Corticospinal reorganization after spinal cord injury

Abstract

The corticospinal tract (CST) is a major descending pathway contributing to the control of voluntary movement in mammals. During the last decades anatomical and electrophysiological studies have demonstrated significant reorganization in the CST after spinal cord injury (SCI) in animals and humans. In animal models of SCI, anatomical evidence showed corticospinal sprouts rostral and caudal to the lesion and their integration into intraspinal axonal circuits. Electrophysiological data suggested that indirect connections from the primary motor cortex to forelimb motoneurons, via brainstem nuclei and spinal cord interneurons, or direct connections from slow uninjured corticospinal axons, might contribute to the control of movement after a CST injury. In humans with SCI, post mortem spinal cord tissue revealed anatomical changes in the CST some of which were similar but others markedly different from those found in animal models of SCI. Human electrophysiological studies have provided ample evidence for corticospinal reorganization after SCI that may contribute to functional recovery. Together these studies have revealed a large plastic capacity of the CST after SCI. There is also a limited understanding of the relationship between anatomical and electrophysiological changes in the CST and control of movement after SCI. Increasing our knowledge of the role of CST plasticity in functional restoration after SCI may support the development of more effective repair strategies.

Figure 1. Corticospinal tract anatomy in rodents and cats/monkeys/humans

Schematic drawings of the brain and spinal cord illustrating the course of the corticospinal tract (CST) in adult rodents and cats/monkeys/humans. A, in adult rodents, corticospinal axons deriving from neurons in the motor cortex converge in the corpus callosum (CC), course through the internal capsule (IC), and cross the midline (dashed line) in the pyramidal decussation (PYX) and descend in the spinal cord. Most corticospinal axons cross the midline (>90%; contralateral (CL) crossed axons). The remaining corticospinal axons follow the same trajectory but do not cross the midline (<10%; ipsilateral (IL) uncrossed axons). The CST has three bilateral components that course in the ventral part of the dorsal columns, the dorsal aspect of the lateral columns, and the medial aspect of the ventral columns. B, in adult cats, monkeys and humans, corticospinal axons from motor cortex neurons course through the corpus callosum (CC) and internal capsule (IC) to cross the midline (dashed line) in the pyramidal decussation (PYX) and descend in the spinal cord. Most corticospinal axons cross the midline (75–95%; contralateral (CL) crossed axons). The remaining corticospinal axons have a similar route but do not cross the midline (5–25%, ipsilateral (IL) uncrossed axons). In these species, the CST has two bilateral components coursing in the dorsal aspect of the lateral columns (the lateral cerebrospinal fascicles) and the medial aspect of the ventral columns (the ventral cerebrospinal fascicles). For clarity, the illustrations of brain and spinal cord are not to scale.

Figure 2. Corticospinal sprouting after SCI

Schematic drawings of the CST response to SCI in adult rats/mice. A, a dorsal hemisection transecting the dorsal and lateral CST results in extensive sprouting (in red) of the unlesioned ventral component of the CST rostral and caudal to the lesion. Rostral CST sprouts connect with propriospinal neurons (PN) with local or distant projections. The former connections are transient while the latter remain, thereby establishing CST influences over the caudal spinal cord segments. Note that rostral is to the left as indicated in both figures. B, CST sprouting is absent after a complete spinal cord transection in adult rats/mice. Abbreviations: DC, dorsal columns; GM, grey matter; VH, ventral horn; WM, white matter.

Figure 3. Extensive compensatory plasticity of the lesioned corticospinal tract in monkeys

Corticospinal tract axons were labelled with D-A488. Axon density in intact (A), short-term lesioned (B), and long-term lesioned (C) monkey. In D, a single axon is reconstructed showing its origin from the left dorsolateral CST. E, axon density quantification revealed that CST density was reduced ∼75% 2 weeks after injury and recovered to more than half of pre-lesion axon density by 24 weeks post-lesion. F, quantification of axon thickness revealed that long-term lesioned animals exhibited a 20% increase in axon calibre below the lesion. In E and F, dots denote individual animals’ data points, *P < 0.05. Scale bar in A–C, 100 μm. Error bars indicate SEM. Figure modified from Fig. 4 in Rosenzweig et al. 2010.

Figure 4. Nogo-A-specific antibody enhanced corticospinal axon sprouting

Corticospinal axons were labelled using biotinylated dextran amine (BDA) injections in the contralateral motor cortex. BDA-labelled axonal arbors caudal to the lesion were more numerous in monkeys treated with Nogo-A-specific antibody (Mk-AM; left, bottom) than with control antibody (Mk-CH; left, top). Seven monkeys were used to determine the normalized cumulative corticospinal axonal arbor length (in mm; right, top) and the normalized number of axonal swellings by corticospinal axons (i.e. putative re-established contacts with interneurons or motoneurons; right, middle), which were plotted as a function of lesion extent. Monkey Mk-CP had profuse sprouting but was incompletely lesioned. The number of corticospinal axonal swellings was also plotted as a function of the cumulative corticospinal axonal arbor length (in mm) (right, bottom). In all graphs, blue circles represent control antibody-treated monkeys and red squares represent Nogo-A-specific antibody-treated monkeys. The extent of the blue and red zones in the semicircular figures represents the extent of the hemicord lesion. Figure modified from Fig. 2 in Freund et al. 2006.

Figure 5. The effect of dorsal CST lesion on biceps brachii MEPs evoked by TMS in the rat

A, location and extent of the CST lesion in the dorsal funiculus. B–E, MEPs before (Pre; upper traces) and after (Post; lower traces) the lesion. The TMS stimulation intensity was 40, 60, 80 and 100% of maximum stimulator output in B, C, D and E, respectively. Ten traces are shown for each condition separated slightly in order to better visualize the different latencies of the MEPs. At low TMS intensities MEPs with long (15–20 ms) latencies (B and C, Pre) were found and these were suppressed after the lesion (B and C, Post). MEPs with 10 ms latencies were evoked at 80% of the maximum TMS intensity (D, Pre) and these were significantly depressed (D, Post) but not to the same extent as the MEPs with longer latencies. Maximum TMS intensities evoked MEPs at latencies around 7 ms (E, Pre) and these were not depressed following the CST lesion (E, Post). These observations show that it is unlikely that activation of motor cortex CST neurons contributes significantly to at least the earliest occurring MEPs evoked by TMS. Figure from Nielsen et al. 2007.

Figure 6. MEPs in individuals with and without cervical SCI

MEPs recorded from the resting first dorsal interosseous muscle (FDI) of a representative healthy control (A) and an individual with cervical SCI (B) while the other side remained at rest or performed 30% (blue traces) or 70% (green traces) of maximal voluntary contraction (MVC) into index finger abduction or elbow flexion. Group data (C, healthy controls, n = 10; D, cervical SCI, n = 14). The abscissa shows the MVC levels tested (30% of MVC, blue bars; 70% of MVC, green bars). The ordinate shows the size of the FDI MEP as a percentage of the baseline FDI MEP. Note the increase in FDI MEP size during contralateral index finger abduction and elbow flexion in healthy controls but not in individuals with cervical SCI. Error bars indicate SEMs. *P < 0.05. Figure modified from Fig. 1 in Bunday & Perez, 2012.