possible to recognize repetitive activity in individual
fibers and to specify with precision the midroot site of
origin of the spontaneous activity (Fig 4).
Ectopic activity in single fibers arose either as single
impulses (Fig J), in short bursts at frequencies of up to
100 Hz (Fig 5 ) , o r as continuous firing which was
occasionally observed to persist for as long as half an
EPHAPTIC EXCITATION. Impulses originating in
midroot in a single fiber sometimes occurred as part
of a complex including a normally transmitted impulse
(Fig 6). Figure 7 is a diagrammatic reconstruction of
the ventral root complex illustrated in Figure 6; the
most straightforward explanation of the complex, as
detailed in the figure legend, is that there is cross-talk
or ephaptic transmission between two fibers in midroot at a site between the two pairs of recording electrodes. An example of cross-talk between dorsal root
fibers is illustrated in Figure 8.
F i g 4 . Loculization of the site of oriKin of.ipontaneou.i
in a single dyJtrophii rentral root.jiber. A repetitii,efjidi.rchurgi n g fiber 111a.r s imu ftuneously reco riledfrom t f i ' o pair.i oj~proxima
(PROX) anddistal (DIS)e1ectrode.i at .ruiie.isiz~epositin~i~
( A-E). The osrillosr-opesweep was trigLqeredfrom the distal
(A-B) or proximal (C-E) retarding. Eaih set oj-tramiA- w e r u l
.\uperinipo.ied sr1,eep.r. The action c n rrent recorded,fronithe proximal e1eitrode.i remuin.i the .ram throughout. ( A ) The inipulie
t ruvefing t o itlard the iovd ( u pI ( 1urd dejei-tion.i)t ruzwse.ifErst the
distal and then the proximal electrodepaivs. (B)The impidre
traz,ersing the di.rtal eleitrode p d i r hu.r rwersed in polarity. indiiating that the site of origin of the i m p u h e (*) i.i betiitern r e m d
iwg sitei Aund B. (C-E) The centrifugal infpulie traz,erj.eJ-the
progre.i.iizjely more distal recording site.i at progres
10 rnsec'
0 . 5 sec
F i g 5 . Spontaneous singlefiber activity on a dystrophii- tmentral
root simultaneously recorded from proximal (PROX) anddi.rtal
(DIS) electrode pairs. Oppositepolarity of the dejeitions inilicate.i an impuhe originating betzcleen the t w o electrodepairs (rf'
Fig .3 b). At dowerszoeep speed (right) thefiber i s seen tojire i n
short bursts. hiticity i n otherfibers is rdio apparent at slow
.I u jeep .rpeed.
Rasminsky: Ectopic Impulses and Cross-Talk
PROX - ' -
4 *
'10 rnsec'
5 msed
Fig 6. Cross-talk betuseen ticzo single fibers in a dystrophic ventral root. Three separate occurrences of the same complex simuftaneously recordpdfrom proximal (PROX)and distal ( DIS)
electrode pairs are illtrJ-trated.An impulse originating i n midroot (*) i.i associated u i t h an impulse traveling au'ayfrom the
Jpinal cord (arrows) (see F i g 7).
F i g 8. Cross-tulk between two singfejihers i n a dystrophic dorsal
root. Simultaneous recordings were madefvom a distalpair of
electrodes (D1S)atafixed site near the exit from the spinal
canalund a proximal pair of electrodes (PROX)vhich u'as
nzovedprogresshelycloser t o the spinal rord. In the first three
pairs of recordings an inipulse tmreling tou'ard the .spinal cord
(upward dejection-dpen arrows) is follouied by an impulse
traceling away from the spinal cordcdou'nic,urddepertionblack arrows). At thejinafproximal recording Jite, the action
current of the second impuhe (black arrows) is revened in pofarity, indicating that this impulse is now traveling toward the
spinal cord. The second impulse presumably ari.tes as a result of
cross-talk at the site designated ephapse. Note that the latency
betumeen the centripetaland centrifugal impulses at the distal
electrodes is not absolutely constant (6.5 t o 6.8 mseci.
It must be convincingly argued that the complexes
illustrated in Figures 6 and 8 (in which impulses travel
in opposite directions) could not represent activity in a
single fiber before it is accepted that these complexes
d o indeed represent cross-talk between two fibers. In
principle, there are two ways in which an impulse in a
single fiber could reverse direction within a spinal root
(Fig 7).
F i g 7 . Diagrammatic reconstructionof cross-talk illustrated in
Figure 6. At time tl a centrifugal impulse injiber A traverses
the proximal electrodepair. causing a downward deflection. A t
time t2fiber B is excited in midroot. initiating an impulse
which travels in both directions. At time t3 the impulse in fiber
B traverses the proximal electrodepair. causing an upward
dejection. At time 4 the impulse iizfiber B traver.resthe distal
A t time t j the
electrodepair, causing a dou~nu~arddejection.
impulse i n fiber A traverses the distal electrode pair, causing a
second downiuarddeflection. (PROX =proximal; DIS = distal.)
354 Annals of Neurology Vol 3 No 4 April 1978
1. Bifurcation, with one branch being a recurrent
collateral. In this situation the orthodromic impulse at
the first pair of electrodes would be followed by an
antidromic impulse at the first pair of electrodes and
by one impulse (rather than two) at the second pair of
electrodes. From Figure 6 it is clear that the two
impulses traversing the distal pair of electrodes have
entirely different configurations, indicating transmission in two different fibers.
2. Reflection of an impulse (possibly at a branch
point). There is both theoretical [ 13, 331 and experi-
F i g 9. Theoretical mechanismsfor reversal ofdirection of impulses i n single spinul rootfibers: (A)recurrent rolhtevalization,
(8)rejection of imprilws.
F i g 10. Variable larenry of rross-talk between t w o dystrophiczaent ral mot Jzberi. A cent rifugai impulse (downwurd dejertionl
triggering an osi-illampesweep is succeeded at inconstant Latency
OY nut at all by r i c-entvipetd impu1J.e rupu~arrl~le~ectioni.
mental [ 171 evidence that such reflections d o occur at
points of anatomical o r metabolic discontinuity in
single nerve fibers. At such reflections, the appreciable interval between the arrival of the impulse at the
site of reflection and initiation of transmission in the
reverse direction is due to the time required for repolarization of the portion of the fiber just proximal to
the reflection site. In complexes recorded close to the
site of putative ephapses (,e.g.,third complex of Figure
8) there was a clear temporal overlap of action currents of impulses proceeding toward and away from
the ephapse. This i s inconsistent with reflection of an
impulse in a single fiber.
Figures 6 and 8 show single oscilloscope sweeps
during which an impulse in one fiber excited another
fiber in midroot. Such excitation was not an invariable
consequence of passage of the exciting impulse and
sometimes occurred at a variable latency in response
to the passage of the exciting impulse (Figs 8, 10).
These experiments demonstrate that nerve impulses
arise in the midroot of lumbosacral spinal root
fibers of dystrophic mice. In midroot of these fibers,
there is a transition between a myelinated portion in
which conduction is saltatory and a bare portion in
which it is continuous [361. T h e present experimental
data permit no conclusion as to whether the ectopic
activity originates from the bare portion of the spinal
root fibers; at heminodes, i.e., at the junctions between the bare and myelinated portions of the spinal
root fibers; or from nodes of Ranvier in the myelinated portion of spinal root fibers. The last possibility is unlikely since most of the ectopic activity arises
at least several millimeters away from the spinal cord
or the exit from the spinal canal, within the region
where most axons are bare o r undergoing transition
from myelination to nakedness.
The possibility that ectopic impulses arise at
heminodes is consistent with the known hyperexcitability of the junction between myelinated and unmyelinated portions of normal nerve fibers. Following
tetanic stimulation of a motor nerve, a single stimulus
may give rise to repeated discharges. This posttetanic
repetition is thought KOarise ar the junction between
[he myelinated portion of the motor fiber and its
unmyelinated terminal 1381.
Ephaptic transmission between adjacent demyelinated or injured axons in peripheral nerves has been
repeatedly invoked in the clinical neurological literature to explain causalgic pain, gustatory lacrimation
and sweating, hemifacial spasm, heart block in association with giossopharyngeai neuralgia, and other
phenomena [ I , 10, 121. Phenomena such as paroxysmal simultaneous sensory and motor symptoms in
multiple sclerosis have been attributed to lateral
spread of impulses in central white matter [28,30]. An
artificial synapse between adjacent nerve fibers was
lirst observed in invertebrate preparations [ 2 , 2 I]; the
subsequent demonstration by Granit et a1 114, 151 of
an artificial synapse in acutely transected o r crushed
mammalian nerve is frequently cited in support of the
contention (based largely o n clinical inference) that
ephaptic interactions may occur in the human pathological nervous system.
Although the experiments of Granit e t a1 [14, 151
have been widely cited in the clinical neurological
literature, physiologists have generally been cautious
in assessing their significance. In the original experiments, the artificial synapse which was created at or
near the site of a cut or crush injury functioned for
only a brief period following the acute injury. Subsequent attempts by Wall e t al[40]to reproduce these
experiments have been unsuccessful. A further reason
for caution in extrapolating the results of experiments
o n acute nerve injury to chronzc pathological stares is
the fact that the afferent side of the artificial synapse
comprised multiple simultaneously activated fibers,
the “postsynaptic” response also being activation of
multiple fibers.
The concept of cross-talk between adjacent axons in
Rasrninsky: Ecropic Impulses and Cross-Talk
pathological nerve was recently revived by Huizar et aI
[ 191, who found that stimulation of one of the tibia1
and common peroneal nerve branches in dystrophic
mice invariably produced discharges in the other
nerve branch, even following section of the dorsal
roots. The abolition of the multifiber response when
the appropriate ventral roots were sectioned far
enough distal to the spinal cord suggested that sideto-side communication occurred within the spinal
roots or just outside the spinal column. T h e present
experiments, which demonstrate side-to-side communication between single fibers in dystrophic roots,
establish that such cross-talk is a physiological phenomenon and not simply an artifact of simultaneous
activation of many fibers.
The minimal morphological conditions that must be
fulfilled for side-to-side communication between
axons have not y e t been defined. Electrotonic
synapses between nerve cells are associated with
localized membrane specializations o f closely apposed
membranes 1311. In preliminary freeze-fracture
studies of dystrophic mouse spinal roots, Bray et a1 [6]
have observed structures suggestive of small intercellular bridges which resemble bridges seen in normal
developing mammalian nerve fibers [?I.
The bare axons of dystrophic roots are electrically
excitable [36]and closely apposed 14, 5 , 391. If the
coupling resistance between adjacent axons were sufficiently low, it would be unnecessary to invoke intercellular channels as a morphological requirement for
cross-excitation. Transmission of an impulse in one
axon influences the excitability of its neighbods); in
normal axons. such changes in excitability are subthreshold and d o not result in cross-excitation [23].
However, in artificially apposed invertebrate axons,
ephaptic transmission is observed in metabolic conditions enhancing nerve excitability [2, 341.
Spontaneous activity arising in dystrophic root
fibers must reflect hyperexcitability of axon membranes at the sites of ectopic impulsegeneration. Such
hyperexcitable sites could in principle be triggered to
threshold for action potential generation by relatively
small changes in excirability provoked by an impulse
traversing an adjacent axon. Variability in latency
and/or inconsistency of response of the excited fiber
could reflect fluctuations in the excitability of the site
of ectopic impulse generation at the time the exciting
impulse traverses the neighboring fiber. In dystrophic
roots, each fiber forms part of the extracellular pathway for currents generated by activity of neighboring
fibers; thus, excitability of possible sites of impulse
generation in any given single fiber will be a complex
and unpredictable temporal function of ongoing activity in many neighboring fibers in varying degrees of
apposition or contiguity to the fiber in question.
The continuous myotoniclike activity of dystrophic
356 Annals of Neurology Vol 3 N o 4
April 1978
hind limb muscles, which has previously been shown
to have an extramuscular origin [ 9 , 111, can now be
explained as a manifestation of ectopic impulse generation in spinal ventral roots. Some of this muscle
activity may represent a cascade effect, an impulse
originating in a single ventral horn cell or more
peripherally in a ventral root fibergiving rise to excitation of other fibers within the root by lateral spread,
the excited fibers in turn exciting yet other fibers. The
present experiments d o not permit any estimate of the
relative importance of cross-talk as a source of spontaneous activiry. Both reduced conduction velocity
[ 361 and spontaneous impulse generation would give
rise to major distortion in the pattern of motor
outflow reaching the periphery and sensory input
reaching the central nervous system; these distortions
would be increased by the amplifying effect of lateral
spread of impulses if this is indeed a frequent phenomenon i n the unanesthetized animal.
There is strong inferential evidence that the continuous muscle activity seen in some of the human
syndromes of continuous muscle fiber activity reflects
generation of impulses in peripheral nerve distal to
the spinal cord [ 3 , 20, 411. Spontaneous activity also
arises in nerves of patients with amyotrophic lateral
sclerosis [ 4 2 ] , in peripheral nerve experimentally demyelinated with Lehmann and Ule’s [ 2 5 ] experimental granuloma technique [ 181o r diphtheria toxin (personal unpublished observations), and in the peripheral
nerves of trembler mice (personal unpublished observations), another mutant with abnormally myelinated
peripheral nerve fibers [26,2?]. It is not clear whether
the human syndromes of nerve hyperexcitability have
some critical morphological abnormality in common
with the animal models or whether the human
hyperactivity syndromes reflect functional abnormalities in permeability properties of axon membrane
similar to those provoked by certain nerve toxins [8,
28, 371.
The present experiments may also have some relevance to human central nervous system demyelination. Many symptoms of demyelinating disease such as
paroxysmal pains, paresthesias, and muscle spasms are
most easily understood as a reflection of abnormally
generated activity within the central nervous system,
i.e., as positive rather than negative symptoms in the
Jacksonian sense [ 3 0 , 3 5 ] .Closely apposed bare axons
are seen in experimental demyelination in the central
nervous system [16, 321 and in chronic multiple
sclerosis plaques (Prineas J: personal communication,
1977). T h e present experiments support the clinical
inference [28, 301 that lateral spread of impulses
within a plaque of demyelination may be one of
perhaps several mechanisms involved in ectopic generation of nerve impulses in central nervous system
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Rasminsky: Ectopic Impulses and Cross-Talk
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spina, уdystrophicф, talk, generation, nerve, mice, cross, roots, impulses, ectopic
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