J. Neurol. 211,293---296 (1976) © by Springer-Verlag 1976
Conduction Velocity during the Supernormal and Late Subnormal Periods in Human Nerve Fibres H . C. H o p f , K . Lowitzsch, a n d J . G a l l a n d Neurologische Universitiitsklinik GSttingen (Direktor: Prof. Dr. H. Bauer) Received November 3, 1975
Zusammenfassung. An die relative Refrakt~rperiode schlie0t sich eine supernormale Phase an und daran wiederum eine sp~te subnormale Phase. Die Wirkung dieser beiden letzten Phascn auf die Leitgeschwindigkeit wurde an sensiblen Nervenfasern uutersucht. 80% der Untersuehten zeigten w~hrend der supernormalen Phase (4---10 msee nach der ersten Aktivierung) eine Beschleunigung der Leitgeschwindigkeit auf 106~/o des Normwertes. Die Beschleunigung ist weniger ausgepr~gt, wenn die Gewebstemperatur erniedrigt ist. Bei 65o//o der Versuchspersonen wurde eine VerzSgerung der Impulsfortleitung wiihrend der subnormalen Phase (10--100 msec nach voraufgegangener Aktivierung) beobachtet. Die Ver~nderungen der Leitgeschwindigkcit laufen zu den bekannten Ver~nderungen der 1Kembranerregbarkeit parallel. Key words: Nerve conduction velocity - - Sensory fibres supernormal period - - Subnormal phase - - Velocity of nerve conduction.
F o l l o w i n g a c t i v a t i o n t h e n e r v e fibre u n d e r g o e s several stages o f a l t e r e d excita b i l i t y , such as t h e u n r e s p o n s i v e i n t e r v a l , t h e r e l a t i v e r e f r a c t o r y period, a supern o r m a l p e r i o d a n d , in m o s t cases, a l a t e s u b n o r m a l phase. T h e decrease in excita b i l i t y is closely r e l a t e d t o a r e d u c e d spike p r o p a g a t i o n w h e n t h e n e r v e is ref r a c t o r y . D u r i n g t h e s u b s e q u e n t s u p e r n o r m a l p e r i o d a n increase in c o n d u c t i o n v e l o c i t y was t o be e x p e c t e d b u t has been r e p o r t e d o n l y b y G r a h a m in 1934 a n d 1935. T h r e e y e a r s l a t e r , however, G r a h a m herself a n d L o r e n t e de N 6 were u n a b l e t o confirm t h e earlier findings. Nevertheless, s u p e r n o r m a l c o n d u c t i o n v e l o c i t y was o b s e r v e d in skeletal muscle fibres b y B u c h t h a l a n d E n g b a e c k (1963) a n d S t a l b e r g (1966). As i t was u n l i k e l y t h a t muscle fibres b e h a v e d i f f e r e n t l y from n e r v e fibres in t h i s respect, we ree x a m i n e d t h e s u p e r n o r m a l p e r i o d o f h u m a n sensory nerves a n d , in a d d i t i o n , t h e i r l a t e s u b n o r m a l phase.
Methods In 16 subjects the digital nerves of the fifth finger were stimulated percutaneously through ring electrodes. The cathode was placed at the metacarpophalangeal joint and the anode in a more distal position 30 mm apart. Rectangular shocks of 0.1 msec duration and supramaximal intensity served as stimuli, and were delivered in pairs with variable intervals by a battery operated stimulation unit (Digitimer 2533/3290). The action potential was picked up by needle electrodes from the ulnar nerve at the wrist. The different electrode was placed
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close to the nerve trunk and the indifferent one subcutaneously over the dorsal aspect of the wrist at the same level. The nerve action potentials were recorded using an averager (Hewlett-Packard 5480 A). Latencies were measured from the stimulus artefact to the first positive peak of the potential. Pictures at 10 times magnification were used for evaluation so that differences in latency of 0.02 msec could be read easily. Averaging 20 to 30 responses the noise level was about 0.4 ~V. After having determined the end of the relative refractory period (see Hopf et al., 1974) the supernormal and the late subnormal phases were tested. The stimulus intervals were increased progressively in steps as follows: by 1 msec from 4 to 10 msec intervals, by 5 msec from 10 to 30 msec intervals and by 10 msec steps from 30 to 100 msec intervals. To exclude spontaneous changes in conduction velocity (induced by changes in temperature and other influences during the testing procedure) for each interstimulus interval the paired stimulus response and, immediately after it, the single second response were superimposed on the screen and photographed and their latencies were compared. Cooling was accomplished by putting ice bags around the arm. The tissue temperature was continuously taken at the point of stimulation using a thermocouple needle. Results S u p e r n o r m a l spike p r o p a g a t i o n was o b s e r v e d in all b u t 2 subjects. I t d e v e l o p e d i m m e d i a t e l y a f t e r t h e end o f t h e r e l a t i v e r e f r a c t o r y period a n d l a s t e d for 5 t o 10 msec. T h e m a x i m u m increase in c o n d u c t i o n v e l o c i t y u s u a l l y t a k e s place w i t h i n t h e initial one t h i r d o f t h e s u p e r n o r m a l phase. This increase a v e r a g e d a p p r o x i m a t e l y 106% of t h e resting or n o n c o n d i t i o n e d v e l o c i t y a t n o r m a l or n e a r l y n o r m a l tissue t e m p e r a t u r e s a n d was less p r o n o u n c e d a t lower t e m p e r a t u r e s (Table 1). T h e l a t e s u b n o r m a l phase l a s t e d from a p p r o x i m a t e l y 15 to 100 msec a n d was a c c o m p a n i e d b y a d e l a y in c o n d u c t i o n t i m e in o n l y two t h i r d s o f t h e subjects i n v e s t i g a t e d . T h e onset was defined less precisely as c o m p a r e d to t h e s u p e r n o r m a l period, a n d t h e change of c o n d u c t i o n v e l o c i t y was smaller. T h e course o f t h e l a t e n c y r e c o v e r y cycle o f a n i n d i v i d u a l nerve is shown in Fig. 1. Table 1. Percentage of supernormal spike propagation in sensory fibres of the fifth finger digital nerves in man and the effect of temperature Mean
Range
Mean
Range
Tissue temperature (oC)
33.6
(30.1--35.8)
24.0
(19.5---28.5)
Conduction velocity (m/sec)
54.2
(48.5--58.7)
36.9
(27.9---44.1)
106.4
(103.9--110.1)
104.6
(100.9---106.5)
Degree of supernormality (%) N
7
9
Discussion T h e l a t e c o m p o n e n t s o f t h e (conditioning) c o m p o u n d nerve response show a m p l i t u d e s o f less t h a n 0.2 ~V u p to 6 msec a n d of less t h a n 0.1 ~V u p t o 9 msec following t h e initial positive p e a k (control subjects, electronic a v e r a g i n g o f 500 r e s p o n s e s - - s e e B u c h t h a l , 1973). As t h e a m p l i t u d e of t h e m a i n positive deflection
Conduction Veloeity during SupernormM Period
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C o n d u c t i o n velocity
(% of resting velocity) 110.
~eriod.......................................................................................................... Stimulus i'nterval (ms)
Fig. 1. Recovery cycle of human sensory nerve fibres (digital nerves of the fifth finger) as measured by changes in latency of an evoked testing action potential
is 20 to 60 times t h a t of those late components there will be very little distortion of the positive peak of the second response t h a t is relevant for latency measurements. I n several aspects our results confirm the early reports of Graham, who, to our knowledge, was the first and the only one to investigat~ spike propagation in nerve fibres during the supernormal and subnormal phases. 1. Supernormal conduction velocity is not always observed, or, in other words, sometimes is too small to be detected. This was the ease in 4 of 16 experiments of Graham and in 2 of 12 subjects in our series. 2. The m a x i m u m increase in propagation velocity was always less t h a n the m a x i m u m decrease in threshold, when both are expressed as percent of the unconditioned (resting) value. The change in conduction rate was 5 - - 1 0 % , the change in threshold 10--20°/o . The latter value corresponds to the findings of Uttal (1959), Gilliatt and WiUison (1963), Shagass and Schwartz (1964), and Bergmans (1973). 3. The duration of supernormality varies to a considerable extent and under normal conditions ends with 10--14 msee stimulus intervals. Gilliatt and Willison (1963) and Bergmans (1973), referring to excitability changes, reported identical figures. Threshold changes during the late subnormal phase were observed b y Gilliatt and Willison (1963) for sensory fibres and b y Bergmans (1973) for motor axons. Our results demonstrate t h a t at the same time there is a slight but unequivocal reduction in spike propagation. I n respect to the time course no differences between ours and the values reported b y Bergmans (1973) were found.
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The practical significance of the two late stages of recovery, the supernormal a n d the late s u b n o r m a l stages, are still u n k n o w n . As the s u p e r n o r m a l period is influenced b y several factors (hydrogene ion c o n c e n t r a t i o n - - A d r i a n , 1920; p o t a s s i u m c o n c e n t r a t i o n - - t I o d g k i n , 1965) changes induced b y a b n o r m a l ion c o n c e n t r a t i o n s m a y be expected. I n this c o n t e x t we would like to m e n t i o n 6 p a t i e n t s with h y p o k a l e m i a i n whom the s u p e r n o r m a l a n d relative refractory periods were shorter t h a n n o r m a l (Maurer et al., 1975).
References Adrian, E. D. : The recovery process of excitable tissues. J. Physiol. (Lond.) 54, 1--35 (1920) Bergmans, J. : Physiological observations on single human nerve fibres. In: :New developm. in EMG and clin. neurophysiol. (ed. J. E. Desmedt), Vol. 2, pp. 89--127. Basel: Karger 1973 Buchthal, F. : Sensory and motor conduction in polyneuropathies. In: New develop, in EMG and clin. neurophysiol. (ed. J. E. Desmedt), Vol. 2, pp. 259 271. Basel: Karger 1973 Buchthal, F., Engbaeck, L. : Refractory period and conduction velocity of the striated muscle fibre. Ac¢~ physiol, scand. 59, 199--218 (1963) Gilliatt, R. W., Willison, R. G. : The refractory and supernormal periods of the human median nerve. J. Neurol. Neurosurg. Psychiat. 26, 136---147 (1963) Graham, H. T. : Supernormality, a modification of the recovery process in nerve. Amer. J. Physiol. 110, 225---242 (1934) Graham, H. T. : The subnormal period of nerve responses. Amer. J. Physiol. 111, 452--465 (1935) Graham, H. T., Lorente de NS, R. : Recovery of blood perfused mammalian nerves. Amer. J. Physiol. 123, 326--340 (1938) Hodgkin, A. L. : The conduction of the nerve impulse. The Sherrington lectures VII. Liverpool: Liverpool University Press 1965 Hopf, H. C., LeQuesne, P., Willison, R. G. : Refractory periods and lower limiting frequencies of sensory fibres of the hand. In: Studies on neuromuscular diseases (eds. K. Kunze, J. E. Desmedt), pp. 258--263. Basel: Karger 1974 Maurer, K., Hopf, H.C., Lowitzseh, K.: Hypokal~mie und Refrakt~rzeiten sensibler peripherer Nerven. Tagg. Dtseh. Ges. Neurol., Hamburg, 24.--27. 9. 1975 Shagass, C., Schwartz, M. : Recovery functions of somatosensory peripheral nerve and cerebral evoked responses in man. Electroenceph. clin. Neurophysiol. 17, 126--135 (1964) Stalberg, E. : Propagation velocity in human muscle fibres in situ. Acts physiol, seand., Suppl. 287, 70, 1--112 (1966) Uttal, W. R. : A comparison of neural and psychophysical responses in the somesthetic system. J. comp. physiol. Psychol. 52, 485--490 (1959) Prof. Dr. H. C. Hopf Neurologisehe Universit44tsklinik Langenbeckstral]e 1 D-6500 Mainz Federal Republic of Germany