Effect of maturation on nerve excitability in an experimental model of threshold electrotonus

ABSTRACT: Threshold electrotonus (TE) is a new tool for investigatingaxonal function noninvasively in vivo. To increase its potential clinical value,we developed a rat model of TE, and examined the effects of maturation andpharmacological intervention. We recorded TE in 92 male rats (body weight90–650 g) by stimulating the motor nerve in the tail, and applying 100-msconditioning currents. Motor conduction velocities increased up to a bodyweight of 330 g, and remained constant thereafter. TE in mature rats wassimilar to that in humans, and two parameters were analyzed: TEd10–20 orthe mean threshold reduction 10–20 ms after the onset of the depolarizingconditioning current at 40% of threshold intensity; and TEh10–20 or the cor-responding threshold decrease on hyperpolarization. Like latency, the ab-solute value of TEh10–20 decreased up to 330 g, and then stabilized there-after, probably reflecting the progressive increase in the axonal diameterand relative reduction in internodal impedance. In contrast, TEd10–20 gradu-ally decreased up to 330 g, and then jumped to a higher level, which wasmaintained for animals of >400 g. 4-Aminopyridine, a blocker of fast potas-sium channels, selectively increased TEd10–20 only in the immature or young(<330 g) rats. This suggests that, in the mature animals, fast potassiumchannels become sequestrated from the nodal membrane and not activatedin response to nodal depolarization. These findings indicate that mature rats(>400 g) may provide a useful experimental model for interpreting abnormalTE responses in humans, and provide evidence for nonlinear maturation ofpotassium channel function in myelinated axons.

© 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 498–506, 2000

EFFECT OF MATURATION ON NERVEEXCITABILITY IN AN EXPERIMENTAL MODELOF THRESHOLD ELECTROTONUS

QING YANG, MD,1 RYUJI KAJI, MD, PhD, 1 NOBUYUKI HIROTA, MD, 1

YASUHIRO KOJIMA, MD, 1 TSUNEKAZU TAKAGI, MD, 1 NOBUO KOHARA, MD, 1

JUN KIMURA, MD, 1 HIROSHI SHIBASAKI, MD, PhD, 1 and

HUGH BOSTOCK, PhD 2

1 Department of Neurology, Kyoto University Faculty of Medicine, Shogoin Sakyoku,Kyoto 606-8507, Japan2 Sobell Department of Neurophysiology, Institute of Neurology, Queen Square,London, UK

Accepted 22 October 1999

Conventional electrophysiological tests of nervefunction focus on the number of conducting fibersand their conduction velocity. These tests are sensi-tive to the integrity of the myelin sheath, but providelittle information about the axonal membrane. Bycontrast, threshold electrotonus (TE) is a new tech-nique to test nerve excitability, which depends onthe membrane properties of the axons at the site of

stimulation.5,6 TE is sensitive to membrane poten-tial, and to changes in membrane potential causedby activation of ion channels and pumps, includingthose under the myelin sheath.

The principle of TE is to explore subthresholdmembrane potential changes (electrotonus), caused bypassing conditioning currents, by tracking thethreshold changes (Fig. 1). Electrotonus and thresh-old parallel each other, unless the sodium channelsare strongly inactivated as in the case of severe de-polarization.1 In clinical settings, threshold trackingis performed on compound action potentials, andthe threshold is defined as the current intensity re-quired to evoke a response of defined amplitude(usually 30–40% of maximum). When a long-

Abbreviations: ALS, amyotrophic lateral sclerosis; 4-AP, 4-aminopyri-dine; CMAP, compound muscle action potential; Ih, inward rectifier; S1-dep, slow phase depolarizing conditioning pulse; S1-hyp, slow phasehyperpolarizing conditioning pulses; TE, threshold electrotonusKey words: animal model; conduction velocity; excitability; input imped-ance; maturation; potassium channel; threshold electrotonusCorrespondence to: R. Kaji; e-mail: [email protected]

© 2000 John Wiley & Sons, Inc.

498 Threshold Electrotonus and Maturation MUSCLE & NERVE April 2000

duration, subthreshold conditioning current is ap-plied, the nodal membrane first polarizes quickly (Fin Fig. 2B,D), and subsequently undergoes slow po-tential changes (S1, S2, and S3 in Figs. 2 and 3),reflecting slower charging of the internodal mem-brane and activation of slow, voltage-dependent ionchannels.2 The initial slow phase S1 is different be-tween the plots on the depolarizing (S1-dep) and thehyperpolarizing conditioning pulses (S1-hyp).

Because of the activation of the potassium chan-nels in response to depolarization, S1-dep showsfewer threshold changes than S1-hyp, and the initialthreshold decrease is followed by a “sag” or partialreversal (S2), as the nerve accommodates to the de-polarizing current. On the hyperpolarizing side, nochange in ion channel activity is evident immediatelyafter the conditioning pulse and the threshold ap-pears to increase in accordance with the slow, passivehyperpolarization of the internodal axon. If hyper-polarization lasts longer than 40–50 ms, the inwardrectifier (Ih) is activated to antagonize the mem-brane hyperpolarization.2 When sufficiently strong(Fig. 3A,B), this current causes a clear depolarizing“sag” (S3). Ih passes sodium and potassium ions intothe axon, and plays an important role in preventingexcessive hyperpolarization after impulse trainscaused by the electrogenic sodium–potassium pump.In an extensive study of threshold electrotonus indiabetic patients, Horn et al.13 reported that diabeticneuropathy is associated with a deficit in inward rec-tification.

Abnormal TE has also been reported in ALS,8,13

a toxic neuropathy,20 multifocal motor neuropa-thy,14 and in monomelic amyotrophy with spinalhemiatrophy.17 Although TE is able to reveal other-wise undetectable abnormalities in nerve mem-branes, its clinical utility has been limited partly bythe uncertainties regarding its interpretation. Be-cause of the complexity of the interactions betweenmultiple ion channel species and membrane poten-tial that determine nerve excitability, it is impossiblein most cases to infer the nature of the membraneabnormality responsible for a particular abnormalityin TE. An in vivo experimental model that enablesvarious manipulations would help analysis of TE ab-normalities in humans. In this study, we report ananimal model for which the maturational changes ofTE were investigated. The results were interpretedwith the help of pharmacological modification ofpotassium currents and with reference to previousreports on the developmental changes of the fastpotassium channel.10,11,16,18

MATERIALS AND METHODS

Animals. We used 92 male Wistar rats having bodyweights ranging from 90 to 650 g. Of these, 5 animalswere used for pharmacological studies (see later).This animal model has previously been found toshow a continuous increase in body weight withage.21 We therefore used body weight as an index ofmaturation. A body weight of 330 g corresponds ap-proximately to the age of 90 days.

TE Recording. The principle of threshold elec-trotonus tracking has previously been described indetail.7,15 In brief, alterations in current strength ofa 1-ms pulse (test stimulus) required to elicit a con-stant muscle action potential amplitude (threshold)was measured during the application of long-lastingsubthreshold de- or hyperpolarizing currents. Theprogram QTRAC (© Institute of Neurology) was usedon an IBM 486 computer to record muscle actionpotentials, to generate stimuli, and to display results.

The excitability of the motor nerve in the tail(caudal motor nerve) was tested with current pulsesof 1 ms, automatically adjusted to maintain a con-stant compound muscle action potential (CMAP)amplitude, which was fixed at about 40% of the am-plitude after supramaximal stimulation (Fig. 1). Thenerve was stimulated at 1-HZ, and five stimulus con-ditions were tested in turn: 1-ms test stimulus alone(control), and the test stimulus superimposed on

FIGURE 1. Diagram showing the method of TE recording in therat.

Threshold Electrotonus and Maturation MUSCLE & NERVE April 2000 499

100-ms polarizing conditioning currents, set to 20%,−20%, 40%, and −40% of the last control stimulus.The starting time of the conditioning currents wasstepped from 2 ms after the test stimulus to 198 msbefore it, over a period of 10–15 min.

A Wistar rat was anesthetized using sodium pen-tobarbital (50 mg/kg IP) and its tail was set on aheating plate with temperature automatically con-trolled at 35°C. We used a disposable Ag–AgCl elec-trode with saline-soaked pad (30 × 22 mm) for stimu-lating the caudal nerve. The cathode was attached tothe lateral side of the tail at 1.5 cm from the base.The anode was placed on the skin of the hip wherethe hair was removed. Stainless steel needle elec-trodes were used for recording CMAPs and for theground. The recording electrode for pick-up was in-serted into the ipsilateral side of the tail 6 cm distalto the stimulating cathode. The reference electrodewas inserted into the ipsilateral side of the tail 2 cmdistal to the pick-up electrode. The ground elec-trode was inserted into the contralateral side of thetail 2 cm proximal from the pick-up electrode. Thelatencies to the onset of CMAPs thus recorded weremeasured as an index of the conduction velocity.

We also recorded human TE for comparisonfrom 8 normal human subjects (6 men, age 27–40years, mean 34.1 years) as reported previously.8,13

The cathode was positioned over the right ulnarnerve at the wrist, and CMAPs were recorded fromthe abductor digiti minimi.

All procedures were approved by the Institu-tional Review Board at the Kyoto University Facultyof Medicine.

Analysis of TE Findings. To quantify the early re-sponse to depolarization, TEd10–20 was measured asthe mean threshold decrease from 10–20 ms afterthe onset of the depolarizing conditioning pulse at40% of threshold intensity (Fig. 4A). Similarly,TEh10–20 was measured as the corresponding thresh-old decrease on hyperpolarization (Fig. 4C). Be-cause the threshold always increased after hyperpo-larization, TEh10–20 had a negative value. TEd90–100

was the mean threshold decrease 90–100 ms afterthe onset of the depolarizing conditioning pulse(40%), after activation of fast and slow potassiumchannels (Fig. 4B).7 Statistical analyses of correlationcoefficients were performed, with P < 0.05 consid-ered significant.

TE findings obtained in the maturation studywere compared with those in pharmacological inter-vention (see later), which depicts the contributionfrom active membrane properties such as ion chan-nels. The waveforms in part resemble the spreading

out of a fan on its side, and thus the term “fanning-out” conveniently expresses the changes in a familyof TE waveforms corresponding to the opening ofthe fan. The degree of TE fanning-out can be relatedto the changes in membrane potential occurring onthe internodal axon membrane, which increase asthe electrical resistance of this membrane increases.(An analysis of the relationship of fanning-out to thepassive membrane properties and fiber size is givenin the Appendix.)

Pharmacological Intervention. We examined theeffects of a blocker of the fast potassium channel,4-aminopyridine (4-AP; 8 mg/kg IP), and a blockerof the inward rectifier, cesium chloride (CsCl; 500mg/kg IP) on TEs of 5 immature (body weight 90–120 g), 5 young (200–310 g), and 5 mature (440–650g) rats. Two of each age group were used for 4-APstudies, and the remaining 3 for CsCl studies. TE wasrecorded 20 min after the intraperitoneal adminis-tration of the agent.

RESULTS

Comparison of Human and Rat TE Waveforms. Fig-ure 2 compares recordings of threshold electrotonusfrom the caudal nerve of mature rats (Fig. 2A,B) withthose from human median nerves (Fig. 2C,D). TheTE recordings were comparable, although the ratsshowed smaller threshold changes than humans toboth depolarizing and hyperpolarizing conditioningcurrents.

Effect of Maturation on TE and CMAP Latencies. Toexamine the sequential changes of TE recordingduring maturation, three groups of rats were com-pared: immature (Fig. 3A; body weight 90–120 g, n =12); young (Fig. 3B; 250–330 g, n = 12); and mature(Fig. 3C, 440–650 g, n = 20) rats. There were twonotable features of maturation; that is, accommoda-tion to depolarizing currents was stronger and oc-curred earlier in the young rats than in either theimmature or mature group. On the other hand, theresponses to hyperpolarization progressively flat-tened; that is, both the early increase in thresholdand the later inward rectification decreased withmaturation. These findings were seen equally in TEsusing conditioning currents at 20% and 40% ofthreshold intensity, but were more prominent inthose using 40% current.

Figure 4 plots TEd10–20 (Fig. 4A), TEd90–100 (Fig.4B), TEh10–20 (Fig. 4C), the ratio of TEd10–20 toTEh10–20 (Fig. 4D), the difference between TEd90–100

and TEd10–20 (Fig. 4E), and CMAP latencies (Fig.4F), in relation to body weight, using data from 87


rats. The most surprising findings was the plots ofTEd10–20 and TEd90–100, which displayed a rather sud-den increase at the body weight of 330 g. We there-fore separately analyzed all parameters in rats belowand above 330 g.

For animals below 330 g, there were linear rela-tionships between variables and age. Statistically sig-nificant correlations between body weight andCMAP latency (r = −0.71, P < 0.0001) indicated thatconduction velocities increased linearly up to 330 g.Body weight was also significantly correlated withTEd10–20 (r = −0.57, P < 0.0001), TEh10–20 (r = 0.69, P< 0.0001), and TEd90–100 (r = −0.67, P < 0.0001). Forthose above 330 g, no statistically significant correla-tions were found for these parameters, all of whichremained fairly constant. The ratio of TEd10–20 toTEh10–20 (Fig. 4D), which reflects the asymmetry be-tween the depolarizing and the hyperpolarizing po-tential changes, also increased from around 0.5 to

near 1.0 at 330 g. Because both TEd90–100 andTEd10–20 are affected by fast potassium channel ac-tivities, the difference between them (Fig. 4E) rep-resents mainly slow potassium channel activities, andshowed a weak tendency toward a decrease with age.

Effects of 4-AP and CsCl. To further analyze thechanges during maturation, we challenged the im-mature, young, and mature rats with 4-AP, a blockerof the fast potassium channel, and CsCl, a blocker ofthe inward rectifier. Figure 5 depicts averaged TErecordings from 2 rats for 4-AP and those from 3 ratsfor CsCl.

In immature and young rats (Fig. 5, upper andmiddle traces), 4-AP selectively increased the earlyresponse to depolarization, but did not affect theresponses to hyperpolarizing currents except for aslight change in S3. The mature rats (Fig. 5, lowertrace), however, showed an increase in both depo-

FIGURE 2. Comparison of the rat TE (A and B) and human TE (Cand D). Parts (A) and (C) are the superimposition of all the plots;(B) and (D) are the averaged plots. The lower traces are theapplied conditioning currents (upward: depolarizing; downward:hyperpolarizing). Four plots in each recording are (from top:those at 40% (of the threshold current) depolarizing; those at20% depolarizing; those at 20% hyperpolarizing; and those at40% hyperpolarizing conditioning currents as shown in lowerpanel. F, fast phase; S1∼S2, slow phases. S1-dep, S1 on thedepolarizing conditioning current; S1-hyp, S1 on the hyperpolar-izing conditioning current.

FIGURE 3. Comparison of the TE recording among the immature[(A) 90∼120 g body weight, n = 12], the young [(B) 250∼330 g, n= 12], and the mature [(C) 440∼650 g, n = 12] rats. The displaydetails are the same as in Figure 2. F, fast phase; S1∼S3, slowphases; S1-dep, S1 on the depolarizing conditioning current; S1-hyp, S1 on the hyperpolarizing conditioning current.


larizing and hyperpolarizing responses, thus produc-ing “fanning-out.” In contrast, the effects of CsClwere restricted to the hyperpolarizing responses,and most conspicuously affected the late inward rec-tifying sag (S3) in the young and immature rats.

DISCUSSION

We have developed an animal model with a TE plotsimilar to that in humans. The main difference be-tween them was the relatively flat appearance of theplots after depolarizing or hyperpolarizing condi-tioning pulses in the rat TE. We also studied the TEchanges during maturation in this model, and theeffects of pharmacological challenge with 4-AP and

CsCl to clarify the contributions of different ionchannels.

The changes in the rat motor axons with matu-ration were of two kinds: changes in latency andearly hyperpolarizing response TEh10–20 were mono-tonic with body weight, whereas the depolarizing re-sponses changed abruptly at about 330 g. Bothmonotonic changes may be accounted for by asimple increase in fiber size, without any change inspecific membrane properties.

According to Rushton’s proposal19 for the scal-ing of axonal dimensions, the internodal conductiontime should remain constant despite the growth ofthe internode, so that the latency between two fixed

FIGURE 4. Plots in relation to body weight (n = 87) of: TEd10–20 (A), which is related to the input impedance and inversely to the nodalfast potassium channel activity; TEd90–100 (B), which reflects both the fast and slow potassium channel activities; and TEh10–20, (C), whichinversely reflects the input impedance of the axon. The ratio of TEd10–20 to TEh10–20 (D), which is related to the nodal potassium channelactivity, the difference between TEd90–100 and TEd10–20 (E), which mainly reflects the slow potassium channel activity, and the CMAPlatencies (F) are also plotted. All data are calculated from TEs at 40% de- or hyperpolarizing conditioning currents.


points should decrease in inverse proportion to theincrease in internodal length. Rushton did not con-sider changes in membrane potential of the inter-nodal axon membrane, because the “nodal resis-tance” in his model was assumed to be a property ofthe nodal axon membrane. Barrett and Barrett3 latershowed that this apparent nodal resistance reflectsmainly an access resistance to the internode. If Rush-ton’s theory is applied to the Barrett and Barrettmodel (see Appendix, Fig. 6) then both the steep-ness and the degree of fanning-out are expected tofall with increasing fiber size. The similar changes in

latency and the absolute value of TEh10–20 may there-fore primarily reflect axonal growth, and need notimply any changes in specific membrane propertieswith maturation.

In contrast, the conspicuous changes in depolar-izing TE responses in Figures 3 and 4 indicate thatpotassium channel function, responsible for the ac-commodation to depolarizing currents, cannot beconstant. In particular, the rather abrupt change at330 g suggests that, at this stage, fast potassium chan-nels are excluded from the nodal membrane, so thatthey are no longer activated by nodal depolarization.

FIGURE 5. Effects of intraperitoneal 4-aminopyridine (4-AP; left column) and CsCl (right column) on TE in rats at various ages. Each traceis the average of those from 2 (4-AP) or 3 (CsCl) rats. Thick lines are the traces before administration, and thin lines are those after. Bodyweights of rats used are shown at each recording. Note selective changes of S1-dep in the immature and the young rats (upper and middletraces), and the changes of both S1-dep and S1-hyp in the mature rats (lower traces) after 4-AP. CsCl affected the S3 segment in all agegroups.


This interpretation is strengthened by the observa-tions on the effects of 4-AP in Figure 4, since it af-fects only the early depolarizing responses in animalsweighing less than 330 g.

Previous studies of the effects of 4-AP on potas-sium channel function in developing motor axons9,18

have indicated a progressive reduction with matura-tion in the broadening of the action potential by4-AP, indicating a progressive reduction in nodal po-tassium channels contributing to spike repolariza-tion, although the time course of this change has notbeen documented in detail. The abruptness of theapparent change in potassium channel function at abody weight of 330 g indicated by TE is thereforesurprising, although the difference between youngerand older animals is not.

In light of the previous studies, the decline inTEd10–20 with body weight up to 330 g should not betaken as evidence for an increase in nodal fast po-tassium channel density: the passive cable propertieswere also undergoing large changes during this pe-riod, and the degree of fast rectification, as indicatedby the ratio TEd10–20/TEh10–20, did not change sig-nificantly during this period (Fig. 4D). It did, how-ever, approximately double between 300 and 400 g.

The “fanning-out” action of 4-AP on TE in themature animals, affecting both depolarizing and hy-perpolarizing responses, most likely reflects the in-creased input impedance of the axon through block-age of internodal potassium channels open at theresting potential. This is consistent with previous ob-servations on the effects of 4-AP on electrotonus inrat spinal roots, which causes “fanning-out” despite asmall membrane depolarization.2,12

The effect of CsCl was selective for the delayedresponse to hyperpolarization (S3), and confirmedthe previous results in vitro that S3 reflects the activ-ity of the inward rectifier, Ih.1,2,5 In immature rats, italso affected the early response to hyperpolarization,suggesting that, in these animals, Ih may be active atthe resting potential. Although the immature andyoung animals seemed to express more Ih than ma-ture animals (Figs. 4 and 5), the degree of hyperpo-larization induced by the conditioning current wasless in the mature animals, so that Ih activity couldnot be compared between these groups.

Threshold tracking is a powerful tool for investi-gating excitable membranes; it is well suited to thestudy of human peripheral nerves in vivo, but has sofar only been infrequently exploited clinically. Bystudying the maturational changes in TE, recordedtranscutaneously in rat tail motor axons in vivo, wehave found that mature rats can provide consistentrecordings comparable with those from human pe-

ripheral nerve. We expect this animal model to serveas a useful tool for interpreting the changes in hu-man TE in disease, and particularly for explorationof the pathophysiology of toxic and metabolic neu-ropathies.

APPENDIX: EFFECT OF THE PASSIVE MEMBRANEPROPERTIES ON TE

Because a clear finding in this study is that the slowthreshold changes induced by conditioning currentsare progressively reduced during maturation, weanalyze here the dependence of TE waveforms onthe passive membrane properties of a fiber, and thelikely effects of axonal growth (Fig. 6).

Passive Components of Electrotonus and TE. Sev-eral features of TE can be related to the passive(non–voltage-dependent) properties of axons andthe changes in membrane potential (electrotonus)produced by an applied current. The passive mem-brane potential changes (V) after applying a con-stant current (I) can be understood by reference tothe simplified circuit diagram in Figure 6A and areillustrated in Figure 6B and C.

At the onset of a current I, the potential acrossthe internodal axolemma (Fig. 6A) does not changebecause of the large internodal capacitance Ci, andthe fast change in potential VF is given by:

VF = I z R = I z Ril z Rn/(Rn + Ril) (1)

where:

1/R = 1/Ril + 1/Rn

This is followed by a slow component, VS, whichreaches a maximum when no current passes throughthe internodal capacitance Ci, and the total potentialchange:

VF + VS = I zR8 = I z (Ril + Ri) z Rn/(Rn + Ril + Ri) (2)

where:

1/R8 = 1/(Ril + Ri) + 1/Rn

The time constant for the slow component (tS) isgiven by the product of the internodal capacitance,Ci, and the effective resistance across it (R9); that is:

tS = Ci z R9 = Ci z Ri z (Ril + Rn)/(Rn + Ril + Ri) (3)

where:

1/R9 = 1/(Ril + Rn) + 1/Ri

The initial slope of the slow component is there-fore given by:

(dV/dt)t∼0 = VS/tS (4)

and the slow components appear to fan out from atime before the current was applied, which is desig-


nated in Figure 6B as the “fan origin” O. The timefrom the fan origin to the start of the applied cur-rent (tf) is then given by:

tf = VF/[(dV/dt)t=0] = tS z VF/VS (5)

which, by substitution of eq. (1), (2), and (3) in eq.(5) reduces to:

tf = Ci z Ril z (Ril + Rn)/Rn (6)

The ratio of slow to fast electrotonus provides ameasure of the degree of “fanning-out” [accordingto eqs. (5), (3), and (6)]:

VS/VF = tS/tf = Ri zRn/Ril z (Rn + Ril + Ri) (7)

Scaling of Passive Membrane Parameters with FiberSize. The simplest assumption to make about thescaling of membrane properties with fiber diameter(D), is that they follow the rules proposed by Rush-ton.19 He proposed that specific membrane proper-ties (i.e., membrane properties per unit area), nodalwidth, and action potential amplitude and durationwere independent of fiber size, but that internodallength, conduction velocity, membrane current,nodal area, and capacitance scaled linearly with di-ameter (D). Applying this principle to the Barrettand Barrett3 model in Figure 6, and then in our eq.(1), Rn and Ril scale as 1/D (like nodal resistance inRushton’s analysis). However, in eq. (6), the capaci-tance of the internodal axolemma (Ci) must be pro-portional to the product of axonal diameter and in-ternodal length, and therefore to D2 (unlike thecapacitance of the myelin sheath, which is propor-

tional to D). It follows that tf must be proportional toD, and that Rushton’s prediction that time relationsshould be the same for all nerves, which is approxi-mately true for action potentials, cannot be ex-tended to the slow components of electrotonus orTE. Instead, the prediction is that if specific mem-brane properties do not change, the slow passivecomponents should become both slower and smallerwith increasing fiber size. [The degree of “fanning-out” should also decrease with increasing axon di-ameter, because Ri, unlike Rn and Ril, should scalewith 1/D2, but eq. (7) predicts a factor less than1/D].

This work was supported by a grant for Peripheral Nerve ResearchProjects from the Japanese Ministry of Health and Welfare and agrant from Ono Pharmaceutical Co., Ltd.

REFERENCES

1. Baker M, Bostock H. Depolarization changes the mechanismof accommodation in rat and human motor axons. J Physiol(Lond) 1989;411:545–561.

2. Baker M, Bostock H, Grafe P, Martius P. Function and distri-bution of three types of rectifying channel in rat spinal rootmyelinated axons. J Physiol (Lond) 1987;383:45–67.

3. Barrett EF, Barrett JN. Intracellular recording from vertebratemyelinated axons: mechanism of the depolarizing afterpoten-tial. J Physiol (Lond) 1982;323:117–144.

4. Bostock H. Mechanisms of accommodation and adaptation inmyelinated axons. In: Waxman SG, Kocsis JD, Stys PK, editors.The axon. New York: Oxford University Press; 1995. p311–327.

5. Bostock H, Baker M. Evidence for two types of potassiumchannel in human motor axons in vivo. Brain Res 1988;462:354–358.

6. Bostock H, Burke D, Hales JP. Differences in behaviour of

FIGURE 6. A mathematical model of TE based solely on passive membrane properties. (A) A simplified equivalent circuit of myelinatedaxon (passive components only), according to Barrett and Barrett,3 which generates fast and slow components of electrotonus. Rn, nodalresistance; Ril, internodal leakage resistance [access resistance to internodal axolemma, through and under myelin, also known as“Barret and Barrett resistance,” illustrated in (C)]. Ri and Ci, resistance and capacitance of internodal axon. (B) Electrotonic changes inmembrane potential (V) to long current pulses (I) predicted by the circuit in (A). Vf and VS, fast and slow components of electrotonus; O,apparent origin of fanning determined by lines tangential to the initial part of the slow component; tf, the time from O to the start of thecurrent pulses. (C) Schematic illustration of the current paths in the circuit (A). Adapted from Bostock4 and Kaji.15


sensory and motor axons following release of ischaemia.Brain 1994;117:225–234.

7. Bostock H, Cikurel K, Burke D. Threshold tracking tech-niques in the study of human peripheral nerve. Muscle Nerve1998;21:137–158.

8. Bostock H, Sharief MK, Reid G, Murray NM. Axonal ion chan-nel dysfunction in amyotrophic lateral sclerosis. Brain 1995;118:217–225.

9. Bowe CM, Kocsis JD, Waxman SG. Differences between mam-malian ventral and dorsal spinal roots in response to blockadeof potassium channels during maturation. Proc R Soc Lond BBiol Sci 1985;224:355–366.

10. Eng DL, Gordon TR, Kocsis JD, Waxman SG. Development of4-AP and TEA sensitivities in mammalian myelinated nervefibers. J Neurophysiol 1988;60:2168–2179.

11. Foster RE, Connors BW, Waxman SG. Rat optic nerve: elec-trophysiological, pharmacological and anatomical studiesduring development. Brain Res 1982;255:371–386.

12. Grafe P, Bostock H, Schneider U. The effects of hyperglycae-mic hypoxia on rectification in rat dorsal root axons. J Physiol1994;480:297–307.

13. Horn S, Quasthoff S, Grafe P, Bostock H, Renner R, SchrankB. Abnormal axonal inward rectification in diabetic neurop-athy. Muscle Nerve 1996;19:1268–1275.

14. Kaji R. Pathophysiology and clinical variants of multifocal mo-tor neuropathy. In: Kimura J, Kaji R, editors. Physiology ofALS and related diseases. Amsterdam: Elsevier; 1997: p 85–98.

15. Kaji R. Physiological and technical basis of peripheral nerveand motoneuron testing. In: Kimura J, Kaji R, editors. Physi-ology of ALS and related diseases. Amsterdam: Elsevier; 1997:p 15–41.

16. Kocsis JD, Waxman SG, Hildebrand C, Ruiz JA. Regeneratingmammalian nerve fibers: changes in action potential wave-form and firing characteristics following blockage of potas-sium conductance. Proc R Soc Lond B Biol Sci 1982;217:77–87.

17. Kojima Y, Kaji R, Hirota N, Kohara N, Kimura J. Thresholdelectrotonus in monomelic amyotrophy with spinal hemiatro-phy. Electroencephalogr Clin Neurophysiol 1995;97(Sup-pl):S172.

18. Ritchie JM. Sodium and potassium channels in regeneratingand developing mammalian myelinated nerves. Proc R SocLond B Biol Sci 1982;215:273–287.

19. Rushton WAH. A theory of the effects of fiber size in medul-lated nerve. J Physiol 1951;115:101–122.

20. Schilling T, Heinrich B, Kau R, et al. Paclitaxel administeredover 3 h followed by cisplatin in patients with advanced headand neck squamous cell carcinoma: a clinical phase I study.Oncology 1997;54:89–95.

21. Watanabe T, Kaji R, Oka N, Bara W, Kimura J. Ultra-high dosemethylcobalamin promotes nerve regeneration in experi-mental acrylamide neuropathy. J Neurol Sci 1994;122:140–143.


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Effect of maturation on nerve excitability in an experimental model of threshold electrotonus