The Amount of Spared Hardware Determines the Degree of Spontaneous Recovery
Spontaneous functional recovery can be found for a few weeks after CNS injury. The duration of this process and the degree of recovery greatly depend on the severity of the injury. For example, it is generally acknowledged that more severe injuries allow a lesser degree of spontaneous recovery and likely reduced efficacy of rehabilitative training. Robust repair mechanisms to replace lost tissue are limited because of insufficient availability of stem cells and the inability of neurons to regenerate in the adult mammalian CNS (17). Consequently, beyond the obvious observation that more severe lesions result in more severe deficits, the number of spared neuronal building blocks also determines the degree of plasticity and, thus, spontaneous and training-induced functional recovery. When comparing this with a building, extensive damage to all bricks, analogous to a complete transection of the spinal cord or the ablation of an entire cortical area, results in no pieces remaining for meaningful rebuilding or plasticity (Fig. 2G). However, small injuries to the brain or spinal cord can be compensated for immediately without any obvious effects and often are hardly noticeable in animal models or the clinical setting (12,14). This offers a straightforward analogy to a building block structure: the more damage that occurs, the less restructuring without additional building materials is possible. Minor damage can be “patched up” without influencing the overall stability of the building but, when critical load bearing components are destroyed, reconstruction is impossible (Fig. 2A, B).
The Nonlinear Relation Between Structural Damage and Function
Although severe lesions to the CNS hardly allow spontaneous recovery controlled by descending input from the brain and small lesions can be compensated for immediately (see previous section), the relation between functional recovery and tissue loss generally is not linear (12,16,30). For example, the success rate in a reaching task in an animal model of spinal cord injury (SCI) remains high after small lesions; with increasing tissue damage, however, a drastic decline in function occurs before a plateau is reached. This plateau can be maintained for a surprisingly large increase in lesion size. Yet, when a critical point in lesion size is exceeded, the ability to reach is abolished even though not all tissue has been injured (Fig. 2). This could be interpreted as compensation by using spared, previously noncritical components to take on more critical roles when small losses of neuronal hardware occur. Adaptive strategies allow for the maintenance of a new plateau in motor function after a significant loss of tissue. No functionally meaningful neuronal network can be established once a critical amount of tissue loss has been exceeded. This is comparable to a house where a few building components can be damaged and, if they are essential for the house to be habitable, they can be compensated for by using components less critical for the structural integrity of the house (Fig. 2B, C). However, with a continuous increase in damage, a threshold will be reached where the house will have to be remodeled to remain habitable, for example, by downsizing (Fig. 2D, E). With further increase in the number of damaged building components, too many pieces will be missing and even the smaller house will become uninhabitable (Fig. 2F). Although pieces of the structure might still be available, it cannot be remodeled to be habitable again. These findings especially are important when attempting to judge and compare the efficacy of treatments including rehabilitative training. Treatment effects may range from significant to nonexistent depending on the severity of the lesion.
When Remodeling, Specific Use of Building Components Determines the Outcome
Currently, the most successful treatment after injuries to the CNS is rehabilitative training. It has been reported that training effects are often task specific and may even influence untrained motor functions negatively. For example, training to walk forward on a treadmill does not translate into recovery of backward walking or stepping in place in individuals with SCI (9). Cats with complete SCI that were trained to stand have more difficulty relearning to step compared with untrained cats and step-trained cats (10). Similarly, step-trained cats are not able to stand as well as stand-trained cats. Comparably, rats with SCI trained to grasp for food pellets showed deficits in an untrained task, that is, crossing a horizontal ladder (8). In addition, it has been reported that training of one language after stroke in bilingual individuals reduces the ability to reestablish speech in the second language (1). These findings suggest that spared neuronal hardware can be “remodeled” after an injury to the CNS according to the trained tasks. Similar to the developing nervous system (11), this process is driven by activity and illustrates an important aspect of postinjury rehabilitative training. After injury, this process will result in compensation, or functional substitution, rather than repair to reach the status quo.
In contrast, it is well established that disuse of an affected limb or of particular tasks after CNS injuries can contribute to further dysfunction, an idea clearly stated by the phrase “use it or lose it,” which is established firmly in the field of stroke (25). Constraint-induced movement therapy is an approach commonly used to counteract this effect on affected function by enforcing the use of the affected limb/function, thereby preventing compensatory approaches. The continuous training of the affected limb and its motor function by using this therapy is used successfully in the clinical setting to counteract the disuse of the affected limb (22,35). The success of constraint induced movement therapy inspired similar approaches in other areas, including retraining of speech where compensatory mechanisms of communication are restricted (21).
In summary, it can be generalized that the available neuronal hardware is dedicated in a competitive manner on a first-come, first-served basis, and tasks that require higher neuronal activity are favored. This scenario is comparable to a building where, once a structure is damaged, broken components become useless and spared pieces can be reused to recreate certain portions of the original structure. There will be competition for the limited building materials, which will decide the final structure and, therefore, functional capabilities (Fig. 3A). For example, the roof will be leaky if building pieces from the roof are used to stabilize the walls. Even though moving building pieces from the nervous system is not a realistic option, integrating neurons in different circuitries may result in an alternative utilization for them.
The Damaged Location Can Be Used to Predict Functional Outcome
Recovery after injury is not only determined by the amount of tissue damage but also depends on the location of the injury (6,16,30). This is based on the fact that the CNS is built by functional units. For example, different parts of the body are represented by specific cortical areas, and specific spinal tracts with different functions project in bundles in specific locations within the spinal cord. This can explain why a small lesion in the ventral spinal cord can have more severe effects on locomotor ability than a big lesion in the dorsal cord because tracts that are involved in initiating locomotion project in the ventrolateral portion of the spinal cord. Another example is that recovery in reaching function is better when two descending tracts involved in reaching are lesioned partly rather than the complete ablation of one track. Parallels to a building can be drawn, where it would be easier to create a downsized structure when pieces of all the building components are still available (Fig. 3B).
Effects of Spinal Lesions Staggered in Time Support the Reconstruction Idea
So far we have described a model in which the building blocks of the nervous system, similar to building components of a house, can be reassembled/rewired in an alternative manner after injury. Furthermore, we discussed that rehabilitative training is a key component to achieve this. Illustrative examples where an injury induces permanent changes to the nervous system are provided by experiments with two lesions staggered in time. This approach has been used with injuries to the spinal cord, where convincing differences in the response to a lesion were found depending on whether a second spinal lesion was induced at the same time as the initial one or later in time. For example, a spinal lesion ablating one side of the cord allows for nearly complete recovery of stepping in rats and cats alike (3,18). Following our hypothesis, this is caused by an activity-based rearrangement of building materials and reinforcing remodeling. When such a lesion is followed by a complete spinal transection caudal to the first lesion a few weeks later, the spinal networks below the lesion are able to recover the same stepping pattern much faster when compared with animals that only received a single transection (19). This demonstrates that the first injury induced compensatory rewiring within the spared spinal cord network that is maintained even when disconnected completely from the brain. Thus, if a house that was remodeled after a first earthquake had to overcome a second earthquake, the overall damage would not be necessarily comparable to the damage that same house would have had if only a single stronger earthquake had hit it.
Another example demonstrating the “remodeling” of the CNS after injuries comes from an experiment where we examined the recovery of reaching function for weeks following a cervical lesion of the corticospinal tract in rats. This recovery is paralleled by rewiring of injured corticospinal tract (CST) fibers to alternate targets, a process that is amplified by rehabilitative training (8). A second lesion of the corticospinal tract rostral to these new connections abolishes the observed recovery completely (15), indicating that this compensatory rewiring is meaningful functionally.
These results provide strong evidence for the involvement of plasticity in recovery and demonstrate that training is a key concept to enhance it. The spontaneous recovery found after CNS injuries is likely based on activity and training performed inadvertently during daily life. This has been demonstrated dramatically by the lack of spontaneous recovery in rats with thoracic SCI when the use of their hindlimbs was disabled (5).
Building Block Structure Analogy Applies Not Only to Common Treatment Strategies
In this article, we have compared the injured CNS with a structure where new building supplies are unavailable. Obviously, treatments designed to introduce new “building materials” or to minimize damage after CNS injury would be desirable. For example, a much-anticipated approach is the grafting of stem cells into injured areas of the CNS (17,28). Theoretically, these cells have the ability to develop into various cells types, including neurons and glia, thereby replacing damaged building materials. This approach would extend the opportunities to repair an injured structure greatly; however, to properly integrate new building blocks, rehabilitative training likely will be needed to connect the pieces in a functionally meaningful manner.
An alternative and already used approach for treating CNS injuries is based on the knowledge that lost neuronal hardware is difficult to replace. These treatments focus on neuroprotection. To be effective, these treatments have to be applied as soon as possible after injury. Following CNS injuries, there are various approaches in clinical use, in trials, or currently tested in animal models ranging from cooling the injured CNS to the application of antiinflammatory drugs (27,32). In our model, they could be compared with dampening the effects of the earthquake by reinforcing structures immediately after the damage to prevent further (secondary) damage.
In conclusion, a detailed understanding of the mechanisms of neuronal plasticity is important for optimizing treatments for CNS injury. However, from a more clinical point of view, these intricate details may be unnecessary. Viewing the CNS as a house made out of different components of neuronal hardware that can be reassembled in response to injury is not necessarily a simplified view of injury-induced plasticity, but a metaphor derived from various findings. A more tangible view of injury-induced plasticity in the brain and spinal cord may be helpful in communicating the process of plasticity.
The authors thank Dr. Jaynie Yang for comments on the manuscript.
This work was supported by the Canadian Institute of Health Research and Alberta Innovates Health Solutions.
K. Fouad is supported by AIHS, CIHR, and ISRT.
The authors declare no conflict of interest.
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central nervous system; spinal cord; motor function; plasticity; rehabilitation
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