MATRIZ DE ACTIVIDADES DIRECCIONADAS AL FORTALECIMIENTO DE LAS COMPETENCIAS EMPRENDEDORAS

From the end of the 19th _{century until the middle of the 20}th _{century various}

researchers, including Kennedy (1897), Osborne (1909), Marina (1912, 1915), Perthes (1918, 1922), Foerster (1930), Stopford (1930), Bethe and Fischer (1931), Anokhin and colleagues (1935, 1940), were firmly convinced that complete readjustment of the nervous system on both the cortical and subcortical level was possible, after injury to the motor (and sensory) system resulting in aberrant innervation of the end organs (SPERRY, 1945). However, in the late 1930s and early 1940s these very optimistic opinions came under fierce attack by Ford and Woodhall (1938) and Sperry (1940-1943) after new studies featuring findings which stood in direct contradiction to earlier views were presented. Instead of complete and rapid reorganisation, nerve-muscle rearrangements were found to result in discoordinations with no sign of correction (SPERRY, 1945). Additionally, it was found that the earlier investigations did not analyse the action of individual muscles in detail, but merely the animals’ general use of the hind limb in running, walking and other activities, and that control experiments had only very rarely been conducted. The term “trick movements” (also “compensatory”, “supplementary” or “anomalous” muscle function) was introduced for situations which tend to lead to mistaken conclusions regarding the extent of motor recovery. The most popular mechanisms cited for the induction of trick movements have been described as follows:

(1) remaining sound muscles can often, with or without practice, be made to reproduce the actions previously performed by the affected muscles,

(2) after contracture of a joint, the ankle joint being the one most frequently affected, the direction of action of the affected muscles can often be attained simply by relaxation of the antagonist muscles,

(3) owing to the mechanical relations of tendons and ligaments of joints, the displacement of one joint can often cause a passive movement of a joint further distal (often seen in knees and ankles of mammals),

(4) movements of the heavier limb segments can simply be produced by gravity,

(5) movements especially of the distal joints can simply be produced by momentum,

(6) contractures can support the utilisation of a joint due to stabilisation, whereas flaccid paralysis would not be beneficial (SPERRY, 1945).

Transection of the sciatic nerve at the level described in the present study, resulted in all muscles distal to the knee being denervated. This means that of the mechanisms described above, mechanisms (1), (2) and (4) can be excluded. The mechanism for the induction of a trick movement most frequently observed was (5), i.e. the production of a movement, especially of the distal joints, simply by momentum.

Freshly operated animals tended to walk on the dorsum of the toes and paws of the operated hind limb for the first two or three days. After that, however, they quickly learnt that with an exaggerated flexion of the knee during the swing phase and relatively late positioning of the foot on the ground in the stance phase, it was possible to achieve appropriate positioning of the foot of the operated hind limb. Animals with extensive reinnervation (mostly Group A) would then proceed to a state, beginning approximately three weeks after the operation, in which slight to moderate contractures of the ankle and the toes could be seen (Fig.17), occasionally making it rather difficult to acquire clearly defined footprints from these rats. In contrast to this, rats experiencing no regeneration would continue to exhibit flaccid paralysis of the lower leg of the operated hind limb (Fig.17). Comparison of the gait patterns showed that the animals with flaccid paralysis appeared to walk more smoothly and also always were able to position their foot flat on the ground with the plantar side downwards (unpublished observations).

Fig.17 Images taken from videos of rats walking: the rat on the left experienced extensive neural regeneration and suffered from contractures, whereas the rat on the right had no regenerating fibres at all and exhibited flaccid paralysis of the operated hind limb.

These observations can be very misleading, since flexion contractures are closely connected with reinnervation of the distal target muscles. They seem to result from the natural imbalance which exists between flexor muscles and extensor muscles, with the flexor muscles being more powerful than their antagonists (CHAMBERLAIN et al., 2000). The imbalance might further further aggravated by there also being slower or less complete reinnervation of the antagonists (CHAMBERLAIN et al., 2000). Furthermore, rats suffering from contractures most probably also have to cope with the consequences of aberrant innervation, which can highten the impression of their gait being more choppy and less coordinated than that of rats “simply” displaying unchanging flaccid paralysis. This leads us back to Sperry’s remark (SPERRY, 1945), that instead of scoring the overall use of an operated hind limb, the individual muscles need to be analysed in detail in order not to be deceived by trick movements.

For this reason more detailed assessment of ambulatory abilities was carried out on balancing devices of varying widths, since the placement of the hind limb on narrower beams and parallel bars requires particularly intricate hind limb coordination and is closely associated with motor learning (DING et al., 2000, 2001).

The results of the ambulatory tests revealed that all surgical groups exhibited similar numbers of placement mistakes, which means that extensive reshaping of the motor representational maps on the cortical and subcortical level must have taken place.

7.5.2.3 Central plasticity

The motor cortex, unlike the sensory cortex, is not divided into a somatotopically ordered representational map. Instead it is divided into subregions which function rather like a web interacting to trigger certain movements (WEISS & KELLER, 1994; SANES & DONOGHUE, 2000). It therefore seems that sites responsible for individual parts of the body are widely distributed and overlapping (SANES & DONOGHUE, 2000). However, motor maps, just like sensory maps, still have a flexible relationship on the various cortical and subcortical levels with their target organs, the muscles (DONOGHUE et al., 1990; SANES et al., 1990; SANES & DONOGHUE, 2000), and can be remodelled throughout life (NUDO et al., 1996; NUDO et al., 1997). Similar to those changes affecting the organisation of the somatosensory maps, motor maps can also undergo changes due to peripheral nerve lesions (DONOGHUE et al., 1990; SANES et al., 1990; HUNTLEY, 1997; CHEN et al., 2002) or motor skill training (NUDO et al., 1997; SANES & DONOGHUE, 2000; REMPLE et al., 2001); these changes are also reversible, but not completely (NUDO et al., 1996). After peripheral nerve lesions an enlargement of the adjacent representations in the motor cortex can be observed; this results in affected areas in the motor cortex becoming associated with new muscle groups (DONOGHUE et al., 1990; SANES et al., 1990; HUNTLEY, 1997). Changes in the target area of the motor cortex therefore enable the cortex to devote more attention to non-affected muscles. This means that motor control for the new target muscle can possibly be adjusted more finely (DONOGHUE et al., 1990; CHEN 2002). In the present study the muscles in question most probably were the thigh muscles. It is very conceivable that fine-tuning of the quadriceps muscle, but especially of the biceps femoris, semimembranosus and semitendinosus muscles would lead the rat to being able to place the hind paw of the affected hind limb relatively selectively when walking, in addition to being able to execute a smooth gait pattern. This would especially be the case if the muscles below the knee were affected by permanent denervation, a situation that was seen in most rats of Groups B and C. Consistency in the peripheral changes would allow the CNS to adjust better to the new situation resulting in a better adaptation to actual conditions and therefore in a gradual decrease in placement mistakes, as was observed in all the rats examined. Animals in Group A went through a patch of increased misplacements during week 4 and week 5, setting them behind the other groups. It could be speculated that these periods of extra mistakes could be due to regular and/or aberrant reinnervation of both muscles and sensory end organs, as these periods coincided

with the times where first real motor recovery progress could be observed in this group, as indicated by SFI and SSI evaluations. Reinnervation of the end organs, whether physiological or aberrant, would render newly acquired maps useless and the process of reorganisation would begin all over again, resulting in increased placement mistakes until new fine-tuning had sufficiently taken place.

The alterations to the motor maps described above are established within hours and can persist for long periods following nerve injury (DONOGHUE et al., 1990; SANES et al., 1990; HUNTLEY et al., 1997). Two main mechanisms have been put forward to explain reorganisation on the various cortical and subcortical levels after a peripheral lesion. The first, resulting in short-term changes, consists of unmasking already present, but functionally inactive, connections (DONOGHUE et al., 1990; KAAS, 1991; HUNTLEY, 1997; DUPONT et al., 2001; CHEN et al., 2002; KOERBER et al., 2006). There are numerous factors which could produce this result, such as increased excitatory neurotransmitter release, dephosphorylation of receptors, upregulation of postsynaptic receptors, changes in membrane conductance, decreased inhibitory inputs, or the removal of inhibition from excitatory inputs (CUSICK et al., 1990; DONOGHUE et al., 1990; JACOBS & DONOGHUE, 1991; KAAS; 1991; LITTLE et al., 1999; SANES & DONOGHUE, 2000; DUPONT et al., 2001; CHEN et al., 2002). Ultimately, however, it is the underlying anatomical features which define the extent to which short-term plasticity can take place (CALFORD, 2002). The second main mechanism, resulting in long-term plasticity, requires either NMDA receptor activation (ABRAHAM & BEAR, 1996; NUDO et al., 1996; BUONOMANO & MERZENICH, 1998; CALFORD, 2002; WIELOCH & NIKOLICH, 2006), which results in long term potentiation and/or long term depression, or axonal sprouting (KAAS, 1991; CHEN et al., 2002; BALLERMAN & FOUAD, 2006; WIELOCH & NIKOLICH, 2006) and synaptogenesis (KOERBER et al., 2006) featuring alterations in sizes and types of synapses (CHEN et al., 2002). Axonal sprouting and synaptogenesis might be initiated and controlled by the expression of cell adhesion molecules, which are also very important for forming connections between neurons during embryonic development (FIELDS & ITOH, 1996).

It has been suggested that trophic factors prompt the reorganisation of motor maps on the spinal level, while changes to sensory inputs trigger alterations in the cortex (DONOGHUE et al., 1990).

As with the central plasticity of the sensory system, the scope of the present study did not extend to determining exact degree of changes to the cortical and

subcortical motor maps. On the basis of the results of the ambulatory assessments it is, however, safe to assume that the alterations were extensive.

The most probable reason why such an impressive display of functional plasticity could be observed in the present study, is that all rats received extensive physiotherapy, both on a mandatory (twice weekly in the stress–free ambulatory assessments) and voluntary (during their daily “playtime” in the motor enriched cage) basis. Positively reinforced movement has been proven to induce and promote plasticity (WIELOCH & NIKOLICH) and this phenomenon has in turn been used in recent years as a means of promoting functional recovery after extensive lesions to the nervous system (LANKHORST et al., 2001; NORRIE et al., 2005; BEHRMAN et al., 2006).