1977 Waxman - A Review of G-ratios

7/26/2019 1977 Waxman - A Review of G-ratios

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Progress in Neurobiology 1977, Vol. 8, pp. 297-324. PergamonPress.Printed n Great Britain

T H E C O N D U C T I O N P R O P E R T IE S O F A X O N S I N C E N T R A L

W H I T E M A T T E R

STEPHEN G. WAXMAN and HARVEY A. SWADLOW

Department of Neurology Harvard M edical School B eth Israel Hospital

Boston Ma ss. 02215; Research Laboratory of Electronics and Program in

He alth Sciences and Technology Massachusetts Insti tute of Technology

Cambridge Mass. 02139

Contents

1. Introduction

2. Diameter spectra in central white matter

3. Relative conducti on velocities of myelinated and non-myelinated fibers in the central

nervous system

4. Developmental constraints on myelination in central white matter

5. Properties of axons in the rabbit corpus callosum

5.1. Morphology

5.2. Physiology

5.2.1. Conduction velocity and refractory period

5.2.2. The supernormal period

5.2.3. The subnormal period

5.2.4. Variations in conduction properties of other axons

6. Alterations in conduction in demyelinated white matter

7. Conclusions and implications

Acknowledgements

References

1. Introduction

297

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298

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321

I t is t h e p u r p o s e o f th i s a rt i cl e t o r e v i e w th e a v a i l a b l e d a t a c o n c e r n in g t h e c o n d u c t i o n

p r o p e r t i e s o f a x o n s i n t h e w h i t e m a t t e r o f t h e c e n tr a l n e r v o u s s y s te m . I n t e r p o s e d b e tw e e n

c e ll b o d y a n d p r e s y n a p t i c e n d in g , t h e a x o n p l a y s a n im p o r t a n t r o l e in d e t e r m in in g

th e n a tu r e o f i n f o r m a t io n t r a n sf e r i n t h e n e r v o u s s y s te m . D e s p i t e t h i s fa c t, a n d d e s p i t e

t h e o b v io u s cl i ni c al im p o r t a n c e o f d i s e a se s o f t h e c e n t ra l w h i t e m a t t e r t h e re a r e , f o r

exam ple , a lm os t 100,000 iden t i f iab le cases o f mul t ip le sc le ros i s a t an y t im e in the U ni ted

S ta t e s a l o ne ) , th e r e i s a r e l a ti v e p a u c i t y o f i n f o r m a t io n c o n c e r n in g t h e c o n d u c t i o n

p r o p e r t i e s o f a x o n s i n m a m m a l i a n c e n t r a l w h i t e m a t t e r . T h i s d o e s n o t r e fl e ct a l a c k

o f i n te r e st , b u t r a t h e r i n d i c a te s t h e r e l a t iv e i n a c c e s s a b i l it y o f m a m m a l i a n c e n t r a l a x o n s ,

a n d t h e d i f fe r e n ce i n si ze w h e n c o m p a r e d t o m a m m a l i a n p e r i p h e r a l a x o n s a n d t o t h e

e v e n l a r g e r i n v e r t e b r a t e a x o n s w h ic h h a v e p r o v id e d e x p e r im e n ta l m o d e l s .

Ea r l i e r p a p e r s W a x m a n , 1 97 2, 19 75 a) h a v e re v i e w e d t h e c o n d u c t i o n p r o p e r t i e s o f

the p re te rm ina l reg ions o f the axon , w here the re i s a h igh degree o f reg iona l d i f fe ren tia -

t i o n a n d a c o r r e s p o n d in g ly c o m p le x s e t o f f u n c t i o n a l s p e c ia l iz a t io n s . I n t h e p r e s e n t

a r t ic l e w e e x a m in e t h e p r o p e r t i e s o f t h e u n b r a n c h e d a x o n i n c e n t r a l w h i t e m a t t e r . T h e

b e h a v io r o f t h e s e a x o n a l t r u n k s i s n o t s im p le . S u r p ri s in g ly , t e m p o r a l t r a n s f o r m a t io n s

o f im p u l s e t r ai n s m a y o c c u r e v e n i n t h e p r im a r y a x o n a l t r u n k , i n r e g io n s d e v o id o f

b r a n c h p o in t s o r t e r m in a l s p e c i a l iz a t io n s . W e a l s o d i s c u ss t h e a l te r a t i o n s i n c o n d u c t i o n

w h ic h o c c u r i n a b n o r m a l ly m y e l i n a t e d a n d d e m y e l in a t e d a x o n s . W e h o p e t h a t t h i s

a r ti c le w il l s t im u la t e i n t e re s t in t h e c o n d u c t i o n p r o p e r t i e s o f b o th n o r m a l a n d p a th o lo g i -

ca l cen t ra l axons .

2 . D iameter Spectra in Centra l White M at ter

Bisho p 1966) noted that , wh i le large my el inated f ibers are more he av i ly represented

i n m a m m a l i a n c o r t e x t h a n i n th e f o r e b r a in s o f i n f r a m a m m a l i a n s p e ci e s, t h e m y e l i n a t e d

Please address reprint requests to the Harvard Neurological Unit, Beth Israel Hospital, 330 Brookline

Ave., Boston, Mass. 02215.

297


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298 S.G . WAXMANAND H. A. SWADLOW

fiber popu la t ion in mammal ian co r t ica l sys tems s t i l l con ta ins re la t ive ly few la rge f ibe rs

c o m p a r e d t o p e r i p h e r a l n e r v e . H e r e p o r t e d t h a t , i n m a m m a l i a n c o r t e x , l e s s t h a n 2 0 %

of f ibe rs exh ib i ted d iam ete rs g rea te r than 3 #m. B ishop an d Smi th (1964) , u s ing e lec t ron

m ic r o s c o p y , d e m o n s t r a t e d m y e l i n a t e d f i b er s c o n s id e r a b ly s m a l le r t h a n 1 /~ m in m a m -

mal ian and rep t i l i an co r t ica l wh i te ma t te r .

B i s h o p e t a l ( 19 69 ) d e r i v e d d i a m e te r s p e c t r a w i th p e a k s a t a p p r o x im a te ly 1 ~ m a n d

wi th appr ox im ate ly 35% of fibe r d iamete rs le ss than 1 .5 ~ tm in ca t op t ic ne rve , w h ich

m ay be cons ide red as a pe r iphe ra l ex tens ion o f the w hi te ma t te r . A xons exh ib i t s imi la rly

s m a l l d ia m e te r s i n m a n y o th e r r e g io n s o f t h e c e n t ra l w h i t e m a t t e r . F ib e r d i a m e te r s p e c t r a

f rom ca t g rac i le and cun ea te fa sc icu li , do rsa l pa r t o f do rsa l co lum ns , an te r io r and pos -

t e r i o r l a t e r a l f u n i c u l i , a n d p y r a m id a l t r a c t , w e r e s t u d i e d b y H i ld e b r a n d a n d S k o g l a n d

(1971) . The la rges t do rsa l c o lum n f ibe rs in adu l t ca t s had d iam ete rs o f 12 -15 pm bu t

o n ly 3 0 - 4 0 % h a d d i a m e te r s o f 4 # m o r m o r e i n t h e d o r s a l r e g io n o f d o r s a l c o lu m n s ,

and on ly 17% measu red 4 #m or m ore in g rac ile fascicu li . In po s te r io r la te ra l fun icu l i

o n ly 1 3 - 2 2 % o f f i be r s m e a s u r e d 4 # m o r m o r e . I n t h e p y r a m id a l t r ac t , s l i gh t ly m o r e

th a n 5 0% o f f i be r s h a d d i a m e te r s o f l es s th a n a p p r o x im a te ly 1 p m w i th o n ly 6 - 9 %

hav ing d iam ete rs o f m ore than 4 #m. L oew y (1974) , in s tud ies on ca t do rsa l sp ino ce rebe l -

la r trac t , found tha t 50 -75% of f ibe rs had a d iam ete r o f less than 5 /~m. F ibe r d iam ete rs

i n t h e v is u a l c o m p o n e n t o f t h e c o r p u s c a l l o s u m o f t h e r a b b i t a r e d e s c r i b e d b e lo w .

Th e a b o v e e x a m p le s a r e n o t i n t e n d e d a s p a r t o f a s y s t e m a t i c su r v e y o f f ib e r d i a m e te r s

bu t a re , ra the r , m ean t to i l lu s t ra te the re la t ive ly smal l d iam ete rs o f mye l ina ted f ibe rs

in the cen t ra l wh i te ma t te r . I t shou ld be kep t in mind , in th is rega rd , tha t seve ra l

p a p e r s ( W a x m a n a n d Be n n e t t , 1 9 7 0 ; S c h n e p p a n d S c h n e p p , 1 9 7 1 ; E ld r e d a n d M o r a n ,

1974) have ca l led in to que s t ion the p rac t ice o f de te rm in ing f ibe r d iam ete rs by l igh t

mic roscop y , s ince m any f ibe rs (e spec ia l ly in the cen t ra l ne rvo us sys tem) appr oac h o r

fal l be lo w the l imi t o f re so lu t ion o f the l igh t mic rosc ope .

The d i f fe rences in d iamete rs o f my e l ina ted f ibe rs in d i f fe ren t t rac t s o f the cen t ra l

ne rvous sys tem, a s compared to pe r iphera l ne rve , may have phys io log ica l s ign i f icance ,

s i n c e i t i s n o w k n o w n th a t a x o n a l c o n d u c t i o n p r o p e r t i e s a r e n o t s c a l e - i h v a r i a n t i n t h e

t ime dom ain . Fo r examp le , sp ike dura t ion , r i se - t ime and fa l l- t ime (Pa in ta l , 1966 , 1967),

r e f r a c to r y p e r i o d ( P a in t a l, 1 9 6 6 , 1 96 7; S w a d lo w a n d W a x m a n , 1 9 7 6 ), i n t e r n o d a l c o n d u c -

t i o n t im e ( Co p p in a n d J a c k , 1 97 2) , a n d t h e d u r a t i o n o f t h e s u p e r n o r m a l p e r i o d ( S w a d lo w

and W axm an , 1976 ; see a l so be low) va ry sys tem at ica l ly wi th f ibe r d iamete r .

3 . Rela t ive Conduction Velocities o f M yelinated and

Non myelinated Fibers in the Central Nervous System

A s s h o w n a b o v e , a s ig n i fi c an t n u m b e r o f m y e l i n a t e d a x o n s i n c e n t r al w h i t e m a t t e r

have d iam ete rs o f le ss than 1 #m, the smal le s t f ibe rs be ing 0 .2 #m in d iam ete r . I f conduc -

t ion ve loc i ty o f my e l ina ted f ibe rs va rie s d i rec t ly wi th f ibe r d iame te r , wh i le the con duc t ion

ve loc i ty o f non -m ye l ina ted f ibe rs va rie s wi th d iam ete r 1/2 , i t sh ou ld be e xpec ted tha t

t h e r e l a ti o n s h ip s b e tw e e n c o n d u c t i o n v e lo c i ty a n d d i a m e te r f o r t h e tw o g r o u p s o f f i b er s

s h o u ld i n t e r se c t a t s o m e p o in t . Be lo w th is c ri t ic a l d i a m e te r a n o n - m y e l i n a t e d f i b e r w o u ld

b e e x p e c t e d t o c o n d u c t m o r e r a p id ly t h a n a m y e l i n a t e d f i b e r o f t h e s a m e d i a m e te r .

Th e p r o p o r t i o n a l i t y b e tw e e n c o n d u c t i o n v e lo c it y a n d f i b e r d i a m e te r f o r m y e l i n a t e d

a x o n s d e p e n d s o n t h e a s s u m p t io n s 1 ) t h a t s p ec i fi c m e m b r a n e p r o p e r t i e s a r e t h e s a m e

for f ibe rs o f d i f fe ren t d iamete r , a nd 2 ) tha t the f ibe rs exh ib i t d im ens ion a l s imi la r i ty

(Rush ton , 1951). The la t te r, pu t in som ew ha t s impl i f ied fo rm, requ i res th a t no da l a rea

v a r y d i re c t ly w i th d i a m e te r a n d t h a t i n t e r n o d a l l e n g th b e p r o p o r t i o n a l t o f i b e r di a m e te r.

Ru s h to n o b s e r v e d t h at , t o a r o u g h a p p r o x im a t io n , d im e n s io n a l s im i la r it y d id a p p ly

to pe r iphera l axons . He fu r the r obse rved tha t in the pe r iphera l ne rvous sys tem, a l l

f i be r s w i th d i a m e te r s o f m o r e t h a n a p p r o x im a te ly 1 # m a r e m y e l i n a t e d ( V i s o z o a n d

Yo ung , 1948 ; see a l so Mat the ws , 1968) , and p resen ted a se t o f a rgum ents lead ing to

th e c o n c lu s io n t h a t 1 # m w a s t h e d i a m e te r a t w h ic h t h e tw o d i a m e te r - c o n d u c t i o n v el-

oc i ty re la t ionsh ips c rossed , i . e . tha t 1 /~m was a ph ys io log ica l ly c r i ti ca l d iam ete r abo ve


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THE CONDUCTION PROPERTIES OF AXONS IN CENTRAL W HITE MATTER 299

at / I

i I

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F I / I

, L . / -

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o /

1 2 3 4

i b r e d i a m e t e r ~ )

F IG . 1 . P re d ic t e d r e l a t io n s b e tw e e n c o n d u c t io n v e lo c i ty a n d f ib e r d i a me te r fo r s ma l l my e l in a te d

a n d n o n - my e l in a te d f ib e rs , mo d i f i e d f ro m R u s h to n s (1 9 51 ) F ig . 5 a s in d ic a t e d in th e t e x t . T h e

e n c i rc l e d p o in t r e p re s e n t s G a s s e r s (19 5 0) me a s u re m e n t s fo r t h e l a rg e s t C f ib e rs . T h e r e v i s e d

l i n e a r r e l a t i o n ( - . . . . . . ) f o r m y e l i n a t e d fi b e rs i n t e rs e c ts t h e p a r a b o l i c re l a t i o n ( ) f o r n o n -

m y e l i n a t e d f ib e r s a t a p o i n t c o r r e s p o n d i n g t o a d i a m e t e r o f a b o u t 0 .2 /~ m . T h e d a s h e d l i n e

( - - - - - ) i s R u s h t o n s r e la t i o n fo r m y e l i n a t e d fi be rs . F r o m W a x m a n a n d B e n n e t t , 19 72 .

which myelin increases conduction velocity and below which conduct ion is faster

without myelination . This conclusion is referred to widely. I t is based on the relations

shown in Fig. 1 which are redrawn from Rushton's (1951) Fig. 5. The diameter-conduc-

tion velocity relation for non-myelinated fibers is a parabola perpendicular to the

ordinate at the origin, drawn on the basis of the proportionality of conduction velocity

to diameter 1/2, using Gasser 's (1950) measurements of the diameter (1.1 #m) and conduc-

tion velocity (2.3 m/sec) of the largest unmyelinated fibers. The nearly linear relation

between conduction velocity and diameter for myelinated fibers intersects the parabola

at a point corresponding to a diameter of 1 #m, suggesting that small central myelinated

fibers should conduct less rapidly than non-myelinated fibers of the same diameter.

Furthermore, extrapolation of the diameter-conduction velocity relationship downward

leads to intersection of the abscissa at a diameter of 0.6/~m, suggesting that myelinated

fibers smaller than this should not conduct impulses at all.

Since myelinated fibers smaller than 1 #m, and in many cases smaller than 0.6 #m,

are commonly present in the central nervous system, Waxman and Bennett (1972) re-

examined the arguments leading to the conclusion that 1 #m constitutes a physiologically

critical diameter for myelination. Rushton derived the d iameter-conduction yelocity rela-

tion for myelinated fibers from the relation

V a O g ~ / l o g ~ g

(1)

where V = conduct ion velocity, D = overall fiber diameter, and g is defined as the ratio

of axon diameter to overall fiber diameter. Sanders' (1948) measurements of the value

of g were used to compute the left side of the equation, and the resulting curve was

fit to Hursh's (1939) data relating diameter and conduction velocity, as shown in Fig.

2. The extrapolated region of the curve (dashed line) was replotted on an expanded

scale as the relation between diameter and conduction velocity for myelinated fibers

in Rushton's Fig. 5.

Sanders' measurements on the values of g were derived from light microscopic obser-

vations on rabbit peroneal nerve, and suggest that the value of g decreases rapidly

for small fibers, approaching a value of zero for a diameter of 0.6 #m. This accounts

for the predicted failure of conduction at this diameter, since core resistance is infinite

when g = 0. More recent data, derived from electron microscopy, indicates that the

value of g does not approach 0 for small myelinated fibers, but rather remains in the

range between 0.6 and 0.9. This observation applies to peripheral nerve (Friede and


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300 S .G . WAXMANAND H. A. SWADLOW

14

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2 4 6 8 1 12 14 16 18

2

F i b r e d i a m e t e r / z )

FIG. 2. Predicted relations between condu ction velocityand fiber diameter for myelinatedaxons,

modified from R ushton 's (1951) Fig. 3. O pe n and closed circles represen t Hursh's (1939) observa-

tions on conduction velocity of fibers fro m kittens and cat s respectively. Rushton's relation

computed using Sanders' measurements of g (the ratio of axo n d iameter to overall fiber diameter)

is indicated by the solid curve with dashed extrapo lation for sm all diameters. The linear relation

based on the assumption of constant g is indicated by the br ok en lin e; its slope is

5.5 m sec -'/lm -1. From W axman and Bennett, 1972.

S a m a r a j s k i , 1 9 6 7 ; S c h n e p p a n d S c h n e p p , 1 9 7 1 ) , n e u r o p i l i n t h e c e n t r a l n e r v o u s s y s t e m

( W a x m a n a n d B e n n e t t , 1 9 7 0 ; W a x m a n , 1 9 75 b ), a n d c e r e b r a l w h i t e m a t t e r ( B i s h o p e t

a l . 1971 ; s ee a l so Se c t i on 5 .1 . o f t h i~ p a pe r ) .

I f i t i s a s s u m e d t h a t t h e v a l u e o f g r e m a i n s c o n s t a n t , i t f o l lo w s f r o m e q u a t i o n (1 )

t h a t c o n d u c t i o n v e l o c i t y s h o u l d b e p r o p o r t i o n a l t o fi b e r d ia m e t e r , a n d t h a t t h e r e l a t i o n

b e t w e e n c o n d u c t i o n v e l o c i ty a n d d i a m e t e r s h o u l d i n t e rs e c t t h e o r i g in . T h e r e v is e d , li n e a r

r e a t i o n b e t w e e n c o n d u c t i o n v e l o c i ty a n d d i a m e t e r , t o g e t h e r w i t h R u s h t o n ' s r e l a ti o n s

f o r m y e l i n a t e d a n d n o n - m y e l i n a t e d f i b e r s , a r e s h o w n i n F i g . 1 . T h e r e v i s e d r e l a t i o n

f o r m y e l i n a t e d f ib e r s i n t er s e c ts t h e r e l a t i o n f o r n o n - m y e l i n a t e d f ib e r s a t a p o i n t c o r r e -

s p o n d i n g t o a d i a m e t e r o f 0 .2 /~ m , s u g g e s ti n g t h a t f o r d i a m e t e r s g r e a t e r t h a n 0 . 2 / tm ,

m y e l i n a t e d f ib e r s s h o u l d c o n d u c t m o r e r a p i d l y t h a n n o n - m y e l i n a t e d f i be r s o f s i m i la r

d i a m e t e r . 0 . 2 # m is , i n f ac t , t h e d i a m e t e r o f t h e s m a l l e s t m y e l i n a t e d f i b e rs o b s e r v e d

i n t h e c e n t r a l n e r v o u s s y s t e m . I t i s i n t e r e s t i n g t o n o t e , i n t h i s r e g a r d , t h a t f o r a v a l u e

o f g o f 0 .6 ( th e v a l u e w h i c h R u s h t o n c a l c u l at e d w o u l d m a x i m i z e c o n d u c t i o n v e lo c it y ),

f ib e rs w i th t h e t h i n n e s t m y e l i n s h e a t h s ( a p p r o x i m a t e l y 2 0 0 4 t h ic k ) w o u l d h a v e d i a m e t e r s

o f 0 .1 # m , a v a l u e q u i t e c l o s e t o t h e s iz e o f t h e s m a l l e s t m y e l i n a t e d f i b e r w h i c h w a s

p r e d i c t e d b y t h e r e v i s e d r e l a t i o n s h i p s s h o w n i n F i g . 1 .

T h e r e is, in f a c t, e v i d e n c e w h i c h s u g g e st s t h a t c o n d u c t i o n v e l o c i ty m a y n o t b e d i r e c t ly

p r o p o r t i o n a l t o a x o n d i a m e t e r . P a i n t a l ( 1 9 6 7 ) h a s s h o w n t h a t s p i k e d u r a t i o n v a r i e s

i n v e r s e ly w i t h d i a m e t e r in p e r i p h e r a l a x o n s , a n d C o p p i n a n d J a c k ( 1 9 7 2 ; se e a l so d a t a

r e p l o t t e d i n J a c k e t a l . 1 9 75 ) h a v e d e m o n s t r a t e d t h a t i n t e r n o d a l c o n d u c t i o n t i m e is

n o t c o n s t a n t , b u t is r a t h e r g r e a t e r i n f i b e r s o f sm a l l d i a m e t e r t h a n i n f i b e rs o f la r g e

d i a m e te r . F u r t h e r m o r e , B o y d a n d D a v e y ( 1 96 8) f o u n d t h a t w h e r e a s t h e r a ti o o f c o n d u c -

t i o n v e l o c i t y t o a x o n d i a m e t e r w a s 5 . 6 f o r c t- m o t o r a x o n s , it w a s 4 . 4 - 4 .5 f o r y - m o t o r

a x o n s . T h e s e o b s e r v a t i o n s c o u l d b e e x p l a i n e d b y e i t h e r d i ff e r en c e s i n s p e ci fi c m e m b r a n e

p r o p e r t i e s f o r f i b e rs o f d i ff e r e n t d i a m e t e r , o r b y a d e v i a t i o n f r o m d i m e n s i o n a l s i m il a ri ty .

T h e r e is s o m e m o r p h o l o g i c a l d a t a s u g g e s t i n g t h a t n o d a l s u r f a c e a r e a i s n o t p r o p o r t i o n a l

t o f i b e r d i a m e t e r , s in c e t h e r a t i o o f n o d a l d i a m e t e r t o f i b e r d i a m e t e r i s s m a l l e r f o r

l a r g e t h a n f o r s m a l l f i b e r s ( s e e , e . g . H e s s a n d Y o u n g , 1 9 5 2 ; R o b e r t s o n , 1 9 6 0 ) . T h e r e

h a v e b e e n , h o w e v e r , n o s y s t e m a t ic s t u d ie s o n t h e r e l a ti o n s h i p o f n o d a l s u r fa c e a r e a

t o fi b e r d i a m e t e r , a n d t h e r e h a v e b e e n n o d i r e c t c o m p a r i s o n s o f t h e m e m b r a n e p r o p e r t i e s

a t t h e n o d e o f R a n v i e r i n l a r g e a n d s m a l l f ib e r s.


5/28

THE CONDUCTION PROPERTIES OF AXONS IN CENTRAL WHITE MATTER 301

4 D e v e l o p m e n t a l C o n s t r a in t s o n M y e l i n a t io n i n C e n tr a l W h i t e M a t t e r

As shown above, there may be a critical diameter above which myelination results

in an increase in conduction velocity. Duncan (1934) suggested that, during develop-

ment, myelination was directly dependent on diameter, with myelination occurring when

axons achieved a diameter of 1 pm in the peripheral nervous system. Seggie and Berry

(1972), on the basis of their studies on corpus callosum of the rat, concluded that

the smallest myelinated fibers have diameters of 0.3 pm and that unmyelinated fibers

have diameters of 0.3 pm or less. This conclusion is not supported by our own data

from rabbit corpus callosum (Figs. 3 and 4), which indicate an overlap in diameter

between the largest unmyel inated and smallest myelinated fibers. Figure 3 shows a field

in the rabbit corpus callosum, including an unmyelinated fiber which is larger than

the adjacent myelinated fibers. The data of Fleischauer and Wartenberg (1967) on ca t

corpus callosum revealed an overlap in the diameters of myelinated and non-myelinated

fibers at all stages in development. Matthews and Duncan (1971) also concluded that

there is no one critical and constant diameter in the central nervous system, above

which all fibers are myelinated and below which myelination does not occur, but that

myelin rather appears first on larger axons and subsequently appears on smaller axons.

Fraher's (1972) data from rat ventral root similarly show that there is no single diameter

at which myelination begins at this site.

If diameter does not provide the signal for myelination, how is specificity in myelina-

tion achieved? Simpson and Young (1945) showed, in cross-union experiments in peri-

pheral nerve, that it is the axon which signals whether or not myelination will proceed.

Furthermore, Weinberg and Spencer (1976), demonstrated that the Schwann cells of

normally unmyelinated nerve trunks will produce myelin when innervated by axons

from a myelinated nerve.

It thus appears that the signal for myelination is (at least in peripheral nerve) initiated

by the axon. Yet the dialogue between axon and myelin-forming cell is more complex

than: I am axon. Myelinate me, because myelin thickness, internode length, and nodal

area are all matched to fiber size and type. Furthermore, the relationships between

FIG. 3. Adjacent unmyelinated U) and myelinated M1, M2) axons from the visual componen t

of the rabbit corpus callosum. The diameter of unmyelinated axon U) is greater than the

diameter axon plus myelin sheath) of myelinated fiber M1. The diameter of axon u is less

than the outer diameter of the myelin sheath of axon M2, but greater than that of axon cylinder

M2 within the sheath. An astrogl ial process a) is present, x 52,000.


6/28

302 S.G. WAXranyAND H. A. SWADLOW

2 1 0

2 0 0

1 9 0

1 8 0

1 7 0

1 6 0

1 5 0

1 4 0

1 3 0

t o 1 2 0

it.

0

r , . - 1 0 0

~ 9

z 8

70

5 O

4 0

3 0

oO

t~ / / f d N O N - M Y E L I N A T E D

t . . . : t M Y E L I N A T E D

D I A M E T E R / ~ m )

F IG . 4 . D ia me te r s p e c t r a fo r a s a mp le o f 8 7 2 my e l in a te d a n d n o n -my e l in a te d f ib e r s i n th e

s p le n iu m o f th e r a b b i t c o rp u s c a l lo s u m. N o n -my e l in a te d f ib e r s a re in d ic a t e d b y o b l iq u e l i n e s .

M y e l in a te d f ib e r s a re in d ic a t e d b y s t ip p l in g . N o te th e o v e r l a p b e tw e e n th e d i a m e te r o f t h e

l a rg e s t u n m y e l in a te d f ib e r s a n d s m a l l e s t my e l in a te d f ib e rs . W a x m a n a n d S w a d lo w , 1 9 7 6 b) .

these parameters and fiber diameter vary in different parts of the central nervous system

(Waxman, 1972). The nature of the signals which determine the specificity of myelination

is not known, and remains an important question in developmental neurobiology.

5 Propert ies o f A xon s in the Rabbit Corpus Ca llosum

This section describes the morphological and physiological properties of axons in

the visual component of the corpus callosum of the rabbit. In particular, it describes

the periods of increased and decreased conduction velocity and threshold which follow

impulse activi ty in these fibers (Swadlow, 1974b; Swadlow and Waxman, 1975, 1976;

Waxman and Swadlow, 1976a). While the diameter spectra of these axons is somewhat

smaller than those of axons in some other areas of the cerebral white matter, the simi-

larity of their morphology to that of other central axons suggests that their conduction

properties may be similar. Indeed, as shown in section 5.2.4. many of the interesting

physiological properties of these axons have been observed at other sites in the central

and peripheral nervous system.

5 1 M O R P H O L O G Y

The splenium of the corpus callosum of the adult rabbit, like most other white matter

tracts, contains both non-myelinated and myelinated fibers. Figure 4 shows the diameter

spectra for 872 fibers fixed with glutaraldehyde and osmium tetroxide (Waxman and

Swadlow, 1976b). Non-myelinated axons comprise approximately 45~o of the fiber popu-

lation. These fibers are round to ovoid in transverse section and range from 0.08 m

to 0.6/~m in diameter (mean = 0.20 m; SD = 0.08). Although occasional single non-


7/28

THE CONDUC TION PROPERTIES OF AXONS IN CENTRAL WHITE MATTER 303

myel inated f ibers are present, the non-my el inated ax ons usua l ly occur in c lust ers o f

a t l east 3 -4 axon s F ig . 5 ). In some areas as many as 10-20 unm yel inated fibers are

c lustered together wi th no in terven ing non-neura l processes . Adjacent non-myel inated

f ibers are in most areas separated f rom each o ther and f rom myel inated f ibers by an

extrace llu lar space a t l east 200 A wide , and there are n o mo rpholog ica l ly sp ec ia l ized

junct ions between non-myel inated f ibers. Astrocyt ic processes are only rarely inters-

F lO . 5. S u r v e y e l e c t r o n m i c r o g r a p h s h o w i n g s li g h t ly o b l iq u e l y c u t a x o n s i n t h e s p l e n i u m o f

t h e r a b b i t c o r p u s c a l l o s u m . C l u s t e r s o f u n m y e l i n a t e d a x o n s u ) a r e s e e n b e t w e e n t h e m y e l i n a t e d

a x o n s . A t r a n s v e r s e s e c t io n t h r o u g h a m y e l i n a t e d a x o n a t a n o d e o f R a n v i e r i s s e e n n ). A

d e n s e c y t o p l a s m i c u n d e r c o a t i n g is p r e s e n t s u b j a c e n t to t h e n o d a l a x o n m e m b r a n e . A n a s t r o g l i a l

p r o c e s s a ) p a r t i a ll y s u r r o u n d s t h e n o d a l a x o n . T h e i n s e t s h o w s a c l u s te r o f u n m y e l i n a t e d a x o n s

u ) a t h i g h e r m a g n i f i c a t i o n . N o t e t h a t a d j a c e n t u n m y e l i n a t e d a x o n s a r e s e p a r a t e d b y a n e x t r a c e l-

l u l a r s p a c e a p p r o x i m a t e l y 2 0 0 A w i d e . x 3 6 , 0 00 . I n s e t 5 2 , 0 00 .


8/28

304 S.G. WAXMAN AND H. A. SWADLOW

FIG. 6. Electron micrograph showing transverse sections of myelinated (m) and unmyelinated

(u) axons in spleniUm of the rabbi t corpus callosum. The axoplasm contains neurofilaments

and microtubules. The largest unmyelinated fibers have diameters of 0.6 m, while myelinated

fibers as small as 0.3/an are present. The inset shows several myelinated fibers with diameters

of less than 0.6/~m; the smallest has a diameter of 0.4 ,am. a = as trocytic process. Bar indicates

1 ,am. x 60,000.

persed between adjacent non-myelinated axons. Axoplasm of the non-myelinated axons

is electron-lucent and contains longitudinally oriented microtubules (approximately

200 A in diameter) and filaments (approximately 60 A in diameter). There are also occa-

sional profiles of tubular reticulum and mitochondria.

The major ity of myelinated fibers have diameters of less than 1/~m. In low-power

fields containing thousands of axons, occasional axons larger than 2/~m are present,

but these are distinctly rare. In the sample shown in Fig. 4, myelinated fibers comprise

approximately 55~o of the axons. The diameters range from 0.3 m to 1.85/~m

(mean = 0.74 m; SD = 0.24). As discussed in Section 4, there is no single diameter

above which all axons are myelinated and below which all axons are non-myelinated.

As in the other regions of the central nervous system (see, e.g. Peters, 1964), the myelin

sheath exhibits a spiral configuration, with a periodicity of approximately 120 A (Figs.

6, 7). Schmidt-Lantermann clefts are not present. The myelin sheaths of some adjacent


9/28

THE CONDUCTION PROPERTIES OF XONS IN CENTR L WHITE M TTER

305

F I G . 7 . E l e c t r o n m i c r o g r a p h s h o w i n g t h e s p i r a l c o n f i g u r a t i o n o f t h e m y e l i n i n c e n t r a l w h i t e

m a t t e r a x o n s . T h e i n n e r a ) a n d o u t e r b ) l i p s o f t h e m y e l i n a r e u s u a ll y l o c a t e d w i t h i n t h e

s a m e s e c to r o f t h e m y e l in s h e a th , a s s h o w n in F ig . 9 . My e l in s h e a th s o f a d ja c e n t f ib e r s o f t e n

c o m e in to c lo s e a p p o s i t io n , w i th th e fo rm a t io n o f a n in t r a p e r io d l i n e l a rg e a r ro w ) . 84 ,0 0 0.

a x o n s c lo s e ly a p p o s e e a c h o th e r , w i th t h e f o r m a t io n o f a n i n t r a p e r io d l i ne b e tw e e n

them, a s desc r ibed in o the r cen t ra l mye l ina ted t rac t s Pe te rs , 1960).

Th e r e l a t io n s h ip b e tw e e n m y e l in s h e a th t h i c k n e s s a n d f i b e r d i a m e te r i s s h o w n in

F ig . 8, wh ich il lu s t ra te s the ra t io 9 axon d iam ete r / to ta l f ibe r d iam ete r ) fo r a rep resen ta -

t ive g ro up o f 54 f ibe rs . Va lues o f g fo r these f ibe rs range f rom 0 .64 to 0 .87 me an = 0 .77 ;

SD = 0 .05) and show o n ly a sma l l va r ia t ion wi th f ibe r s ize. A l ine f it to these po in ts

by the leas t - sq uare m e th od ha s a s lope o f 0 .074 and a y - in te rce p t o f 0.72 ). Th ese va lues

o f 9 a r e s im i la r t o t h o s e w h ic h h a v e b e e n r e p o r t e d b y o th e r w o r k e r s f o r a x o n s i n

o th e r pa r t s o f the whi te ma t te r see , e .g . Bis hop

e t a l .

1971).

Th e e x t e r n a l t o n g u e o f g li a l c y to p l a s m , w h ic h i s c o n t i n u o u s w i th t h e o u t e r m o s t l a y e r

o f t h e m y e l in , c o n t a in s m ic r o tu b u l e s , f il a m e n t s, a n d m e m b r a n e p r o fi le s . In m o s t c a s e s

th e e x t e r n a l gl ia l c y to p l a s m s u b t e n d s a n a n g l e o f l es s th a n 4 5 a r o u n d t h e c i r c u m f e r e n c e

o f t h e m y e l i n s h e a th . T h e i n n e r l i p o f gl ia l c y to p l a s m , a l s o i n c o n t i n u i t y w i th t h e m y e l i n ,

c o n t a in s o c c a s io n a l m ic r o tu b u l e s , f i l a m e n t s , a n d m e m b r a n o u s p r o f i l e s . A s s e e n i n F ig .

7 , t h e in n e r m e s a x o n a n d e x t e r n a l l o o p o f g l ia l c y to p l a s m in m a n y a x o n s a r e l o c a t e d

in the sam e sec to r o f the my e l in shea th ; th i s in t r igu ing re la t ionsh ip was f i rs t desc r ibed

b y P e t e r s 1 96 4) i n t h e o p t i c n e rv e . F ig u r e 9 s h o w s t h e r e l a t i o n b e tw e e n t h e p o s i t i o n s

o f t h e i n n e r m e x a s o n a n d o u t e r t o n g u e o f g l ia l c y to p l a s m in 1 96 v i s u a l c a U o s al a x o n s .

I 0

0 . 9

0 . 8

g

0 7

O . 6

I I

0 . 3

0 4

o e e

. z , . .

. . . . .

I I I I I I I I I

0 5 0 6 0 7 0 8 0 9

1.0 I.I 1.2 1.3

F I B E R D I A M E T E R ( ,~ M )

F IG . 8 . V a lu e s o f r a t io g a x o n d ia m e te r / to t a l f i b e r d i a m e te r ) fo r f ib e r s f ro m th e s p le n iu m .

V a lu e s o f g r a n g e f ro m 0 . 6 4 to 0 .8 7 , w i th a m e a n o f 0 .7 7 . W a x m a n a n d S w a d lo w , 1 9 76 b ).


10/28

306 S. G . WAXMANAND H. A. SWADLOW

0 ~ 0

D < 0 75p . m D _> 075 . m

o ~ ' , I o o ~ I

180* 180*

FIG. 9. Relative positions of inner mesaxon s and external tongues of glial cytoplasm in transverse

sections of small (D < 0.75 #m, grap h A ) and large (D >/0.75 #m, graph B) fibers from the

splenium, measured using the m ethod of Peters (1964). The angle fl was measured between

points a and b, as indicated in the axon in Fig. 7. The relative frequency of angle fl within

each 45 octant is indicated b y a percentage in the m iddle of each diagram and is also sho wn

by the siz e of the black bar at the periphery of the octant. (Waxm an and Swadlow , 1976b).

I n n e r m e s a x o n a n d e x t e r n a l g l ia l c y t o p l a s m a r e l o c a t e d w i t h i n t h e s a m e q u a d r a n t i n

m o r e t h a n 55 ~o o f a x o n s . M o s t f r e q u en t l y , t h e r e i s sl ig h t o v e r l a p ( < 4 5 ) b e t w e e n t h e

o u t e r g li al c y t o p l a s m a n d t h e i n t e rn a l m e s a x o n . T h e i n n e r m e s a x o n a n d o u t e r l o o p

o f g l ia l c y t o p l a s m a r e l o c a t e d i n t h e s a m e h e m i - c ir c l e o f t h e s h e a t h i n m o r e t h a n 8 0~ o

o f t h e a x o n s .

A x o p l a s m o f t h e m y e l i n a t e d c a ll o s a l a x o n s c o n t a i n s m i t o c h o n d r i a , e l e m e n t s o f t u b u l a r

r e t ic u l u m , a n d l o n g i t u d i n a l l y o r i e n t e d m i c r o t u b u l e s a n d f il a m e n ts . I n t h e i n t e r p a r a n o -

d a l r e g i o n t h e p l a s m a m e m b r a n e o f t h e a x o n is s e p a r a t e d f r o m t h e i n n e r l a y er o f

m y e l i n a n d i n n e r g l ia l li p b y a s p a c e a p p r o x i m a t e l y 1 5 0 A w i d e ( L i v i n g s t o n e t a l . 1973) .

I n t h e p a r a n o d a l r e g io n , t h e a x o n m e m b r a n e a n d m e m b r a n e s o f t h e t e r m i n a t i n g

g l ia l la m e l l a e c o m e i n t o c l o s e o p p o s i t i o n s o t h a t , i n t ra n s v e r s e s e c ti o n , t h e s p a c e b e t w e e n

t h e a x o n a l a n d g l ia l m e m b r a n e s a p p e a r s r e d u c e d , a n d i n l o n g i t u d i n a l s e c t io n , p e r i o d i c

d e n s i t i e s w i t h a s p a c i n g o f 1 0 0 - 1 5 0 A a r e p r e s e n t ( H i r a n o a n d D e m b i t z e r , 1 9 67 ). T h e

u n m y e l i n a t e d g a p a t t h e n o d e s o f c a l lo s a l a x o n s i n m o s t c a s e s e x t e n d s 0 . 7 5 - 1 . 2 5 / l m ,

a n d i n n o c a s e s e x t e n d s f a r t h e r t h a n 2 # m a l o n g t h e a x i s o f t h e fi be r. A n e l e c t r o n - d e n s e

c y t o p l a s m i c u n d e r c o a t i n g e x t e nd s 1 0 0 - 2 0 0 A i n t o t h e c y t o p l a s m s u b j a c e n t t o t h e a x o n

m e m b r a n e a t t h e n o d e ( F ig . 1 0 ) a s in o t h e r c e n t r a l n o d e s ( se e, e.g . A n d r e s , 1 9 6 5 ; P e t e r s ,

FIG. 10. Longitudinal section through a node of Ranvier. m indicates terminating myelin

lamellae. The u nmyelinated gap extends 1.1/~ along the axis of the fiber. A de nse cytoplasmic

undercoating (d) is pres ent subjacent to no dal axon m em bran e. The perinodal extracellular

space is indicated e . 50,000. (Waxm an and Sw adlow, 1976b).


11/28

THE CONDUCTION PROPERTIES OF AXONSIN CENTR L WHITE M TTER 307

1966). Dense material is not present subjacent to the axon membrane in the paranodal

or internodal regions. As at the other central nodes of Ranvier (Robertson e t a l . 1963;

Bennett e t a l . 1967) the juxtanodal extracellular space in many cases contains an amor-

phous electron-dense material. Branching was not observed near the midline of callosal

axons, nor was it detected in physiological experiments utilizing appropriate collision

techniques (Swadlow and Waxman, 1976). Astrocytic processes are present between some

axons and usually contain lucent cytoplasm with occasional microtubules and filaments,

but with a paucity of formed organelles. Glial processes only rarely surround axons

or groups of axons in such a way as to segregate them from adjacent axons.

5 2 PHYSIOLOGY

For physiological studies, extracellular single-unit recordings are obtained from the

visual cortex of chronically prepared, unanesthetized, unparalyzed adult rabbits. Record-

ings are obtained from the cell bodies of neurons which send an axon across the corpus

callosum (caUosal efferent neurons). The cell bodies of callosal efferent neurons are

located in the lateral part of visual area I and in visual area II of the cerebral cortex

(Swadlow, 1970. Banks o f stimulating electrodes are implanted near the midline of

the corpus callosum, and in some cases at other locations along the course of the

callosal axons. Electrical stimuli are presented singly, or, in order to determine the

dependence of conduction properties on prior activity, in pairs (a conditioning stimulus

followed by a test stimulus). In some cases the conditioning stimulus consists of a

train of pulses. In other experiments, stimuli are triggered at various intervals following

a spontaneous spike. Recording techniques have been described previously (Swadlow,

1974a; Swadlow and Waxman, 1976).

Callosal efferent neurons are identified by their antidromic activation following electri-

cal stimulation near the midline of the corpus callosum. The principal criterion for

the identification of antidromically activated callosal efferent neurons is the test for

impulse collision (Bishop e t a l . 1962; Swadlow, 1974a). This test is based on the fact

that if a unit is antidromically activated, a stimulus presented during an interval after

a spontaneous or orthodromicaUy evoked spike will not activate the unit due to

a collision of orthodromic and antidromic impulses. This period of non-responsiveness

equals the conduction time along the axon plus the refractory period of the axon at

the site of stimulation. Secondary criteria for the confirmation of antidromic activation

of callosal neurons have been described elsewhere (Swadlow and Waxman, 1976).

For units which are shown to be antidromically activated by stimulation of the corpus

callosum, latency to a single test pulse is determined at various intervals following either

a single conditioning pulse or a train of conditioning pulses. Conditioning and test

pulses in most cases are delivered via the same electrode. Since variations in both

threshold and latency to a test volley follow conditioning volleys, the stimulus threshold

is determined at each conditioning stimulus-test stimulus interval and the test stimulus

intensity is adjusted to 1.2 x threshold value at that particular conditioning stimulus-test

stimulus interval. Threshold of these neurons to antidromic activation is quite sharp,

and is determined by reducing the stimulus intensity in small steps (usually less than

39/o of control threshold value) until each stimulus no longer reliably elicits an ant idromic

spike.

5.2.1. C o n d u c t i o n v e l o c i t y a n d r e f r a c to r y p e r i o d

Figure 11 shows the estimated conduction velocity of 75 visual callosal axons. The

conduction velocities range from 0.3 to 12.9 m/sec and have a median value of 2.8 m/sec.

Except for the fiber with conduction velocity of 12.9 m/sec, the observed values are

similar to those which would be expected on the basis of the diameter spectra, assuming

that the relationship between conduction velocity and diameter is similar to that for

peripheral nerve. The refractory period was determined for most units. Figure 12 shows


12/28

3 0 8 S . G . W A X M A N A N D H . A . S W A D L OW

u ) 1 5

I-

Z

b .

o

I 0

r r

LL/

r n

:E

2 :

5

I

]

I I l ~ I I F - - I

2 4 6 8 I 0 1 2 1 4

C O N D U C T IO N V E L O C I T Y m / s e c )

FIG. 11.

E s t i m a t e d c o n d u c t i o n v e l o c i ti e s o f 7 5 v i su a l c a l l o s a l a x o n s , d e t e r m i n e d b y m e a s u r i n g

l a t e n c y t o a n t i d r o m i c s t i m u l a t i o n a n d e s ti m a t i n g c o n d u c t i o n p a t h l e n g t h . S w a d l o w a n d W a x -

m a n , 1 9 76 .

r e f r a c t o r y p e r i o d s t o d o u b l e v o l l e y a n t i d r o m i c a c t i v a t i o n a t 2 t i m e s t h r e s h o l d , p l o t t e d

a g a i n s t c o n d u c t i o n v e l o c it y . T h e r e f r a ct o r y p e r i o d s r a n g e f r o m 0 . 6 - 2 . 0 m s e c , a n d a s

i n p e r i p h e r a l n e r ve Pa i n ta l , 1967) , th e fas te r ax on s ge n e r a l l y e xh i b i t sh or te r r e fr ac tor y

p e r i o d s t h a n s l o w e r a x o n s .

5.2.2. he supernorm al period

M o s t v i s u a l c a U o s a l a x o n s e x h i b i t a p e r i o d o f i n c r e a s e d c o n d u c t i o n v e l o c i t y a n d

e xc i tab i l i ty fo l l ow i n g th e r e l a t i ve r e fr ac tor y p e r i od . Th i s c an b e d e m on s tr a te d b y m e asu r -

i n g t h e l a t e n c y a n d t h r e s h o l d t o a t e s t s t i m u l u s f o l l o w i n g a n a n t e c e d e n t c o n d i t i o n i n g

s t i m u l u s a t a p p r o p r i a t e i n te r v a ls . A t c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s i n t er v a l s o f

2 . O i

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13/28

THE CONDUCTION PROPERTIES OF AxoNs IN CENTR L WHITE M TTER 3 9

FIG. 13. Oscilloscope tracings showing the decrease in antidrom ic latency of a callosal neuron

with a control axo n conduction velocityof 4.3 m/sec. A: A n a ntidrom ic test stimulus is presented

at 1.2 threshold in the ab sence of a cond itioning stimulus. B: A n an tidrom ic tes t stimulus

is presen ted 11 mse c following an antidrom ic cond itioning stimulus. The cond itioning stimulus

was presented at 1.5 control threshold. Because threshold decreases dur ing the supernormal

period, intensity of the test stimulus was adjusted to 1.2 x threshold at each conditioning stimu-

lus-test stimulus interval in this and the subsequent figures. Negativity upward. Bar indicates

1.0 msec. (W axma n and Swadlow, 1976a).

1 - 2 m s e c , l a t e n c y to t h e t e s t s t i m u l u s i s in m a n y c a s e s g r e a t e r t h a n l a t e n c y t o t h e

c o n d i t i o n i n g s t i m u lu s , p r o b a b l y d u e t o a r e d u c t i o n i n c o n d u c t i o n v e l o c i ty d u r i n g t h e

r e l a ti v e r e f r a c t o r y p e r i o d o f t h e a x o n . A t c o n d i t i o n i n g s t i m u l u s - t e s t s t im u l u s i n t e r v a ls

o f 2 - 4 m s e c , la t e n c y d e c r e a s e s b e lo w c o n t r o l v a l u e s t o r e a c h a l o w v a l u e a t i n t e r v a l s

o f 3 - 1 7 m s e c. L a t e n c y r e t u r n s t o b a s e l in e a t i n t e r v a l s o f 1 8 - 1 6 9 m s ec .

O n t h e b a s i s o f t h e m o r p h o l o g i c a l d a t a , i t i s p o s s i b le t o e s t a b l is h a c r i t e ri o n v a l u e

f o r t h e p h y s i o l o g i c a l i d e n t i f ic a t i o n o f m y e l i n a t e d a x o n s f r o m m e a s u r e m e n t s o f c o n d u c -

t i o n v e l o c it y ( W a x m a n a n d S w a d l o w , 1 9 76 a) . T h e l a r g e st u n m y e l i n a t e d a x o n s i n th e

s p l e n i u m h a v e a d i a m e t e r o f 0 .6 /~ m , a n d i n p e r i p h e r a l n e r v e w o u l d b e e x p e c t e d t o

h a v e a c o n d u c t i o n v e l o c i ty o f 1 .7 m / s e c . S o a s t o a d d a m a r g i n f o r e r r o r , w e c h o s e

3 .4 m / s e c a s a p h y s i o l o g i c a l c r i t e r io n f o r i d e n t if i c a ti o n o f m y e l i n a t e d a x o n s . T w e n t y - s i x

o f 2 8 n e u r o n s w i t h a x o n c o n d u c t i o n v e l o c it ie s g r e a t e r t h a n 3 .4 m / s e c e x h i b i t e d a s u p e r -

n o r m a l p e r i o d o f d e c r e a s e d l a t e n c y a n d t h r e s h o l d f o l l o w i n g a c t i v a t i o n b y a t e st s t im u l u s

w h i c h f o l l o w e d a n a n t e c e d e n t c o n d i t i o n i n g s t i m u l u s a t a p p r o p r i a t e i n t er v a ls . F i g u r e

13 i ll u s t ra t e s t h e d e c r e a s e in l a t e n c y f o r o n e o f t h es e n e u r o n s . F i g u r e 1 3 A s h o w s t h e

r e s p o n s e t o a n a n t i d r o m i c t e s t s t im u l u s p r e s e n t e d a t 1 .2 x t h r e s h o l d i n t h e a b s e n c e

o f a c o n d i t i o n i n g s t im u l u s . T h e c o n t r o l l a t e n c y is 2 .3 7 m s e c ( m e a s u r e d t o t h e n e a r e s t

2 5 s e c) . F i g u r e 1 3 B s h o w s t h e r e s p o n s e t o a t e s t s t i m u l u s p r e s e n t e d 1 1 m s e c f o l l o w i n g

a n a n t i d r o m i c c o n d i t i o n i n g s t i m u lu s . T h e i n t e n s i t y o f th e t e s t st i m u l u s w a s a d j u s t e d

t o b e 1 .2 x t h r e s h o l d v a l u e a t th i s c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s i n t e r v al . A n t i d r o -

m i c l a t e n c y a t th i s c o n d i t i o n i n g - t e s t s t im u l u s i n t e r v a l w a s a p p r o x i m a t e l y 0 . 12 m s e c l e ss

t h a n c o n t r o l l a t e n c y .

F i g u r e 1 4 A - C s h o w s t h e l a t e n c y t o a n t i d r o m i c a c t i v a t i o n t o a t e s t st i m u l u s a s a

f u n c t i o n o f c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s i n t e r v a l f o r 3 n e u r o n s w i t h a x o n c o n d u c -

t i o n v e l o c i t ie s o f 0 .3 , 1 .3 a n d 4 .1 m / s e c . I n e a c h c a s e , t h e c o n d i t i o n i n g s t i m u l u s w a s

p r e s e n t e d a t 1 . 5 t i m e s t h r e s h o l d , a n d t h e t e s t s t i m u l u s w a s p r e s e n t e d a t 1 . 2 t i m e s t h e

t h r e s h o l d f o r th a t c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s i n te r v a l. T h e d a r k c ir c le s i n d i c a te

t h e la t e n c y a t e a c h c o n d i t i o n i n g s t i m u l u s - t e s t s t im u l u s i n te r v a l. F i g u r e 1 4A 1 s h o w s

a v e r y s l o w l y c o n d u c t i n g a x o n , w i t h a n a x o n c o n d u c t i o n v e l o c i ty o f 0 .3 m / s e c . T h e

c o n t r o l l a t e n c y w a s 3 7 . 5 m s e c . A t c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s i n t e r v a l s o f 1 0

a n d 1 7 m s e c , l a t e n c y d e c r e a s e d t o a p p r o x i m a t e l y 3 4 . 7 m s e c . F o r l o n g e r c o n d i t i o n i n g

s t i m u l u s - t e s t s t i m u l u s i n t e r v a l s , t h e l a t e n c y s l o w l y i n c r e a s e d , r e a c h i n g t h e c o n t r o l v a l u e

a t a n i n t e r v a l o f a p p r o x i m a t e l y 1 69 m s e c . F i g u r e 1 4B 1 a n d C ~ p r e s e n t d e c r e a s e s i n

l a t e n c y f o r 2 m o r e r a p i d l y c o n d u c t i n g u n i t s ( c o n t r o l c o n d u c t i o n v e l o c i t i e s o f 1 . 3 a n d

4 .1 m / s ec ) . T h e p r o p o r t i o n a l m a g n i t u d e o f t h e m a x i m a l d e c r e a s e s in l a t e n c y f o r t h e


14/28

3 1 0 S . G . W A X M AY

A N D

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3 8 . 0

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m s e c )

F IG . 1 4. A 1 C 1 : T h i s fi g u r e s h o w s t h e l a t e n c y t o a n t i d r o m i c a c t i v a t i o n t o a t e s t s t i m u l u s a s

a f u n c t i o n o f c o n d i t i o n i n g s t i m u l u ~ t e s t s t i m u l u s i n t e r v al f o r t h r e e r a b b it v i s u a l c a l lo s a l n e u r o n s

w i t h a x o n c o n d u c t i o n v e l o c i t i e s o f 0 .3 , 1 .3 a n d 4 . 1 m / s e c . P o i n t s s h o w t h e a n t i d r o m i c l a t e n c y

a t e a c h c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s i n te r v a l. P a i r s o f s t im u l i w e r e d e l iv e r e d a t a r a t e

o f 1 /3 .3 s e c. E a c h c o n d i t i o n i n g s t i m u l u s i s p r e s e n t e d a t 1 .5 t i m e s t h r e s h o l d i n t e n s i t y , a n d t h e

t e s t s t i m u l u s i s p r e s e n t e d a t 1 .2 t im e s t h e t h r e s h o l d a t e a c h c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s

i n te r v a l. A 2 - C 2 : V a r i a t i o n s i n t h r e s h o l d t o a n t i d r o m i c t e s t v ol l e y fo l l o w i ng a s i n g l e a n t i d r o m i c

c o n d i t i o n i n g v o l le y f o r th e s a m e t h r e e u n i t s w h i c h w e r e p r e s e n t e d i n F i g . 1 4 A I - C 1 . T h e c h a n g e s

i n t h r e s h o l d f o ll o w a s i m i l a r t i m e c o u r s e t o t h e c h a n g e s i n l a te n c y . S w a d l o w a n d W a x m a n ,

1976).

3 units shown in Figs. 14 A-C was quite similar 7.5-11~ of control values). However,

the duration of the decrease in latency was greater for the slower conducting axons.

The relationship between the duration of the latency decrease and conduction velocity

is further illustrated below.

Figure 14A2-C2 shows the variation in threshold to antidromic activation that follows

a single antidromic conditioning volley for the same three units which were shown

in Fig. 14A1-C1. Decreases in threshold follow roughly the same or in some cases

a somewhat longer time course than the decreases in latency. All units which exhibit

a decrease in latency also exhibit a decrease in threshold, which was, in all but one

case, concomitant with the maximal decrease in latency.

Figure 15 shows that there is a roughly inverse relationship between conduction vel-

ocity and the duration of the decrease in latency, for the callosal axons which we

have studied. The duration of the latency decrease varies continuously with conduction

velocity and there is no discrete change which might suggest a qualitative difference

between myelinated and non-myelinated fibers. This finding and the absence of an abrupt

change in refractory period Fig. 12) are similar to those of Paintal 1967), who observed

that although rise time, fall time, and spike duration of myelinated and unmyelinated

fibers vary systematically with conduction velocity, there was no obvious qualitat ive

difference between the two types of fibers.

The maximum

bsolute

magnitude of the decrease in latency, for the units in which

this variable was studied, is shown in Fig. 16A. As might be expected, the absolute

maximal magnitude of the decrease in latency is much smaller for fast units than for

slow units. In particular, neurons with an axon conduction velocity of greater than

7 m/sec had a maximum decrease in latency of 0.1 msec or less, a figure which is often


15/28

Trt

CONDUC TION PROPERTIES OF AXON S IN CENTR AL WHITE M ATTER

200

311

1 5 0

E

z

0 I 0 0

5 0

e l l e l l

e

e l

i _ _ i I

4 8 12

C O N D U C T I O N V E L O C I T Y m / s e c )

F IG . 1 5. R e l a t i o n s h i p b e t w e e n c o n d u c t i o n v e l o c i t y a n d t h e d u r a t i o n o f t h e d e c r e a s e i n l a t e n c y

f o r c a l l os a l a x o n s . E a c h p o i n t r e p r e s e n t s a s i n g le u n i t. ( S w a d l o w a n d W a x m a n , 1 97 6).

c i t e d a s a c r i t e r i o n f o r t h e m a x im u m l a t e n c y v a r i a b i l i t y w h ic h i s a c c e p t a b l e f o r a n

a n t i d r o m ic a l l y a c t i v a t e d u n i t . O n t h e o th e r h a n d , a l l b u t 4 u n i t s w i th c o n d u c t i o n v e lo c i -

t ie s o f le ss than 6 m/sec exh ib i ted la tency d ec reases o f 0 .1 msec o r g rea te r . H ad co l l i s ion

a n d o th e r t e s ts f o r a n t i d r o m ic a c t i v a t i o n n o t b e e n e m p lo y e d , t h e se u n i t s w o u ld p r o b a b ly

h a v e b e e n i n a p p r o p r i a t e ly c l a ss i fi e d a s s y n a p t i c a ll y a c t i v a t e d S w a d lo w a n d W a x m a n ,

1975).

Th e r e l a t i o n s h ip b e tw e e n t h e

proportion l

m a g n i tu d e o f t h e m a x im a l l a t e n c y d e c re a s e

a n d c o n d u c t i o n v e lo c i t y i s s h o w n in F ig. 1 6 B . Th e m a g n i tu d e o f th e d e c r e a s e i n l a t e n c y

r a n g e d f r o m 3 ~ t o 2 2 ~ o f t h e c o n t r o l l a t e n c y. N o c o n s i s t e n t r e l a ti o n s h ip b e tw e e n

th e p r o p o r t i o n a l m a g n i tu d e o f t h e d e c r e a s e i n l a te n c y a n d t h e c o n d u c t i o n v e lo c i t y w a s

o b s e r v e d .

F igure 17 shows tha t the dec rease in la tency i s due to the p rev ious f i r ing o f the

axo n un der s tudy . In F ig . 17a , an a n t id ro m ic vo l ley e l ic it s a sp ike a t a la tency o f

4 .9 msec . In F ig . 17b, the an t id rom ic vo l ley i s p rece eded b y a spon tane ous sp ike which

t r ig g e r s t h e o s c i ll o s c o p e . A n t id r o m ic l a t e n c y w a s r e d u c e d t o a p p r o x im a te ly 4 .4 m s ec .

A d d i t i o n a l c o n t r o l e x p e r im e n t s s h o w th a t a ) w h e r e a s n o d e c r e a s es i n l a te n c y o c c u r

to a te s t s t imulu s tha t fo l lows a sub- th res ho ld co nd i t ion ing s t imulus , dec reases in la tency

v

IM

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z

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I

a. . t

p

e

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4 8 12

C O N D U C T I O N V E L O C I T Y m / s e e )

F I 6 . 1 6. R e l a t i o n s h i p b e t w e e n c o n d u c t i o n v e l o c it y a n d m a g n i t u d e o f t h e d e c r e a s e i n l at e n c y .

A : T h e m a x i m u m a b s o l u t e m a g n i t u d e o f t h e d e c re a s e in l a t en c y . B : T h e r e l at iv e m a g n i t u d e

( p e r c e n t d e c r e a s e ) o f t h e d e c r e a s e i n l a t e n c y . ( S w a d l o w a n d W a x m a n , 1 9 76 ).

J .P .N . ~4 (


16/28

3 1 2 S . G . W A X M A N A N D H . A . S W A I) LO W

FIG. 17. O s c i l l o s c o p e t r a c i n g d e m o n s t r a t i n g d e c r e a s e d a n t i d r o m i c l a t e n c y a f te r a s p o n t a n e o u s

s p i k e , A : A n t i d r o m i c a c t i v a t i o n o f a c a l l o s a l n e u r o n t o a t e s t s t i m u l u s a r r o w ) p r e s e n t e d a t

1.2 x

t h r e s h o l d i n t e n s it y . B : T h e t e s t s t i m u l u s i s p r e c e d e d b y a s p o n t a n e o u s s p i k e w h i c h t r ig g e r s

t h e o s c i l l o s c o p e . N o t e t h e r e d u c t i o n i n l a t e n c y t o t h e t e st s t im u l u s . C a l i b r a t i o n b a r e q u a l s

5 m s e c. S w a d l o w a n d W a x m a n , 1976) .

of a simi lar magni tude and t ime course occur to a t es t s t imulus that fo l low s a condi t ion-

ing st imulus of e ither 1 .1 or 1 .5 t imes threshold, and b) wh en the intensi ty of a condit ion -

ing st imulus i s just at threshold, a decrease in latency occu rs to the test st imu lus on ly

when the in i t ia l condi t ion ing s t imulus resul ts in a sp ike Swa dlow and W axm an, 1976).

It can further be shown that the latency variat ions are proport ional to the length

of the impulse conduct ion path. For these experiments, two pairs of st imulat ing elec-

trodes act ivate the axon at di f ferent distances from the cel l body and col l i s ion techniques

are employed so as to be sure that the st imulat ing electrodes are not act ivat ing two

separate branches o f the same axon Swad low, 1974a; Swad low and W axman , 1976).

Figure 18A presents latency to ant idromic act ivat ion to a test st imulus as a funct ion

of con dit ion ing st im ulus- test st imulus interval for a unit in wh ich st im ulat ion w as pres-

ented through electrode s located 2 m m to the right contralateral to the recording m icro-

electrode) of the midl ine. In Fig. 18B the same neu ron is act ivated by st im ulat ion 2 m m

to the lef t of the midl ine. The durat ion of the decreases in latency are approximately

equal . However , the magni tudes o f the decreases in la t ency fo l lowing s t imulat ion a t

the two s i t es are approx imate ly proport iona l to the contro l l a t ency a t each s t imulat ion

s it e. The dem onstrat ion o f proport iona l changes in la tency fo l lowing s t imulat ion on

both sides of the corpus cal losum indicates that the latency decrease occu rs along the

main axonal t runk , and i s not dependent on changes occurr ing in the unmyel inated

terminals and/or unmyel inated segments near the cel l body.

2 6

2 4

z

t J

b--

2 2

A 68 B

1 4 8 /

I 2 8 I

, b 2 b 3 o , 4 0 5 b , 6 2 0 - 3 0 4 0 5 b

I N T E R V A L m s e c )

FIG. 18.

D e m o n s t r a t i o n t h a t t h e m a g n i t u d e o f t h e d e c r e a s e i n l a t e n c y i s p r o p o r t i o n a l t o c o n d u c -

t i o n p a t h l e n g t h , a n d t h a t c h a n g e s in c o n d u c t i o n v e l o c i t y o c c u r a l o n g t h e a x o n a l t r u n k w i t i n

t h e c o r p u s c a l l o s u m .

I n A ,

b o t h c o n d i t i o n i n g a n d t e s t s t i m u l i a r e d e l i v e r e d t h r o u g h a s t i m u l a t i n g

e l e c t r o d e l o c a t e d a p p r o x i m a t e l y 2 m m t o t h e r i g h t o f m i d l i n e .

I n B ,

b o t h s t i m u l i a r e d e l i v e r e d

v i a a st i m u l a t i n g e l e c t r o d e l o c a t e d a p p r o x i m a t e l y 2 m m t o t h e l e ft o f t h e m i d l i n e . P o i n t s r e p r e s e n t

t h e l a t e n c y t o t h e t e s t s t i m u l i . T h e c o n d i t i o n i n g s t i m u l u s w a s d e l i v e r e d a t 1.5 x t h r e s h o l d w h i l e

t h e t e s t s t i m u l u s w a s d e l i v e r e d a t

1.2 x

t h r e s h o l d a t e a c h c o n d i t i o n i n g s t i m u l u s - t e s t s t i m u l u s

i n t e rv a l . T h e h o r i z o n t a l l i n e r e p r e s e n t s a n t i d r o m i c c o n t r o l l a t e n c y a t

1.2

t h r e s h o l d . W a x m a n

a n d S w a d l o w , 1 9 7 6 a ) .


17/28

THE

CONDUCTION PROPERTIES OF AXONS IN CENTRAL WHITE MATTER 3 3

~ 2 . 6 / l _ p / P - , , ~ . - - - .

> 2 4

U

Z

t,IJ

I-.-

,,~ 2.2

- J I I t i

2 0 0 4 0 0 6 0 0 8 0 0

INTERVAL (msec)

FIG. 19. Time course of the increase in latency for one unit when the conditioning stimulus

consisted of a single pulse (0---0--Q), 20 pulses (A--- . . . A) or 54 pulses (x -- -x -- -x )

delivered at 330 pulses/sec.

5.2.3. he subnormal period

In som e cases , fo l lowing a s ing le an t id r om ic co nd i t ion ing vo l ley , a s l igh t increase

in la tency to a t e s t s t imu lus i s obse rve d to fo l low the in i t i a l dec rease in la tency . Th is

i n c r e as e in l a t e n c y i s a u g m e n t e d b o t h i n m a g n i t u d e a n d d u r a t i o n b y a n i n c r ea s e i n

t h e n u m b e r o f c o n d i t i o n i n g p u l s e s . Ev e n u n i t s t h a t s h o w e d n o i n c r e a se i n l a t e n c y t o

a te s t s t imu lus tha t fo l low s a s ing le cond i t ion ing vo l ley show a c lea r inc rease in la ten cy

f o l lo w i n g a c o n d i t i o n i n g s t i m u l u s t h a t c o n s i s t s o f a t r a i n o f p u l s e s (S w a d l o w a n d W a x -

m a n , 1 9 7 6 ) . F i g u r e 1 9 s h o w s t h e r e s p o n s e t o a t e s t s t i m u l u s o f a u n i t w h i c h r e c e iv e d

a cond i t ion ing s t imulus cons i s t ing o f 1 , 20 o r 54 pu lses (330 pu lses / sec ) . I t i s c lea r

t h a t t h e m a g n i t u d e o f t h e i n c r e a se s i n l a t e n c y w a s r e l a t e d t o t h e n u m b e r o f c o n d i t i o n i n g

p u l se s . I n s o m e u n i t s t h e d u r a t i o n o f th e i n c r e a s e i n l a t e n c y w h i c h f o l l o w e d a c o n d i t i o n -

ing s t imulus c ons i s t ing o f 20 pu lses was a s long as 1 .5 sec . T w o l ines o f ev idence ind ica te

tha t the inc reases in la tency a re a re su l t o f p r io r impu lse ac t iv i ty a long the axon :

( a) i n c r ea s e s i n l a t e n c y o c c u r d u r i n g a n d f o l l o w i n g p e r i o d s o f h e i g h t e n e d s p o n t a n e o u s

o r o r t h o d r o m i c a l l y d r i v e n a c t i v i t y a n d ( b ) n o i n c r e a s e s i n l a t e n c y o c c u r f o l l o w i n g a

c o n d i t i o n i n g t r a i n w h i c h is j u s t s u b - t h r e s h o l d ( S w a d l o w a n d W a x m a n , 1 97 6) .

M o s t u n i t s w h i c h s h o w a n i n c r e a s e in l a t e n c y fo l l o w i n g a t r a i n o f c o n d i t i o n i n g p u l s e s

a l s o s h o w a n i n c r e a s e i n t h r e s h o l d . C h a n g e s i n t h re s h o l d , h o w e v e r , a r e n o t a s c lo s e l y

l i n k e d t o i n c r e a s e s i n l a t e n c y a s t h e y a r e t o d e c r e a s e s i n l a t e n c y , a n d s o m e u n i t s s h o w

c l e a r l a t e n c y i n c r e a s e s w i t h n o c o n c o m i t a n t i n c r e a s e i n t h r e s h o l d .

S i n c e t h e d u r a t i o n a n d m a g n i t u d e o f t h e i n c r e a se i n l a te n c y s u m m a t e w i t h t e t a n ic

s t i m u l a t i o n , w e h a v e a t t e m p t e d t o d e t e r m i n e t h e t e m p o r a l l i m i t a ti o n s o f t h e i n c r e a se s

i n l a t en c y . F i g u r e 2 0 A a n d B i l lu s t ra t e a u n i t w i t h a c o n t r o l c o n d u c t i o n v e l o c it y o f

5 .3 m/sec . Po in ts to the le f t o f the so l id ba r rep resen t a pe r iod dur ing which base l ine

l a t e n c y w a s o b t a i n e d . A n t i d r o m i c v o l l e y s w e r e p r e s e n t e d a t 1 p u l se / 3 .3 s ec . Th e w i d t h

A

E

.3

Z

L U

_J

2.8 I .V.= 5 . 0

2.6 ~'~

2 .4 l - ~ ':

1.0 2.0 :3.0

m / s e c

2.8

2.6

2.4

MINUTES

1.0 2.0 3.0

FIG. 20. Demonstration of long lasting increase in antidromic latency for a single unit with

a conduc tion velocity of 5.3 m/see. Points to the left of the solid bar represent a period during

which baseline latency was obtained. An tidromic volleys were presented at 1 pulse/3.3 sec. The

width of the solid bar represents the duration of a period of tetanic stimulation (33 pulses/see).

Latency was not measured during this period of tetanic stimulation. Points to the right of

the bar represent antidromic latency at various intervals following the tetanic stimulation. During

this period a single test pulse was presented every 3.3 seconds. All stimuli were presented at

1.5 times the control threshold. (Swadlow and Waxman, 1976).


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314 S G WAXMAN AND H A SWADLOW

of the solid bar represents the duration of a period of tetanic stimulation (33 pulses/sec).

Latency was not measured during this period of stimulation. Points to the right of

the bar represent antidromic latency at various intervals following the tetanic stimu-

lation. During this period a single test pulse was presented every 3.3 sec. In this experi-

ment, all stimuli were presented at 1.5 times the control threshold. In Fig. 20A, following

a 40 sec train, the latency increased from just over 2.4 msec to approximately 2.65 msec

and returned to baseline latency in approximately 60 sec. Following a 60 sec train (Fig.

20B), the latency of this unit increased to over 2.7 msec and did not return to control

levels for more than 90 sec.

5.2.4. Variations in the conduction properties o f other axo ns

Preliminary studies on a small number of rabbit somatosensory callosal efferent

neurons and cortico-tectal neurons show after-effects of impulse activity similar to those

described above. The variations in conduction velocity and threshold of somatosensory

callosal axons are very similar to those of visual callosal axons. Most of the corticotectal

axons showed a decrease in latency, while all axons showed a decrease in threshold

to an antidromic test stimulus which followed a single conditioning volley. The duration

and magnitude of the decrease in latency was less than that shown for callosal axons.

For corticotectal neurons, latency always returned to baseline at conditioning stimulus-

test stimulus intervals of 17 msec or less. Parallel fibers of the cat cerebellum provide

another clear example of activity dependent variations in conduction velocity and excit-

ability in the central nervous system (Gardner-Medwin, 1972). These axons are unmye-

linated, and have a supernormal period which lasts more than 100 msec, a value quite

similar to that of the more slowly conducting visual callosal axons of the rabbit (see

Fig. 15). We have recently studied the conduction properties of callosal axons in the

rhesus monkey. In each of over 40 axons studied, we observed after-effects of activity

similar to those seen in the rabbit.

Activity-dependent variations in conduction properties have been demonstrated in

several studies on the vertebrate peripheral nervous system. In the sciatic nerve of the

frog, variations in both threshold (Newman and Raymond, 1971 ; Lass and Abeles, 1975)

and conduction velocity (Bullock, 1951; Lass and Abeles, 1975) have been observed,

while supernormal conduction has been reported in the olfactory nerve of the tortoise

(Bliss and Rosenberg, 1974). In the human, activity-dependent decreases in threshold

have been found in median nerve by Gilliatt and Willison (1963) and median and ulnar

nerve by Bergmans (1973). The activity-dependent decreases in threshold which were

found by Bergmans lasted 15~50 msec, a value similar to that found in the faster conduct-

ing visual callosal axons of the rabbit (see Fig. 15).

6 Alterations in Conduction in Dem yelinated W hite Ma tter

Let us now turn to the characteristics of impulse conduction through demyelinated

white matter. Impulse conduction through demyelinated or abnormally myelinated

axons has been observed to be modified in at least three ways. Slowin of conduction

has been documented in demyelinated axons in both the peripheral (McDonald, 1963;

Hall, 1967) and central (McDonald and Sears, 1970, Mayer, 1971) nervous systems.

Rasminsky and Sears (1972) reported an increase in internodal conduction times, from

normal values of 25.6 + 3.5 (SD) /~sec to over 600 sec in mammalian ventral roots

demyelinated with diphtheria toxin. Certainly part of the clinical deficit in the demyelinat-

ing disease could be due to this slowing of conduction.

A consequence of slowing of conduction may be coherence loss or temporal dispersion

of impulses. It was first suggested by Gill iatt and Willison (1962), on the basis of their

clinical observation that nerve action potentials were lost in some diabetic patients with

motor conduction velocities in the lower limit of the normal range, that unequal slowing

of conduction in the fibers in a nerve trunk might lead to a temporal dispersion in conduc-


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THE CONDUCTION PROPERTIES OF AXONS IN CENTRAL WHITE MATTER 3 5

t i o n t im e s a n d a d i m i n u t i o n o f d e e p t e n d o n r e fl e xe s a n d v i b r a t o r y s en se . I n d e e d , in

c o n t r a s t t o n o r m a l i n t e r n o d a l c o n d u c t i o n t i m e s w h i c h e x h i b i t a s m a l l s t a n d a r d d e v i a t i o n

( a p p r o x i m a t e l y 1 39 /o i n n o r m a l m a m m a l i a n v e n t r a l r o o t , Ra s m i n s k y a n d S e a rs , 1 9 7 2) ,

t h e i n t e r n o d a l c o n d u c t i o n t i m e s o f d e m y e l i n a t e d f ib e r s v a r y o v e r a w i d e r a n g e ( e .g .

f rom 30 sec to ove r 300/~sec fo r success ive in te rn odes a lon g a s ing le fibe r) . I t has

b e e n s u g g e s te d b y M c D o n a l d ( 19 74 ) t h a t t h i s m a y p r o v i d e a b a s i s fo r t h e d i m i n i sh e d

cr i t i ca l f l i cke r fus ion f requency obse rved in pa t ien ts wi th mul t ip le sc le ros i s .

C o n d u c t i o n b l o c k i s a s e c o n d m a n i f e s t a t io n o f d e m y e l i n a t i o n . Th i s , t o o , h a s b e e n

d e m o n s t r a t e d i n b o t h p e ri p h e r a l (M c D o n a l d , 1 96 3; M a y e r a n d D e n n y - B r o w n , 1 9 64 )

a n d c e n t r a l ( M c D o n a l d a n d S e a r s , 1 9 7 0 ) n e r v o u s t i s s u e . Re f r a c t o r y p e r i o d i s p r o l o n g e d

i n d e m y e l i n a t e d f ib e r s ( M c D o n a l d a n d S e a rs , 1 9 7 0 ). I n g e n e r a l, h i g h f r e q u e n c y i m p u l s e

t r a in s a r e m o r e l i k el y t o m a n i f es t c o n d u c t i o n b l o c k t h a n l o w f r e q u e n c y t r ai n s o r s i n g le

i m p u l s e s ( M c D o n a l d a n d S e a rs , 1 9 70 ; D a v i s , 1 9 7 2 ). Th u s , c o n d u c t i o n b l o c k n e e d n o t

b e v i e w e d a s a n a l l - o r - n o t h i n g p h e n o m e n a , b u t m a y r a t h e r r e f l e c t t h e r a t e o r p a t t e r n i n g

o f im p u l s es ( W a x m a n e t a l . 1976).

F ina l ly , i t has been sugges ted tha t w e a k i n t e r a c t i o n s b e t w e e n f i b e r s m a y o c c u r i n

d e m y e l i n a t e d t r a c t s ( W a x m a n e t a l . 1976) . In the i r d i scuss ion o f the d em ye l ina t ing

d iseases, Da v is and Scha uf (1974) po in ted ou t tha t , s ince sa fe ty fac to r in de m ye l ina te d

a x o n s m a y a p p r o a c h a v a l u e o f 1 , t h e s e f i b e r s m a y b e m o r e s u s c e p t i b l e t h a n n o r m a l

axo ns to ex te rna l in f luences on con duc t io n . I t has , in fac t , been show n un der exp er imen-

t a l c o n d i t i o n s t h a t n o r m a l n e r v e f i b e r s s h o w s m a l l c h a n g e s i n e x c i t a b i l i t y a s a r e s u l t

o f ac t iv i ty in con t igu ous f ibe rs (Ka tz and Schmi t t , 1940 ; Arvan i tak i , 1942) an d s imi la r

e f fe c ts h a v e b e e n r e p o r t e d i n i n j u r e d n e r v e s ( Ch u n g e t a l . 1 9 7 0 ). H u i z a r e t a l . (1975)

h a v e a l s o d e m o n s t r a t e d t r a n s m i s s i o n o f n e r v e i m p u l s e s f r o m f i b e r t o f i b e r in t h e a b n o r -

m a l l y m y e l i n a t e d n e r v e r o o t s o f d y s t r o p h i c m i c e .

Th e a v a i l a b l e d a t a t h u s i n d i c a t e t h a t a t l e a s t t h e a b o v e t h r e e m e c h a n i s m s ( d e c r e a s e d

c o n d u c t i o n v e l o c i t y a n d a s s o c i a t e d c o h e r e n c e lo s s, c o n d u c t i o n b l o c k , a n d w e a k i n t e r ac -

t i o n s b e t w e e n f i be r s ) c o u l d c o n t r i b u t e t o t h e c l in i c al a b n o r m a l i t i e s i n d i s e a se s o f w h i t e

m a t t e r . Ce r t a i n e l e c t r o p h y s i o l o g i c a l a b n o r m a l i t ie s , s u c h a s t h e d e l a y i n t h e v i s u a l e v o k e d

p o t e n t i a l ( H a l l i d a y e t a l . 1 97 2; N a m e r o w a n d En n s , 1 97 2) , c o u l d r e f l e ct a n y c o m b i n a t i o n

o f t h e a b o v e m e c h a n i s m s . S i ng l e f i b e r s tu d i e s ( e .g . Ra s m i n s k y a n d S e a rs , 1 9 7 2 ), w h e n

c o m b i n e d w i t h s t u d i e s o n e n s e m b l e s o f f ib e r s, s h o u l d e v e n t u a l l y r e s o l v e t h e r e l at i v e

i m p o r t a n c e o f e a c h o f t h e se m e c h a n i s m s l

W h i l e t h e s t u d ie s s u m m a r i z ed a b o v e h a v e d e m o n s t r a t e d t h e a b n o r m a l i ti e s o f c o n d u c-

t i o n w h i c h o c c u r in d e m y e l i n a t e d fi b er s , t h e c e l l u l ar b a s i s f o r a b n o r m a l c o n d u c t i o n

h a s r e m a i n e d p r o b l e m a t i c a l . F o r e x a m p l e , t h e e l e c t r i c a l c h a r a c t e r i s t i c s o f t h e i n t e r n o d a l

a x o n m e m b r a n e , w h i c h i s b a r e d i n d e m y e l i n a t e d f i b e r s , a r e n o t y e t k n o w n i n d e t a i l .

Co n d u c t i o n b l o c k a t a d e m y e l i n a t e d i n t e r n o d e c o u l d r e f l ec t s h u n t i n g o f c u r r e n t t h r o u g h

b a r e d i n e x c i t a b l e i n t e r n o d a l a x o n m e m b r a n e . A l t e r n a t i v e l y , c o n d u c t i o n b l o c k c o u l d

o c c u r a t a d e m y e l i n a t e d i n t e r n o d e i n t h e p r e s e n c e o f e x c i t a b le in t e r n o d a l a x o n m e m -

b r a n e , i f t h e c u r r e n t d e n s i t y i n t h e d e m y e l i n a t e d r e g i o n w a s s u f f ic i e nt ly sm a l l. W e h a v e

r e c e n t ly s i m u l a t e d t h e c o n d u c t i o n p r o p e r t i e s o f d e m y e l i n a t e d n e r v e f ib e r s u s in g a m o d i f i-

cat ion (Bri l l e t a l . 1977) o f the mo de l o f F i tzhugh (1962) . F igu re 21 sh ow s the p re d ic ted

b e h a v i o r o f a f o c a l ly d e m y e l i n a t e d fi b er . W e h a v e a s s u m e d t h a t t h e d e m y e l i n a t e d i n t er -

n o d a l a x o n m e m b r a n e i s e l e c tr i c al l y e x c it a b le , a n d h a s t h e s a m e s p e c if ic m e m b r a n e

p r o p e r t i e s a s t h e n o d a l a x o n m e m b r a n e ( Br i l l , W a x m a n , M o o r e , a n d J o y n e r , u n p u b l i s h e d

resu l ts , 1976). Th e s imu la ted noda l ac t ion p o ten t ia l s a re show n fo r a f ibe r to ta l ly dem ye-

l i n a te d a t t h e i n t e r n o d e b e t w e e n n o d e s 7 a n d 8 . D e s p i t e t h e a s s u m p t i o n o f e x c it a b i li t y

l ik e t h a t a t th e n o d e f o r t h e d e m y e l i n a t e d i n t e r n o d a l a x o n m e m b r a n e , t o t a l d e m y e l i n a -

t i o n o f a s in g le i n t e r n o d e i s su f fi c ie n t t o c a u s e c o n d u c t i o n b l o c k . I t t h u s b e c o m e s a p p a r -

e n t t h a t i t c a n n o t b e p r e d i c te d , o n t h e b a s i s o f o b s e r v a t i o n s o f c o n d u c t i o n b l o c k a t

s i te s o f d e m y e l i n a t io n , w h e t h e r t h e i n t e r n o d a l a x o n m e m b r a n e i s e x c it a b le o r i n e x c it a b le .

Ra s m i n s k y a n d S e a r s ( 1 9 7 2 ) e l e g a n t l y s h o w e d , i n r a t v e n t r a l r o o t f i b e r s ( i n t e r n o d e

l e n g th s ~> 8 5 0 m ) d e m y e l i n a t e d w i t h d i p t h e r i a t o x in , t h a t c o n d u c t i o n r e m a i n s s a l t a t o r y

t o t h e p o i n t o f c o n d u c t i o n b l o c k . Th e i r e v i d e n c e s u g g e s t e d in c r e a s e d i n t e r n o d a l c a p a c i -


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S. G. WAXM AN AND H. A. SWADLOW

2 3 4 5

F IG . 2 1. C o m p u t e d a c t i o n p o t e n t i a l s a t n o d e s 1 t o 7 fo r a f i b e r t o t a l l y d e m y e l i n a t e d a t i n t e r n o d e

7 8 , u n d e r t h e a s s u m p t i o n t h a t t h e d e m y e l i n a t e d i n t e r n o d a l a x o n m e m b r a n e h a d t h e s a m e

s p ec i fi c m e m b r a n e p r o p e r t i e s a s t h e n o d a l m e m b r a n e . P r o p a g a t i o n f a il s a t n o d e 7 B r il l, W a x -

m a n , M o o r e a n d J o y n e r , u n p u b l i s h e d r e s u l t s ) .

tance and transverse conductance in the demyelinated region, but they did not directly

examine the electrical properties of the internodal axon membrane. In ventral root

axons of dystrophic mice, which are either bare or thinly myelinated, Rasminsky and

Kearney (1976) found that adjacent portions of the axon membrane are capable of

sustaining both saltatory and continuous conduction. Bostock and Sears (1976) also

recently examined conduction in rat ventral root fibers demyelinated with diptheria

toxin, using a refined technique, for measuring external longitudinal currents with a

finer spatial resolution. They recorded five examples of continuous impulse conduction,

in some cases along distances of about 500 m, along fibers with internodal distance

in the range 500-850 m. This data, together with the earlier work (Rasminsky and

Sears, 1972) in which conduction remained saltatory in larger (internode distances

greater than 850 m) demyelinated fibers, suggests a difference in the pathophysiology

of conduction in small, as compared to large, demyelinated fibers. However, as pointed

out by Bostock and Sears (1976) this does not necessarily imply that internodal excit-

ability varies with axonal diameter, since differences in pathology or geometry could

also account for the observed differences.

A number of morphological studies have recently focused on the question of possible

structural differentiation between the nodal and internodal regions of the axon mem-

brane. Quick and Waxman (1976, 1977) demonstrated distinct differences in the binding

of ferric ion and ferrocyanide at the nodal and internodal axon membrane in mammalian

peripheral nerve fibers fixed in cacodylate-buffered aldehydes and osmium tetroxide.

As shown in Figs. 22-24, dense aggregates of stain are observed subjacent to the unmye-

linated axon membrane at the nodes of myelinated fibers, but are no t present in parano-

dal or internodal regions. In contrast to the densely stained nodal axon membranes,

the axon membranes of unmyelinated C-fibers, which are often directly accessable to

the extracellular milieu, do not exhibit the dense precitate (Waxman and Quick, 1977).

Axoplasmic filaments in the myelinated fibers were often stained, indicating that intra-

axonal diffusion of the ferric ion does occur. Absence of staining of the internodal

axolemma was also observed in control experiments, in which the cut ends of axons

which had been severed after fixation and before exposure to staining solutions, were

immersed in stain (Quick and Waxman, 1976b). The results indicate that differential

staining of nodal and internodal regions of the axon membrane is not due to inaccessabi-

lity of the internodal axon to ferric ion, but rather to structural differences between

the nodal and internodal axon membrane. The differences appear to be related to electri-


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THE CONDUCTION PROPERTIES OF AXONS IN CENTRAL WHITE MATTER 3 7

Fro. 22. Electron m icrog raph of a node of Ranvier arrows) in rat sciatic nerve sectioned longitu-

dinally. Th e thin section shown in this figure was cut from the 5 /~m section shown in the

inset. Ferric ion-ferrocyanide staining results in a dense deposit of electron-opaque stain lying

jus t ins ide the nodal axolemma. Othe r parts of the axon m embran e are not s ta ined. P art of

the same section is shown at higher mag nification in Fig. 23. A, axopla sm ; M, m yelin; 16,000.

Inset : Light micro graph of the same node. T he ferr ic ion-ferrocyanide s ta in is conce ntrated

near the nodal axolemma. O range f i lter; 1250. Fro m Q uick and W axm an 1977).

c a l p r o p e r t i e s , s in c e in t h e e l e c t r o c y t e a x o n s o f t h e g y m n o t i d

S t e r n a r c h u s a l b i f r o n s

w h i c h

e x h i b i t b o t h a c t i v e a n d i n a c t i v e n o d e s o f R a n v i e r B e n n e t t , 1 9 7 0; W a x m a n e t a l . 1 9 7 2 ) ,

s t u d i e s b o t h i n s i t u a n d o f d i s s e c t e d si n g le f i b e rs s h o w t h a t o n l y t h e a c t i v e n o d e s a r e

s t a i n e d Q u i c k a n d W a x m a n , 1 97 7). K r i s t o l

e t a l .

1 9 7 7 ) s t u d i e d t h e

S t e r n a r c h u s

e l e c t r o -

c y t e s u s i n g f r e e z e - e t c h i n g e l e c t r o n m i c r o s c o p y . T h e y f o u n d d i ff e r en c e s in p a r t i c l e d e n s i t y

i n E - fa c e s b e t w e e n e x c i

1977 Waxman - A Review of G-ratios

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