Brain Research, 594 (1992) 301-306 © 1992 Elsevier Science Publishers B.V. All rights reserved 0006-8993/92/$05.00
301
BRES 25383
Redirection of the hypoglossal nerve to facial muscles alters central connectivity in human brainstem J e a n C l a u d e Wilier a, G e o r g e s L a m a s b, Sylvie Poignonec b, Isabelle Fligny b and Jacques S o u d a n t b a Laboratoire de Neurophysioiogie, Facult~ de M~decine Ptti~-Salp~tri~reand b Department ENT, H~pttal Pttt~-Salp~tnJre, Parts (France) (Accepted 7 July 1992)
Key words: Hypoglossal-facial anastomosis; Synaptic reorganization; Blink reflex pathway; Brainstem; Man
Functional motor control requires perfect matching of central connectivity of motoneurones with their peripheral connections. However, it is not known to what extent central circuitry is influenced by target muscles, either during development or following a lesion. Surgical interventions aimed at restoring function following peripheral nerve lesions provide an opportunity for studying this interaction in the mature human nervous system. We have followed 8 patients in whom the hypoglossal nerve was anastomosed into a lesioned facial nerve, allowing voluntary contractions of the previously paralyzed muscles. We show that, in addition to replacing the facial neurons at peripheral synapses, a new short-latency trigemino-hypoglossal reflex) of the R! blink reflex type, can be demonstrated in patients showing recovery, implying a sprouting of trigeminal neurons towards hypoglossal motoneurones, over a distance of at least 0.5 cm. These surprising results show an unexpected influence of the periphery in remodelling central connectivity in man.
In various animal models of neuronal plasticity, it has often been reported that environmental perturbations of the afferent systems are able to induce synaptic rearrangements downstream from the conditioning lesion.~,~,,Ta3-tT,3a. By contrast, the aptitude of the adult CNS for synaptic remodelling upstream from a peripheral lesion of the efferent motor axons has been considered not to occur. Surgical interventions aimed at restoring a function following a peripheral nerve lesion provide an opportunity for studying this interaction in the mature human nervous system. Following the agreement of a local Committee and after informed consent was obtained, we studied the electrophysiological features of the trigemino-facial blink reflex (a brainstem reflex) in 6 normal subjects (3 men, 3 women, aged 39-59 years) and in 8 patients (4 men, 4 women, aged 41-61 years) who had undergone peripheral hypoglosso-facial (XII-VII) anastomosis as a restorative surgery after removal of a part of the facial nerve (Fig. 1). These patients had an extensive cerebeilopontine neuroma of the acoustic nerve that
reached the facial nerve, necessitating the removal of part of this nerve during the surgical ablation of the neuroma. The restorative XII-VII cross-over was carried out about 1 month after the surgery for the neuroma. In the interval, all patients had clinical signs of an infranuclear palsy, showing that the motor axons of the VIIth nerve were totally impaired: the affected side of the face acquired a smooth and empty expression. The angle of the mouth drooped and could not be drawn laterally when patients tried to show their teeth, the eye could not close, patients could not frown, were unable to whistle, and their speech suffered. All reflex contractions were totally abolished. In 4 patients, the sense of taste and secretory functions (tears and saliva) were severely impaired, showing that the facial-intermediate nerve of Wrisberg was also damaged. About 8 to 10 months after the surgical anastomosis, 6 patients had clinical signs of a partial recovery of facial muscle activity, to the extent that they could perform some specific voluntary contractions of these previously paralyzed muscles, such as blinking, sucking, whistling or
Correspondence: J.C. Wilier, Laboratoire de Neurophysiologie, Facultd de M~decine Piti~-SalpC:tri~re, 91, Bd. de rh6pital, 75013 Paris, France. Fax: (33) 40 77 95 96.
302
To taclal muscles
VII
Xll-Vll crossover
Fig. !. Schematic drawing of the hypoglosso-facial anastomoms. On the left is shown the intact aspect of the respective VII and XII nerves. On the right is indicated the final peripheral anastomosis between the central stump of the Xil and the peripheral segment of the VII.
making faces. However, as usually observed in this kind of patient, massive contractions of the whole facial muscles were also observed, either clinically or electromyographicaily, during spontaneous or vohmtary efforts to swallow. Nevertheless, in these patients, direct motor responses were recorded using routine EMG techniques in facial muscles following electrical stimulation of the peripheral branches of the anastomosis in its pre-auricular pathway, showing that the peripheral re-innervation of the facial muscles by the hypoglossal motor axons was functionally active (individual and mean values of the motor responses from orbicularis oculi muscles on normal and operated sides are presented in Table !). However, as can be seen from Table 1, there was a consistent increase in the latency (+ 1.44 ms) and in the threshold (+4.12 mA+ of the motor response while its maximal amplitude was greatly re. duced (-3.64 mV), indicating that the peripheral re-
innervation of the facial muscles by the hypoglossal motor axons was incomplete and involved only a few motor fibres. In the 2 remaining patients, there were neither clinical nor electrophysiological signs of recovery and the facial palsy ~emained total. The present study was undertaken 15 months after the restorative surgery on the whole group of 8 patients. In normal subjects and on the non-lesioned side of patients, electrical stimulation of the supraorbital nerve elicited the well-known, two-component blink reflex responses in the orbicularis oculi muscles (Fig. 2, upper panel), the first one (R1) of short latency (10.8 + 0.2 ms) strictly ipsilateral to the stimulus, and a second component (R2) of longer latency (32 + 1.5 ms), bilateral in controls but absent on the operated side of patients. The R1 response followed high rates of stimulation (up to 1 Hz) without being modified, while the R2 component habituate:.l at 0.25 Hz stimulation rate m-~4. The R1 response is known to be mediated in the periphery by fast-conducting A~ fibresmaL31; in mammals, its central path is oligosynaptic (2 or 3 synapses) and completely intrapontine 2°'2~'2s'4°'4s. After a relay in the principal trigeminal nucleus (Fig. 3, left side), the afferent messages project directly to the ipsilateral intermediate facial subnueleus which contains motoneurons innervating the orbicularis oculi muscles 22'2"~''~s'41.In the lizard, it was demonstrated that primary trigeminal afferents project directly on retractor bulbi and facial motoneurons, thus suggesting that the R I component of the blink reflex is monosynaptie in this species 2, The R2 response is known to be
TABLE I
hulil'idual and mean rahr,s ( ~: S,E,M.) of the main electrophysiologk'al characteristics of the direct motor response recorded from the orbicularis oculi muscles on tlw normal and operated sides Values obta;ned from the normal side are similar to those obtained in the 6 normal subjects (not shown), in contrast, values obtained on the operated side indicate that only a few number of hypoglossal axons re-innervated the facial muscles (amplitude of the potential decreased by 3,64 mV, t - 9.4, P < 1),001). Furthermore, these axons showed some abnormalities compared to the normal side since their excitability was decreased (increase of the threshold by 4,12 mA, t - 6,58, P < 0,001) and their conduction velocity was slowed (increase of the latency by 1,44 ms, t = 4,04, P < [),01). These peripheral observations may explain, at least in part, similar modifications observed in the electrophysiological features of the trigemino-hypoglossal blink reflex, namely the increase in latency and threshold, and the decrease of the amplitude of the reflex response. NR, no response.
Patients
Normal side
Ol~.,rated side
Latem-v (ms)
Thrvdtohl (mA)
Amplitude OnV)
Latency (ms)
Threshokl OnA)
Amplitude OnV)
Dela. Delo. Demo Goli. Jour. Le No. Van E. Vial.
3.1 3.2 3.4 3,2 3.4 3.1) 3,4 2,6
!.8 1,5 1,7 1,9 2.0 1,6 1,8 2,0
5,1 4,9 4,5 5,5 3,6 2,8 3,5 3,6
4,2 6,5 4,1 4,4 No response 4.2 No response 4,2
5,6 6,4 5,8 6.0
0.22 0,09 1.20 0.15
5.3
0.25
6.5
0.60
Mean S.EM
3,16 1)08
1.78 0,05
4,18 0,31
4.60 0,34
5,90 0,17
0.54 0.19
303 Stimulation on right (normal) side
NORMAL SIDE
..o.o.
I500 uV
L.O,O. ~
I I
10
C
OPERATED SIDE
n
ms
Stimulationon left(operated)side
2
L,O.O, Fig. 2. An example of the blink reflex responses recorded from the right orbicularis oculi (R.O.O.) and the left orbicularis oculi (L.O.O.) muscles following electrical stimulation of the supraorbital nerve on the normal side (upper) and on the operated side (lower) in a patient who sustained a left hypoglossal-facial anastomosis. Each trace is a superimposition of 5 successive stimulations. The electrophysiological procedure is extensively described elsewhere4~. Briefly, the subjects were comfortably installed in an armchair, with a head-rest, in order to ensure a state of general muscle relaxation. The blink reflex was evoked by electrical stimulation of the supraorbital nerve by means of a pair of surface electrodes. Square-wave single pulses (0.2 ms) were delivered at a rate of 0.16 Hz by a constant-current stimulator. Reflex responses were recorded electromyographically from the orbicularis oculi muscles (pars inferior) of both sides through surface electrodes. Note that the right supraorbital nerve stimulation (normal side) elicits a typical two-component blink reflex response of normal latencies in the ispflateral muscle (RI = 10.5 ms; R 2 - 32 ms) whereas no response is recorded in the contralateral muscle, in contrast, supraorbital nerve stimulation applied to the left side (operated side) elicits an unexpected RI reflex response of 11.3 ms latency in the ipsilateral muscle. Such a stimulus also elicits a normal crossed R2 blinking response (32 ms latoncy) in the contralatoral orhicularis oculi muscle.
mediated by similar peripheral afferents to those for R1 II. its central circuitry (largely polysynaptic) is complex: afferent impulses descend along the spinal
Hypoglosnl n
Iosso-faclsl ansstomosls
Fig. 3. Schematic drawing showing the central pathways for the RI response of the blink reflex on the normal side (left) and on the operated side (right). On the normal side, the well-known physiological connections involve a relay in the principal trigeminal nucleus and subsequent projection to the facial motoneurons2°'2L2~'45. On the operated side, since the facial nucleus is bypassed by the peripheral anastomosis, the only apparent explanation for transmission of the RI response to the facial muscles is that it is mediated through a neosynaptic V-Xll connection which does not exist in normal conditions. This new connection could be established by heterotopic sprouting (over 0.5 to 1 cm) of trigeminal axons which previously projected to the facial motoneurons.
trigeminal tract to a level caudal to the obex, and are transmitted through a muitisynaptic chain of interncutons to the lateral reticular formation and then project bilaterally to the facial and retractor bulbi motoneurons 20- :t,.
T A B L E II lndit,iduai and mean values ( :1:S.E.M.) of the main electrophysiologicai characteristics of tile RI reflex response obtained on the normal and operated sides of the group of patients The values of the RI response from the normal side are similar to those obtained in the 6 normal subjects (not shown). In contrast, the responses obtained from the operated side display similar modifications (increased latency and threshold, decreased amplitude), as do direct motor responses obtained by stimulating the peripheral branches of the anastomosis. NBR, no blink response.
Patients
Normal side Latency (ms)
Threshold (mA)
Amplitude (mY)
Operated side Latency (ms)
Threshold (n~4)
Ampfitude OnV)
Dela. Delo. Demo. Goli. Jour. Le No. Van E. Vial.
10.70 1 i .20 10.70 11.00 10.40 10.10 11.60 10.60
2.00 1.80 2.10 2.00 2.10 1.60 1.50 1.60
1.25 2.80 1.60 1.80 1.00 1.30 0.90 1.10
14.50 13.90 12.30 13.00 NBR 10.10 NBR 11.30
5.50 5.90 6.00 5.30 NBR 5.50 NBR 6.70
0.15 0.20 0.15 0.16 NBR 0.50 NBR 0.15
Mean SEM
10.79 0.16
1.84 0.08
1.46 0.20
12.52 0.61
5.82 0.19
0.22 0.05
304 On the operated side of all patients, supraorbital nerve stimulation elicited the expected trigemino-facial crossed R2 response (34:1:1.2 ms latency) in the contralateral (normal side) orbicularis oculi muscles (Fig. 2, lower panel). Surprisingly, an unexpected reflex response of the RI type (12.5 ± 0.6 ms), not followed by an R2 component, was observed in the ipsilateral muscles (Fig. 2, lower panel) in the six patients showing clinical recovery, whereas no response was observed in the two others. As for normal subjects and for the normal side of th ,= same patients, this R1 response did not show habituation or wind-up facilitation at high rates of stin elation (up to 1 Hz), demonstrating that this response is a genuine short latency and oligosynap° tic reflex component of the R1 type which can not be associated with a startle reaction, which, moreover, would be of longer latency: 30-40 ms ag. Individual and mean values of the main electrophysiological features of the RI response obtained on the normal and operated side are shown in Table ll. in control experiments, we observed that in both controls and patients, supraorbital nerve stimulation did not elicit any reflex activity in the muscles of the tonguc (recorded with needle electrodes), even for high intensities (up to 30 mA) which were clearly able to activate smaller diameter cutaneous afferents of the A8 type, thus producing a pin-prick type sensation of pain. Furthermore, electrical stimulation (up to 15 mA) of the hypoglossal nervo in its peripheral course, i.e. below the posterior belly of the digastric muscle and lateral to the carotid arteries, did not produce any direct motor or reflex response in the facial muscles from normal subjects. Since both the non-functional facial motor nucleus and facial motor axons were bypassed by the peripheral hypoglosso-facial anastomosis, our present data strongly suggest that the short latency RI blink reflex response recorded in the orbicularis oculi muscles on the operated side is centrally mediated through an oligosynaptic (1-2 synapses) and neoformated trigemino-hypoglossal reflex arc. As suggested in the tentative model shown in Fig, 3, the most probable explanatory mechanism is the hetcrotopical sprouting of the axons of the trigeminai neurons from the principal trigeminal nucleus towards the Xlith nucleus. Given the distance between the inferior pole of the facial nucleus and the superior part of the hypoglossal one (0.5-1 cm in man), this sprouting is remarkably extensive. This hypothesis is supported by several arguments: (i) according to autoradiographic tracing data in cats and rabbits, strong ipsilateral projections to the blink motoneuronal cell groups have been found from the ventrolateral pontine
tegmental field and from the medullary medial tegmental field, at the level of the hypoglossal nucleus [s.z4.2s. However, in animals and man there are no data to suggest the existence of anatomical or physiological connections between the forehead cutaneous trigeminal afferents and the hypoglossal motor nucleus 4.5.s.9.28'3°'36'37'44. Thus, the hypothesis that the peripheral anastomosis in fact discloses a pre-existing but silent circuit seems unlikely; (ii) in normal man, there is neither clinical nor electrophysiological evidence for a trigemino-hypoglossal reflex since electrical stimulation of the supraorbital nerve does not elicit activity in the muscles of the tongue; and (iii) in normal man stimulation of the hypoglossal nerve does not elicit any direct motor or reflex response in the facial muscles even with strong electrical stimuli (up to 30 mA). Besides this hypothesis of a surprising, although possible, neoformated trigemino-hypogiossal connection, alternative hypotheses can be considered to explain our present data. They concern a re-growth of the facial nerve axons, either from the central sectioned stump (near the geniculi ganglion) directly towards facial muscles or from the facial motor nucleus through the hypoglossal motor nucleus towards facial muscles via the anastomosis. Although theoretically possible, these alternative hypotheses seem very unlikely, mainly because the observations of synkinesiacs in facial muscles during swallowing clearly indicate that only hypoglossal motoncurons, and not facial ones, are involved in the process. Our el¢ctrophysiological study thus unexpectedly indicates that some central neuronal networks in the adult human CNS can be structurally modified as a function of their peripheral environment, allowing the restoration of a function in which they were involved prior to a peripheral lesion. As suggested in other models of neuronal plasticity t'14'4z our present data could be explained if we postulate, in the hypoglossal motoneurons, the existence of specific chemical factors (possibly at least a nerve growth factor) produced peripherally, firstly by the nerve axotomies (VII and XII) and secondarily by the re-innervated facial muscles which are able to stimulate the heterotopical sprouting of trigeminal afferents onto some hypoglossal motoneurons. Such a hypothesis is supported by the following observations: (i) peripheral nerve axotomy triggers the expression of both nerve growth factor receptor (NGFr) and nerve growth factor (NGF) by Scl~wann cells 4z4a, A transfer of the NGF molecule to the ,NGFI of the neurite tips is believed to attract and guide the regenerating axons. Following internalization by the axon tip, the N G F - N G F r complex is then transported
305 r e t r o g a d e l y to t h e cell body, w h e r e it exerts a t r o p h i c effect ig'2"~'29'43; (ii) in a x o t o m i z e d m o t o n e u r o n s , the spinal reflex e v o k e d synaptic i n p u t s to t h e s e m o t o n e u t o n s are always r e s t o r e d after a f u n c t i o n a l r e c o n n e c tion with t h e muscle is effective 12.3:'-35. T h e s e data, t o g e t h e r with t h e findings r e p o r t e d here, p o i n t to t h e i m p o r t a n c e o f t h e p e r i p h e r y (nerve a n d muscle) in the m a i n t e n a n c e o f c e n t r a l a n d f u n c t i o n a l synaptic organization. We would like to thank Dzs. Constantine Sotelo, Emmanuel Fournier and Christopher Henderson for their valuable help in the preparation of the manuscript and for correcting the English, and Miss N. LeHenaff for the typing. This work was supported by a CRC No. 912209 and by INSERM. 1 Aguayo, A.J., Axonal regeneration from injured neurons in the adult mammalian central nervous system. In C.W. Cotman, (Ed.), Synaptic Plasuctty, Guilford, New York, 1985, pp. 457-483. 2 Barbas-Henry, H. and Wouterlood, F.G., Synaptic connections between primary trigeminal afferents and accessory abducens motoneurons in the monitor lizard varanus-exanthematicus, J. Comp. Neurol., 267 (1988) 387-397. 3 Barker, D. and Boddy, A., Re-innervation of stretch receptors in cat muscle after nerve crush, in J. Taxi (Ed.), Ontogenesis and Functional Mechanisms of Peripheral Synapses, INSERM Symposium no. 13, Elsevier, Amsterdam, 1980, pp. 251-263. 4 Brodal, A., The Cranial Nerves. Anatomy and At,,atomico.clinical Correlations, 2nd edn, Blackwell, Oxford, 1965. 5 Brodal, A., Neurological Anatomy in Relation to Chnical Medicine, 3rd edn., Oxford University Press, 1981. 6 Brown, M.C. and Butler, R.G., Regeneration ot afferent or efferent fibres to muscle spindles after nerve injury in adult cats, I, Physiol., 260 (1976) 253-266, 7 Burgess, P.R. and Horch, K.W., Specific regeneration of cutaneous fibers in the cat, J. Neurophysiol., 36 (1973) 101-114. 8 Carpenter, M,B. and Sutin, J., ltuman Neuroanatomy, VVlllth edn,, Williams and Wilkins, Baltimore, 1983, pp. 315-357. 9 Courville, J., The nucleus of the facial nerve: the relation between cellular groups and peripheral branches of the nerve, Brain Res., 1 (1966) 338-354. 10 Cruccu, G. and Bowsher, D., lntracranial stimulation of the trigeminal nerve in man, ll Reflex responses, J. Neurol. Neuro. surg. Psychiat., 49 (1986) 419-427. I I Cruccu, G. Inghilleri, M., Fraioli, B., Guidetti, B. and Manfredi, M,, Neurophysiologic assessement of trigeminal function after surgery for trigeminal neuralgia, Neurology, 37 (1987) 631-638. 12 Cull, R.E., Role of nerve-muscle contact in maintaining synaptic connexions, Exp. Brain Res., 20 (1974) 307-310. 13 Eccles, J.C., Krnjevic, K. and Miledi, R,, Delayed effects of peripheral severance of afferent nerve fibres on the efficiency of their central synapses, J. Physiol., 145 (1959) 204-220. 14 Gallego, R., Kuno, M., Nunez, R. and Snider, W.D., Enhancement of synaptic function in cat motoneurones during peripheral sensory regeneration, J. Physiol., 306 (1980) 205-218. 15 Goldberger, M.E. and Murray, M. Axonal sprouting and recovery of function may obey some of the same laws. In C.W. Cotman (Ed.), Neuronal Plasticity, Raven, New York, 1978, pp. 73-96. 16 Goldberger, M.E. and Murray, M., Recovery of function and anatomical plasticity after damage to the adult and neonatal spinal cord. In C.W. Cotman (Ed.), Synaptic Plasticity, Guilford Press, New York, 1985, pp. 77-110. 17 Goldring, J.M., Kuno, M., Nunez, R. and Snider, W.D., Reaction of synapses on motoneurones to section and restoration of peripheral sensory connexions in the cat, J. Physiol., 309 (1980) 185-198. 18 Harvey, J.A., Land, T. and McMaster, S.E., Anatomical study of the rabbit's corneaI-VIth nerve reflex: connections between
cornea, trigeminai sensory complex, and the abducens and accessory abducens nuclei, Brain Res., 301 (1984) 307-321. 19 Heumann, R., Korshing, S., Bantlow, C. and Thoenen, H., Changes m nerve growth factor synthesis in non-neuronal cells m response to sciatic nerve transection, J Cell. B~ol, 104 (1987) 1623-1631. 20 Hiraoka, M. and Shimamura, M., Neural mechamsms of the corneal bhnking reflex in cats, Bram Res., 125 (1977) 265-275. 21 Holstege, G., Neuronal organization of the bhnk reflex. In G. Paxinos (Ed.), The Human Nervous System, Academic Press, New York, 1990, pp. 287-296. 22 Holstege, G., Kuypers, H.G.J.M. and Dekker, J.J., The organization of the bulbar fibre connections to the trigemmal, facial and hypogiossal motor nuclei. II. An autoradiographlc tracing study m cat, Bram, 100 (1977) 265-286. 23 Holstege, G., Tan, J., Van Ham, J.J. and Bos, A., Mesencephahc projections to the facial nucleus in the cat: an autoradiographlcal tracing study, Brain Res., 311 (1984) 7-22. 24 Holstege, G., Van Ham, J.J. and Tan, J., Afferent projections to the orbicularis oculi motoneuronal cell group: an autoradiographical study in the cat, Brain Res., 374 (1986) 306-320. 25 Holstege, G., Tan, J., Van Ham, JJ. and Graveland, G.A., Anatomical observations on the afferent projections to the retractor bulbi motoneuronal cell group and other pathways possibly related to the blink reflex in the cat, Brain Res., 374 (1986) 321-334. 26 lwata, N., Kitai, S.T. and Olson, S., Afferent component of the facial nerve: its relation to the spinal trigeminal and facial nucleus, Brain Res., 43 (1972) 662-667. 27 Johnson, E.M., Taniuchi, M., Clark, H.B., Springer, J.E., Koh, S., Tayrien, M.W. and Coy, R., Demonstration of the retrograde transport of nerve growth factor receptor in the peripheral and central nevous system, J. Neurosct., 7 (1987) 923-929. 28 Krammer, E.B., Rath, T. and Lischka, M.F., Somatotopic organization of the hypoglossal nucleus: a HRP study in the rat, Bra:n Res., 170 (1979) 533-537. 29 Kuno, M. and Llinas, R., Enhancement of synaptic transmission by dendritic potentials in chromatolysed motoneurones of the cat, J. PhysioL, 210 (1970) 823-838. 30 Kuypers, H.G.J.M., An anatomical analysis of cortico.bulbar connections to the pens and lower brain stem in the cat, J. Anat., 92 (1958) 198-218. 31 Lindquist, C, and Martensson, A., Mechanisms involved in the cat's blink reflex, Acta PhysioL Scand., 80 (1970) 149-159. 32 Mendell, L,M., Modifiability of spinal synapses, PhysioL Rev., 64 (I 984) 260-324. 33 Mendell, L.M. and Scott, J.G., The effects of rJeripheral nerve cross-union connexions of single la fibres to motoneurones, E~7~. Brain Res., 22 (1975) 221-234. 34 Mendell, L.M,, Munson, J.B. and Scott, J.G., Connectivity changes of la afferents on axotomized motoneurones, Brain Res., 73 (1974) 338-342. 35 Mendell, L.M., Munson, J.B. and Scott, J.G., Alterations el" synapses on axotomized motoneurones, J. Physiol., 255 (1976) 67-79. 36 Panneton, W.M. and Martin, G.F., Brainstem projections to the facial nucleus of the opossum, Brain Res., 267 (1983) 19-33. 37 Papez, J.W., Subdivisions of the facial nucleus, J. Comp. Neurol., 43 (1927) 159-191. 38 Ongerboer de Visser, B.W., Anatomical and functional organization of reflexes involving the trigeminal system in man: jaw reflex, blink reflex, corneal reflex and exteroceptive suppression, Adt'. Neurol., 39 (1983) 727-738, 39 Shimamura, M., Neural mechanisms of the startle reflex in cerebral palsy, with special reference to its relationships v,!th spinobulbo-spinai reflexes. In J.E. Desmedt (Ed.), New Det,elopments in Eiectromyography and Clinical Neurophysiolog", ~.~; J, Karl,el, Basel, 1973, pp. 761-766. 40 Takew'~,;, Y., Nakano, K., Uemura, M. Matsuda, K., Matsushima, R. and Mizuno, N., Mesencephalic and pontine afferent fiber system to the facial nucleus in the cat: a study using the horseradish peroxidase and silver impregnation techniques, Exp. NeuroL, 66 (1979) 330-342.
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301
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Redirection of the hypoglossal nerve to facial muscles alters central connectivity in human brainstem J e a n C l a u d e Wilier a, G e o r g e s L a m a s b, Sylvie Poignonec b, Isabelle Fligny b and Jacques S o u d a n t b a Laboratoire de Neurophysioiogie, Facult~ de M~decine Ptti~-Salp~tri~reand b Department ENT, H~pttal Pttt~-Salp~tnJre, Parts (France) (Accepted 7 July 1992)
Key words: Hypoglossal-facial anastomosis; Synaptic reorganization; Blink reflex pathway; Brainstem; Man
Functional motor control requires perfect matching of central connectivity of motoneurones with their peripheral connections. However, it is not known to what extent central circuitry is influenced by target muscles, either during development or following a lesion. Surgical interventions aimed at restoring function following peripheral nerve lesions provide an opportunity for studying this interaction in the mature human nervous system. We have followed 8 patients in whom the hypoglossal nerve was anastomosed into a lesioned facial nerve, allowing voluntary contractions of the previously paralyzed muscles. We show that, in addition to replacing the facial neurons at peripheral synapses, a new short-latency trigemino-hypoglossal reflex) of the R! blink reflex type, can be demonstrated in patients showing recovery, implying a sprouting of trigeminal neurons towards hypoglossal motoneurones, over a distance of at least 0.5 cm. These surprising results show an unexpected influence of the periphery in remodelling central connectivity in man.
In various animal models of neuronal plasticity, it has often been reported that environmental perturbations of the afferent systems are able to induce synaptic rearrangements downstream from the conditioning lesion.~,~,,Ta3-tT,3a. By contrast, the aptitude of the adult CNS for synaptic remodelling upstream from a peripheral lesion of the efferent motor axons has been considered not to occur. Surgical interventions aimed at restoring a function following a peripheral nerve lesion provide an opportunity for studying this interaction in the mature human nervous system. Following the agreement of a local Committee and after informed consent was obtained, we studied the electrophysiological features of the trigemino-facial blink reflex (a brainstem reflex) in 6 normal subjects (3 men, 3 women, aged 39-59 years) and in 8 patients (4 men, 4 women, aged 41-61 years) who had undergone peripheral hypoglosso-facial (XII-VII) anastomosis as a restorative surgery after removal of a part of the facial nerve (Fig. 1). These patients had an extensive cerebeilopontine neuroma of the acoustic nerve that
reached the facial nerve, necessitating the removal of part of this nerve during the surgical ablation of the neuroma. The restorative XII-VII cross-over was carried out about 1 month after the surgery for the neuroma. In the interval, all patients had clinical signs of an infranuclear palsy, showing that the motor axons of the VIIth nerve were totally impaired: the affected side of the face acquired a smooth and empty expression. The angle of the mouth drooped and could not be drawn laterally when patients tried to show their teeth, the eye could not close, patients could not frown, were unable to whistle, and their speech suffered. All reflex contractions were totally abolished. In 4 patients, the sense of taste and secretory functions (tears and saliva) were severely impaired, showing that the facial-intermediate nerve of Wrisberg was also damaged. About 8 to 10 months after the surgical anastomosis, 6 patients had clinical signs of a partial recovery of facial muscle activity, to the extent that they could perform some specific voluntary contractions of these previously paralyzed muscles, such as blinking, sucking, whistling or
Correspondence: J.C. Wilier, Laboratoire de Neurophysiologie, Facultd de M~decine Piti~-SalpC:tri~re, 91, Bd. de rh6pital, 75013 Paris, France. Fax: (33) 40 77 95 96.
302
To taclal muscles
VII
Xll-Vll crossover
Fig. !. Schematic drawing of the hypoglosso-facial anastomoms. On the left is shown the intact aspect of the respective VII and XII nerves. On the right is indicated the final peripheral anastomosis between the central stump of the Xil and the peripheral segment of the VII.
making faces. However, as usually observed in this kind of patient, massive contractions of the whole facial muscles were also observed, either clinically or electromyographicaily, during spontaneous or vohmtary efforts to swallow. Nevertheless, in these patients, direct motor responses were recorded using routine EMG techniques in facial muscles following electrical stimulation of the peripheral branches of the anastomosis in its pre-auricular pathway, showing that the peripheral re-innervation of the facial muscles by the hypoglossal motor axons was functionally active (individual and mean values of the motor responses from orbicularis oculi muscles on normal and operated sides are presented in Table !). However, as can be seen from Table 1, there was a consistent increase in the latency (+ 1.44 ms) and in the threshold (+4.12 mA+ of the motor response while its maximal amplitude was greatly re. duced (-3.64 mV), indicating that the peripheral re-
innervation of the facial muscles by the hypoglossal motor axons was incomplete and involved only a few motor fibres. In the 2 remaining patients, there were neither clinical nor electrophysiological signs of recovery and the facial palsy ~emained total. The present study was undertaken 15 months after the restorative surgery on the whole group of 8 patients. In normal subjects and on the non-lesioned side of patients, electrical stimulation of the supraorbital nerve elicited the well-known, two-component blink reflex responses in the orbicularis oculi muscles (Fig. 2, upper panel), the first one (R1) of short latency (10.8 + 0.2 ms) strictly ipsilateral to the stimulus, and a second component (R2) of longer latency (32 + 1.5 ms), bilateral in controls but absent on the operated side of patients. The R1 response followed high rates of stimulation (up to 1 Hz) without being modified, while the R2 component habituate:.l at 0.25 Hz stimulation rate m-~4. The R1 response is known to be mediated in the periphery by fast-conducting A~ fibresmaL31; in mammals, its central path is oligosynaptic (2 or 3 synapses) and completely intrapontine 2°'2~'2s'4°'4s. After a relay in the principal trigeminal nucleus (Fig. 3, left side), the afferent messages project directly to the ipsilateral intermediate facial subnueleus which contains motoneurons innervating the orbicularis oculi muscles 22'2"~''~s'41.In the lizard, it was demonstrated that primary trigeminal afferents project directly on retractor bulbi and facial motoneurons, thus suggesting that the R I component of the blink reflex is monosynaptie in this species 2, The R2 response is known to be
TABLE I
hulil'idual and mean rahr,s ( ~: S,E,M.) of the main electrophysiologk'al characteristics of the direct motor response recorded from the orbicularis oculi muscles on tlw normal and operated sides Values obta;ned from the normal side are similar to those obtained in the 6 normal subjects (not shown), in contrast, values obtained on the operated side indicate that only a few number of hypoglossal axons re-innervated the facial muscles (amplitude of the potential decreased by 3,64 mV, t - 9.4, P < 1),001). Furthermore, these axons showed some abnormalities compared to the normal side since their excitability was decreased (increase of the threshold by 4,12 mA, t - 6,58, P < 0,001) and their conduction velocity was slowed (increase of the latency by 1,44 ms, t = 4,04, P < [),01). These peripheral observations may explain, at least in part, similar modifications observed in the electrophysiological features of the trigemino-hypoglossal blink reflex, namely the increase in latency and threshold, and the decrease of the amplitude of the reflex response. NR, no response.
Patients
Normal side
Ol~.,rated side
Latem-v (ms)
Thrvdtohl (mA)
Amplitude OnV)
Latency (ms)
Threshokl OnA)
Amplitude OnV)
Dela. Delo. Demo Goli. Jour. Le No. Van E. Vial.
3.1 3.2 3.4 3,2 3.4 3.1) 3,4 2,6
!.8 1,5 1,7 1,9 2.0 1,6 1,8 2,0
5,1 4,9 4,5 5,5 3,6 2,8 3,5 3,6
4,2 6,5 4,1 4,4 No response 4.2 No response 4,2
5,6 6,4 5,8 6.0
0.22 0,09 1.20 0.15
5.3
0.25
6.5
0.60
Mean S.EM
3,16 1)08
1.78 0,05
4,18 0,31
4.60 0,34
5,90 0,17
0.54 0.19
303 Stimulation on right (normal) side
NORMAL SIDE
..o.o.
I500 uV
L.O,O. ~
I I
10
C
OPERATED SIDE
n
ms
Stimulationon left(operated)side
2
L,O.O, Fig. 2. An example of the blink reflex responses recorded from the right orbicularis oculi (R.O.O.) and the left orbicularis oculi (L.O.O.) muscles following electrical stimulation of the supraorbital nerve on the normal side (upper) and on the operated side (lower) in a patient who sustained a left hypoglossal-facial anastomosis. Each trace is a superimposition of 5 successive stimulations. The electrophysiological procedure is extensively described elsewhere4~. Briefly, the subjects were comfortably installed in an armchair, with a head-rest, in order to ensure a state of general muscle relaxation. The blink reflex was evoked by electrical stimulation of the supraorbital nerve by means of a pair of surface electrodes. Square-wave single pulses (0.2 ms) were delivered at a rate of 0.16 Hz by a constant-current stimulator. Reflex responses were recorded electromyographically from the orbicularis oculi muscles (pars inferior) of both sides through surface electrodes. Note that the right supraorbital nerve stimulation (normal side) elicits a typical two-component blink reflex response of normal latencies in the ispflateral muscle (RI = 10.5 ms; R 2 - 32 ms) whereas no response is recorded in the contralateral muscle, in contrast, supraorbital nerve stimulation applied to the left side (operated side) elicits an unexpected RI reflex response of 11.3 ms latency in the ipsilateral muscle. Such a stimulus also elicits a normal crossed R2 blinking response (32 ms latoncy) in the contralatoral orhicularis oculi muscle.
mediated by similar peripheral afferents to those for R1 II. its central circuitry (largely polysynaptic) is complex: afferent impulses descend along the spinal
Hypoglosnl n
Iosso-faclsl ansstomosls
Fig. 3. Schematic drawing showing the central pathways for the RI response of the blink reflex on the normal side (left) and on the operated side (right). On the normal side, the well-known physiological connections involve a relay in the principal trigeminal nucleus and subsequent projection to the facial motoneurons2°'2L2~'45. On the operated side, since the facial nucleus is bypassed by the peripheral anastomosis, the only apparent explanation for transmission of the RI response to the facial muscles is that it is mediated through a neosynaptic V-Xll connection which does not exist in normal conditions. This new connection could be established by heterotopic sprouting (over 0.5 to 1 cm) of trigeminal axons which previously projected to the facial motoneurons.
trigeminal tract to a level caudal to the obex, and are transmitted through a muitisynaptic chain of interncutons to the lateral reticular formation and then project bilaterally to the facial and retractor bulbi motoneurons 20- :t,.
T A B L E II lndit,iduai and mean values ( :1:S.E.M.) of the main electrophysiologicai characteristics of tile RI reflex response obtained on the normal and operated sides of the group of patients The values of the RI response from the normal side are similar to those obtained in the 6 normal subjects (not shown). In contrast, the responses obtained from the operated side display similar modifications (increased latency and threshold, decreased amplitude), as do direct motor responses obtained by stimulating the peripheral branches of the anastomosis. NBR, no blink response.
Patients
Normal side Latency (ms)
Threshold (mA)
Amplitude (mY)
Operated side Latency (ms)
Threshold (n~4)
Ampfitude OnV)
Dela. Delo. Demo. Goli. Jour. Le No. Van E. Vial.
10.70 1 i .20 10.70 11.00 10.40 10.10 11.60 10.60
2.00 1.80 2.10 2.00 2.10 1.60 1.50 1.60
1.25 2.80 1.60 1.80 1.00 1.30 0.90 1.10
14.50 13.90 12.30 13.00 NBR 10.10 NBR 11.30
5.50 5.90 6.00 5.30 NBR 5.50 NBR 6.70
0.15 0.20 0.15 0.16 NBR 0.50 NBR 0.15
Mean SEM
10.79 0.16
1.84 0.08
1.46 0.20
12.52 0.61
5.82 0.19
0.22 0.05
304 On the operated side of all patients, supraorbital nerve stimulation elicited the expected trigemino-facial crossed R2 response (34:1:1.2 ms latency) in the contralateral (normal side) orbicularis oculi muscles (Fig. 2, lower panel). Surprisingly, an unexpected reflex response of the RI type (12.5 ± 0.6 ms), not followed by an R2 component, was observed in the ipsilateral muscles (Fig. 2, lower panel) in the six patients showing clinical recovery, whereas no response was observed in the two others. As for normal subjects and for the normal side of th ,= same patients, this R1 response did not show habituation or wind-up facilitation at high rates of stin elation (up to 1 Hz), demonstrating that this response is a genuine short latency and oligosynap° tic reflex component of the R1 type which can not be associated with a startle reaction, which, moreover, would be of longer latency: 30-40 ms ag. Individual and mean values of the main electrophysiological features of the RI response obtained on the normal and operated side are shown in Table ll. in control experiments, we observed that in both controls and patients, supraorbital nerve stimulation did not elicit any reflex activity in the muscles of the tonguc (recorded with needle electrodes), even for high intensities (up to 30 mA) which were clearly able to activate smaller diameter cutaneous afferents of the A8 type, thus producing a pin-prick type sensation of pain. Furthermore, electrical stimulation (up to 15 mA) of the hypoglossal nervo in its peripheral course, i.e. below the posterior belly of the digastric muscle and lateral to the carotid arteries, did not produce any direct motor or reflex response in the facial muscles from normal subjects. Since both the non-functional facial motor nucleus and facial motor axons were bypassed by the peripheral hypoglosso-facial anastomosis, our present data strongly suggest that the short latency RI blink reflex response recorded in the orbicularis oculi muscles on the operated side is centrally mediated through an oligosynaptic (1-2 synapses) and neoformated trigemino-hypoglossal reflex arc. As suggested in the tentative model shown in Fig, 3, the most probable explanatory mechanism is the hetcrotopical sprouting of the axons of the trigeminai neurons from the principal trigeminal nucleus towards the Xlith nucleus. Given the distance between the inferior pole of the facial nucleus and the superior part of the hypoglossal one (0.5-1 cm in man), this sprouting is remarkably extensive. This hypothesis is supported by several arguments: (i) according to autoradiographic tracing data in cats and rabbits, strong ipsilateral projections to the blink motoneuronal cell groups have been found from the ventrolateral pontine
tegmental field and from the medullary medial tegmental field, at the level of the hypoglossal nucleus [s.z4.2s. However, in animals and man there are no data to suggest the existence of anatomical or physiological connections between the forehead cutaneous trigeminal afferents and the hypoglossal motor nucleus 4.5.s.9.28'3°'36'37'44. Thus, the hypothesis that the peripheral anastomosis in fact discloses a pre-existing but silent circuit seems unlikely; (ii) in normal man, there is neither clinical nor electrophysiological evidence for a trigemino-hypoglossal reflex since electrical stimulation of the supraorbital nerve does not elicit activity in the muscles of the tongue; and (iii) in normal man stimulation of the hypoglossal nerve does not elicit any direct motor or reflex response in the facial muscles even with strong electrical stimuli (up to 30 mA). Besides this hypothesis of a surprising, although possible, neoformated trigemino-hypogiossal connection, alternative hypotheses can be considered to explain our present data. They concern a re-growth of the facial nerve axons, either from the central sectioned stump (near the geniculi ganglion) directly towards facial muscles or from the facial motor nucleus through the hypoglossal motor nucleus towards facial muscles via the anastomosis. Although theoretically possible, these alternative hypotheses seem very unlikely, mainly because the observations of synkinesiacs in facial muscles during swallowing clearly indicate that only hypoglossal motoncurons, and not facial ones, are involved in the process. Our el¢ctrophysiological study thus unexpectedly indicates that some central neuronal networks in the adult human CNS can be structurally modified as a function of their peripheral environment, allowing the restoration of a function in which they were involved prior to a peripheral lesion. As suggested in other models of neuronal plasticity t'14'4z our present data could be explained if we postulate, in the hypoglossal motoneurons, the existence of specific chemical factors (possibly at least a nerve growth factor) produced peripherally, firstly by the nerve axotomies (VII and XII) and secondarily by the re-innervated facial muscles which are able to stimulate the heterotopical sprouting of trigeminal afferents onto some hypoglossal motoneurons. Such a hypothesis is supported by the following observations: (i) peripheral nerve axotomy triggers the expression of both nerve growth factor receptor (NGFr) and nerve growth factor (NGF) by Scl~wann cells 4z4a, A transfer of the NGF molecule to the ,NGFI of the neurite tips is believed to attract and guide the regenerating axons. Following internalization by the axon tip, the N G F - N G F r complex is then transported
305 r e t r o g a d e l y to t h e cell body, w h e r e it exerts a t r o p h i c effect ig'2"~'29'43; (ii) in a x o t o m i z e d m o t o n e u r o n s , the spinal reflex e v o k e d synaptic i n p u t s to t h e s e m o t o n e u t o n s are always r e s t o r e d after a f u n c t i o n a l r e c o n n e c tion with t h e muscle is effective 12.3:'-35. T h e s e data, t o g e t h e r with t h e findings r e p o r t e d here, p o i n t to t h e i m p o r t a n c e o f t h e p e r i p h e r y (nerve a n d muscle) in the m a i n t e n a n c e o f c e n t r a l a n d f u n c t i o n a l synaptic organization. We would like to thank Dzs. Constantine Sotelo, Emmanuel Fournier and Christopher Henderson for their valuable help in the preparation of the manuscript and for correcting the English, and Miss N. LeHenaff for the typing. This work was supported by a CRC No. 912209 and by INSERM. 1 Aguayo, A.J., Axonal regeneration from injured neurons in the adult mammalian central nervous system. In C.W. Cotman, (Ed.), Synaptic Plasuctty, Guilford, New York, 1985, pp. 457-483. 2 Barbas-Henry, H. and Wouterlood, F.G., Synaptic connections between primary trigeminal afferents and accessory abducens motoneurons in the monitor lizard varanus-exanthematicus, J. Comp. Neurol., 267 (1988) 387-397. 3 Barker, D. and Boddy, A., Re-innervation of stretch receptors in cat muscle after nerve crush, in J. Taxi (Ed.), Ontogenesis and Functional Mechanisms of Peripheral Synapses, INSERM Symposium no. 13, Elsevier, Amsterdam, 1980, pp. 251-263. 4 Brodal, A., The Cranial Nerves. Anatomy and At,,atomico.clinical Correlations, 2nd edn, Blackwell, Oxford, 1965. 5 Brodal, A., Neurological Anatomy in Relation to Chnical Medicine, 3rd edn., Oxford University Press, 1981. 6 Brown, M.C. and Butler, R.G., Regeneration ot afferent or efferent fibres to muscle spindles after nerve injury in adult cats, I, Physiol., 260 (1976) 253-266, 7 Burgess, P.R. and Horch, K.W., Specific regeneration of cutaneous fibers in the cat, J. Neurophysiol., 36 (1973) 101-114. 8 Carpenter, M,B. and Sutin, J., ltuman Neuroanatomy, VVlllth edn,, Williams and Wilkins, Baltimore, 1983, pp. 315-357. 9 Courville, J., The nucleus of the facial nerve: the relation between cellular groups and peripheral branches of the nerve, Brain Res., 1 (1966) 338-354. 10 Cruccu, G. and Bowsher, D., lntracranial stimulation of the trigeminal nerve in man, ll Reflex responses, J. Neurol. Neuro. surg. Psychiat., 49 (1986) 419-427. I I Cruccu, G. Inghilleri, M., Fraioli, B., Guidetti, B. and Manfredi, M,, Neurophysiologic assessement of trigeminal function after surgery for trigeminal neuralgia, Neurology, 37 (1987) 631-638. 12 Cull, R.E., Role of nerve-muscle contact in maintaining synaptic connexions, Exp. Brain Res., 20 (1974) 307-310. 13 Eccles, J.C., Krnjevic, K. and Miledi, R,, Delayed effects of peripheral severance of afferent nerve fibres on the efficiency of their central synapses, J. Physiol., 145 (1959) 204-220. 14 Gallego, R., Kuno, M., Nunez, R. and Snider, W.D., Enhancement of synaptic function in cat motoneurones during peripheral sensory regeneration, J. Physiol., 306 (1980) 205-218. 15 Goldberger, M.E. and Murray, M. Axonal sprouting and recovery of function may obey some of the same laws. In C.W. Cotman (Ed.), Neuronal Plasticity, Raven, New York, 1978, pp. 73-96. 16 Goldberger, M.E. and Murray, M., Recovery of function and anatomical plasticity after damage to the adult and neonatal spinal cord. In C.W. Cotman (Ed.), Synaptic Plasticity, Guilford Press, New York, 1985, pp. 77-110. 17 Goldring, J.M., Kuno, M., Nunez, R. and Snider, W.D., Reaction of synapses on motoneurones to section and restoration of peripheral sensory connexions in the cat, J. Physiol., 309 (1980) 185-198. 18 Harvey, J.A., Land, T. and McMaster, S.E., Anatomical study of the rabbit's corneaI-VIth nerve reflex: connections between
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