Promoting functional plasticity in the damaged nervous system.

Damage to the central and peripheral nervous system often produces lasting functional deficits. A major focus of neuroscience research has been to enhance functional restitution of the damaged nervous system and thereby produce recovery of behavioral or physiological processes. Promising procedures include surgical, physical, and chemical manipulations to reduce scar formation and minimize the disruption of support elements, administration of growth-stimulating substances, tissue grafts to bridge gaps in fiber pathways, and embryonic brain tissue grafts to provide new cells with the potential to generate fiber systems. Two elements are required for functional nervous system repair: (i) neurons with the capacity to extend processes must be present, and (ii) the regenerating neurites must find a continuous, unbroken pathway to appropriate targets through a supportive milieu.

Local autoimmune reaction and behavioral abnormalities after repeated nerve injury: an experimental study.

Sciatic nerves of rats were submitted to single and repeated injuries. The animals' gait was used to study motor function; autophagia was used to study sensory effects. An association with local post-traumatic autoimmune reaction was sought, after histochemical studies of the nerves. Our results indicated that a preliminary nerve lesion had a slight but significant influence on the recovery observed after a subsequent injury: after secondary damage, motor recovery was slightly delayed and sensory abnormalities were suggested by significant increase in autophagia. A causal role of autoimmunization was suggested but not proven. An interpretation of autophagia is proposed.

Interpreting nerve morphometry data after experimental traumatic lesions.

Morphometric data were obtained in 2 experimental conditions: crush lesions of the sciatic nerve of rats, and transection of this nerve followed by repair. Ratios were used in order to facilitate comprehension of data. Results were compared to those obtained using a method of functional assessment. The study indicated that morphometric data provided a reliable picture of the trophic condition of regenerated nerves but did not correlate with the level of function.

How to correctly match 175,000 neurites: two postulates for a quick solution.

I propose two postulates that allow precise matching of an indefinite number of neurites when repairing a transected nerve. The first one, based on the principle of de Saint-Venant, indicates how to keep nerve fibers in proper longitudinal alignment, by diverting stress to an appropriate distance from the tip of the stumps. The second postulate, based on the symmetrical mechanical resistance of the stumps, indicates how to restore correct transversal alignment of the fibers, by circularizing the severed nerve extremities.

Is it possible to predict the outcome of peripheral nerve injuries? A probability model based on prospects for regenerating neurites.

The long term functional consequences of peripheral nerve injuries are notoriously unpredictable. We hypothesized that considering the individual regrowth of the elementary components of a nerve (the neurites) rather than the global regeneration of the organ could lead to a better understanding of the mechanisms of nerve repair. Our basic assumptions were that regrowth was random and regrowth of any individual neurite could be defined in terms of its influence on recovery; this influence could be either valid, neutral or invalid. We designed a probability model describing the prospects of regrowth for nerves composed of several types of fibers. Our goal was to propose a general explanation of nerve healing rather than to predict the outcome in individual situations. The results suggested that this model satisfactorily described the events taking place in a healing nerve.

Cold and post-traumatic pain: modeling of the peripheral nerve message.

Hypersensitivity to cold is a relatively frequent sequel of peripheral nerve injuries but its mechanism is not well understood. We suggested that incomplete recovery of diameter of regenerated fibers is one of the factors involved in cold intolerance after nerve damage. Conduction velocity is correlated to fiber diameter, and is slowed down by cold. In normal subjects, cold does not desynchronize the volleys of sensory impulses sufficiently to change the intelligibility of the peripheral 'messages'. Sensory perceptions remain accurate although they acquire a characteristic numbness. On the other hand, post-traumatic reduction in fiber diameters causes a permanent distortion of the messages. We considered that when the distortion is severe, the resulting messages may be perceived by the centers as containing nociceptive components. We further hypothesized that, even in cases of moderate permanent distortion, cold acts by increasing the post-traumatic abnormalities of impulse synchronization. In winter, decompensation is observed when a threshold of desynchronization is reached. We constructed a model of peripheral nerve messages in an attempt to represent and quantitate the desynchronizations produced by cold and crush damage lesions in peripheral nerve messages. A number of parameters concerning fiber anatomy, exposure to cold, and type of nerve damage were taken into consideration. Four elementary types of desynchronization could be recognized by considering the times of arrival of pairs of impulses at the nervous centers. The difference between a normal and a distorted message could be expressed by eight variables. Thus, although our model was quite simple, a large amount of data was obtained and a preliminary statistical study was necessary in order to orient the final analysis. Then, we used factor analysis in an attempt to obtain a satisfactory interpretation of the data. The results indicated that peripheral desynchronization might explain, at least in part, the painful sensations experienced in winter by many patients after peripheral nerve injury.

Applying "cell surgery" to nerve repair: a preliminary report on the first ten human cases.

We have applied a new technique of nerve repair, based on the principles of "cell surgery", to ten nerve lesions of the upper limb. Eight lesions were recent, five to 36 hours; they were divisions of the ulnar nerve (1), median nerve (2), sensory radial nerve (1), palmar and digital nerves (4). One lesion was 15 days old (median nerve). One eight-month-old loss of 4.5 cm. of the median nerve was grafted. In nine out of the ten cases, the short-term results were encouraging. Poor local conditions (fibrosis of the nerve bed) or poor general health (chronic alcoholism) had no adverse influence on the results. In the remaining case, the protocol was not followed in its entirety: it was not possible to crystallise properly the nerve, and trimming was done with scissors in the conventional way instead of smoothly trimming the solidified tips. The functional result in this case is a failure. These preliminary results seem to indicate that correctly applying the technique in its entirety may be more important than local conditions. We think that this technique can be applied to the majority of nerve lesions. The appropriate equipment is absolutely necessary in order to apply the method.

Primary nerve repair in the upper limb. Our preferred methods: theory and practical applications.

After years of controversy, it is now generally agreed that primary nerve repair by end-to-end coaptation, whenever feasible, yields better results than secondary procedures. We reviewed the theoretic basis of current methods of repair and described our preferred techniques and indications.

[180 cases of umbilical hernia repaired in a new way (author's transl)]. / A propos de 180 cas de hernies ombilicales opérées selon un nouveau procédé de réparation.

We describe a new method for the cutaneous repair of umbilical hernias. The cut of the skin makes two flaps suppressing the navel which is generally salient. After the aponevrotic repair which is made by vertical suture with slowly resorbable material, the repair of the two cutaneous flaps builds a new navel which aspect is very close to the natural one. This method has been used once with complete satisfaction, for the repair of an omphalocel.

Functional consequences of experimental nerve lesions: effects of time, location, and extent of damage.

The purpose of this experiment was to investigate the part played by each of the four fundamental components of a nerve in functional recovery from injury. In order to single out the role of cellular elements (the neurites), tissular elements (the Schwann cells), structural elements (the basal lamina tubes), and the blood-nerve barrier, various crush lesions were made on sciatic nerves of rats and functional recovery was studied. I examined the effects of the location and number of damaged sites and of the time elapsed between successive injuries. Results were assessed for a post-operative period of 2.5 months by studying tracks obtained from walking rats. This study suggested that (a) as far as neurites were concerned, the location of injury influenced the recovery pattern but the extent of damage did not; (b) the extent of damage to the Schwann cells had no measurable influence; (c) long-lasting deficits could be attributed to disruption of the basal lamina tubes, and (d) damage of the blood-nerve barrier could be responsible for slight and temporary disruption of the recovery pattern. I did not observe any of the possible beneficial effects of conditioning lesions described by some authors. This study emphasized the role of the basal lamina tubes in nerve injury and regeneration.

Functional consequences of experimental nerve lesions: effects of reinnervation blend.

In spite of a constant and irrepressible growth of sprouts from the proximal stump of peripheral nerves that have been injured, functional recovery varies greatly from one case to another. To try and understand the reasons for this variability, I have proposed a novel view of the events occurring in a regenerating nerve; based on this view, a probability model was designed that could represent all situations observed after nerve injury. This model, described elsewhere, is based on the assumptions that the guidance role of basal lamina tubes is fundamentally important and that when this guidance fails, regrowth is random. In the present study, this model was tested; behavioral results were measured after various procedures on rat sciatic nerve, and these data were compared with results predicted for similar injuries through the probability model. A good correlation was observed between theoretical and experimental results, indicating that the probability model was reliable. Using this model as the basis for my conclusions, the inconsistent results of current surgical techniques of nerve repair were tentatively explained.

An anatomical landmark for procedures on rat thoracic spinal cord.

A vein is described that allows easy identification of the fifth thoracic vertebra of the rat. Leading from the dorsal hibernating gland to the azygos vein, the vessel was present in each of 135 rats.

Neurobehavioral evaluation of function following experimental nerve damage.

Accuracy of axonal regrowth is a major factor of recovery after a peripheral nerve lesion. In sciatic nerve studies, gait is a simple indicator of the precision of repair. It is possible to quantify nerve function through measurements made from rats' walking tracks. The rat sciatic nerve trunk was injured in several ways and the resulting changes in sciatic function were measured using tracks. The advantages and limits of the method are discussed.

Peripheral nerve reconnection: inhibition of early degenerative processes through the use of a novel fluid medium.

Two pharmacologic manipulations were applied to injured nerves in the rat to minimize the secondary damage that accompanies peripheral nerve transection. It is known that calcium influx into the nerve is responsible for some of the processes that have been termed Wallerian degeneration. These disruptive effects of high intracellular calcium were retarded by chlorpromazine, a potent inhibitor of calmodulin. Our results suggested a new method for reducing posttraumatic neural disruption and supported our hypothesis regarding the involvement of calmodulin or some other Ca2+ binding protein in Wallerian degeneration. The second part of this report describes changes observed at the tips of a severed nerve and their prevention through the use of polyvinyl alcohol. Finally, we showed that neither substance produced functional deficits when injected directly into the sciatic nerve of rats and could thus be used in animal experimentation.

Peripheral nerve reconnection: immediate histologic consequences of distributed mechanical support.

We tested the possibility of improving the quality of axonal repair after peripheral nerve transection by suppression of all mechanical stresses from the zone of repair. A method was developed involving mechanical support of the sciatic nerve from below in a grooved chamber with additional support provided by suturing the nerve to a rubber sleeve. Histological studies of silver-impregnated specimens from rabbit sciatic nerve using this technique revealed that the axons' tips were closely reconnected with minimal disruption in their direction or in the alignment of fibers and without extraneous material between the severed stumps. Comparison of these results with those of current microsurgical techniques showed the unequivocal superiority of this method in terms of immediate histologic aspects. The course of Wallerian degeneration was not modified.

Experimental nerve reconnection: importance of initial repair.

We believe that the randomness of sprout regrowth is the cause of most poor experimental and clinical functional results after nerve repair. We have elaborated a technique of repair, called "nerve reconnection," aiming to minimize randomness of regrowth. This technique enhances the precision of repair by minimizing physical and chemical damage to the stumps and by ensuring stress-free stump abutment. In this study, the reconnection technique was compared to the conventional microsuture method. First, both techniques were tested as the primary method of repair. A method of behavioral evaluation, the sciatic functional index, was used to assess the results. The reconnection groups consistently showed satisfactory functional results, even after two successive procedures. In contrast, only one-third of the animals in the suture groups reached satisfactory functional levels. In the second part of the study, animals with unsatisfactory results after primary suture were reoperated in an attempt to improve the poor results of initial surgery. The secondary procedures used were either the reconnection technique or conventional microsuture. All secondary procedures failed to improve poor preexisting functional conditions. These findings stress the importance of the original "blueprint" of the nerve and the necessity of maintaining this unique pattern during initial repair.

A method for shortening of the rat spine and its neurologic consequences.

Large laboratory animals are the usual choice for complex surgical procedures on the spine and spinal cord, such as shortening of the spine. It would, however, be advantageous to be able to use a small inexpensive mammal like the rat. We describe a procedure which allows thoracic spondylectomy (T8-T9) to be performed in the rat with a satisfactory survival rate (69%). Functional consequences of the procedure on animals with uninjured spinal cord were monitored over a period of six months, at which time histologic examination was performed. There was a good correlation between operative trauma, consisting of mechanical injury to the cord assessed from the surgical notes, and the duration of postoperative spinal shock. Animals for which the cord appeared laminated or deformed at the time of sacrifice tended to show incomplete functional recovery. Cord cavitation developed in most surviving animals (78%) but did not have a measurable adverse effect on functional outcome. In the present study, the cord was not intentionally injured; however, availability of this procedure may facilitate the future development of methods to implement recovery of function following spinal cord injury.

Functional consequences of isolated nerve stretch: experimental long-term static loading.

The maximum longitudinal tension that can be applied to the stumps of a divided peripheral nerve during surgical repair is not precisely defined. Uncertainty about the threshold of unacceptable nerve tension may be due to the lack of studies on isolated and reproducible stretch, i.e., on quantified elongation without concomitant compression, crush, or transection. The authors devised a simple method for producing isolated, long-term static loading of the nerve in vivo without concomitant compression, crush, or transection. Tension was applied to intact and crushed sciatic nerves in the rat, stretching them by 15 or 30 percent of their initial length, and the corresponding functional consequences were evaluated. Results showed that no measurable functional deficit resulted from stretching a segment of intact nerve to a length 30 percent greater than its initial length. In contrast, a significant delay in functional recovery resulted from stretching a crushed nerve by the same amount. A practical conclusion may be that the site of application of stretch forces during surgical repair, i.e., the location of coapting stitches, could play an important role in clinical practice.

Posttraumatic autoimmune reaction in peripheral nerve: effect of a single injury.

This study was conducted to show that local autoimmune reactions could be observed in rat sciatic nerve after a single injury. Furthermore, we attempted to correlate the intensity of the immunological reaction with the severity of nerve damage, with the type of surgical treatment and with the degree of functional recovery. Through the use of direct immunofluorescence techniques, we found that the severity of the initial damage was associated with the intensity of the local immunological response assessed 2.5 months after surgery. There was an association between type of surgical treatment and intensity of the autoimmune reaction. A correlation between autoimmune reaction and degree of long-term functional impairment was not immediately clear. The probable factors that underlie these results are discussed.