Changes in descending motor pathway connectivity after corticospinal tract lesion in macaque monkey

Abstract

Damage to the corticospinal tract is a leading cause of motor disability, for example in stroke or spinal cord injury. Some function usually recovers, but whether plasticity of undamaged ipsilaterally descending corticospinal axons and/or brainstem pathways such as the reticulospinal tract contributes to recovery is unknown. Here, we examined the connectivity in these pathways to motor neurons after recovery from corticospinal lesions. Extensive unilateral lesions of the medullary corticospinal fibres in the pyramidal tract were made in three adult macaque monkeys. After an initial contralateral flaccid paralysis, motor function rapidly recovered, after which all animals were capable of climbing and supporting their weight by gripping the cage bars with the contralesional hand. In one animal where experimental testing was carried out, there was (as expected) no recovery of fine independent finger movements. Around 6 months post-lesion, intracellular recordings were made from 167 motor neurons innervating hand and forearm muscles. Synaptic responses evoked by stimulating the unlesioned ipsilateral pyramidal tract and the medial longitudinal fasciculus were recorded and compared with control responses in 207 motor neurons from six unlesioned animals. Input from the ipsilateral pyramidal tract was rare and weak in both lesioned and control animals, suggesting a limited role for this pathway in functional recovery. In contrast, mono- and disynaptic excitatory post-synaptic potentials elicited from the medial longitudinal fasciculus significantly increased in average size after recovery, but only in motor neurons innervating forearm flexor and intrinsic hand muscles, not in forearm extensor motor neurons. We conclude that reticulospinal systems sub-serve some of the functional recovery after corticospinal lesions. The imbalanced strengthening of connections to flexor, but not extensor, motor neurons mirrors the extensor weakness and flexor spasm which in neurological experience is a common limitation to recovery in stroke survivors.

Figure 1

Histological and electrophysiological characterization of pyramidal tract lesions. (A) Histological sections of the brainstem from the three experimental animals. Each column presents material from a different animal. Numbers in the bottom left of each photomicrograph are estimated rostro-caudal location of each section, using the anterior-commissure referenced coordinates of Martin and Bowden (1996). Asterisks after these coordinates mark the section at the largest extent of the lesion. Arrows indicate the location of the tip of the pyramidal tract stimulating electrode used in the terminal experiment. Sections were photographed under dark field illumination. (B) Epidural recordings from motor cortex before (blue) and after (red) the lesion, showing potentials evoked by pyramidal tract stimulation caudal to the lesion site. Arrows mark time of the stimulus; traces are blank in the immediate post-stimulus period due to large stimulus artefacts. Yellow shading indicates the earliest (antidromic) part of the response. Calibration bars are 0.25 ms, 20 μV.

Figure 2

Responses of identified motor neurons to ipsilateral pyramidal tract stimulation. (A) Schematic showing the lesioned pyramidal tract (PT, dashed line), and potential pathways descending through the ipsilateral (intact) pyramidal tract that might contribute novel connections. (B–D) Each panel shows averaged intracellular recordings from motor neurons (upper thick lines) and epidural recordings from close to the microelectrode penetration point (lower thin lines). Calibration bars are 0.1 mV, 1 ms (thick lines), and 50 μV (thin lines). The arrival of the descending volley and onset of the EPSP (where present) are shown by dashed and solid vertical lines, respectively. Insets show antidromic spikes elicited by stimulation of the most distal peripheral nerve that gave a response (calibration bars 10 mV, 1 ms). Arrowheads mark time of stimulation. Number of stimuli used to compile the averages (n) is given below each pair of records. (B) Intrinsic hand muscle motor neuron with no synaptic response. (C) Forearm flexor motor neuron with monosynaptic EPSP. (D) Forearm flexor motor neuron with both mono- (m) and disynaptic (d) EPSPs.

Figure 3

Quantitative measurements of input to motor neurons from the ipsilateral pyramidal tract. Data are presented separately according to the muscle group that the motor neuron innervated: (A) forearm flexors; (B) forearm extensors; (C) intrinsic hand muscles. Blue bars relate to control and red to lesioned animals. Filled bars show monosynaptic and open bars disynaptic responses. The left column shows the incidence of EPSPs. The middle column shows the mean amplitudes of EPSPs, where present. The right column indicates the product of amplitude and incidence, which measures the overall strength of input from a given pathway (connection strength). Statistical tests were performed using Fisher’s exact test (incidence) and a Monte Carlo resampling method (amplitude and amplitude × incidence product); there were no significant differences between control and lesioned animals (P > 0.05).

Figure 4

Responses of identified motor neurons to stimulation in the medial longitudinal fasciculus. (A) Schematic showing the lesioned pyramidal tract (PT) and pathways descending through the ipsilateral and contralateral medial longitudinal fasciculus (MLF). (B–G) Averaged intracellular potentials from motor neurons, conventions as in Fig. 2. Calibration bars are 0.1 mV, 1 ms (thick lines) and 20 μV (thin lines). The arrival of the descending volley and onset of the EPSP (where present) are shown by dashed and solid vertical lines, respectively. Insets show antidromic spikes elicited by stimulation of the most distal peripheral nerve which gave a response (muscle category indicated above each panel). Calibration bars for the insets 10 mV and 1 ms. Arrowheads mark time of stimulation. Numbers of stimuli used to compile the averages (n) is given below each pair of records. (B, D and F) Responses to ipsilateral medial longitudinal fasciculus stimulation. (C, E and G) Responses to contralateral medial longitudinal fasciculus stimulation. Panels B and C show recordings from the same motor neuron, D–G are all from different motor neurons. Synaptic responses in B–E were classified as monosynaptic; those in F and G as disynaptic.

Figure 5

Quantitative measurements of input to motor neurons from the medial longitudinal fasciculus. As in Fig. 3, data are presented separately according to the muscle group which the motor neuron innervated: (A) forearm flexors; (B) forearm extensors and (C) intrinsic hand muscles. Blue bars relate to control and red to lesioned animals. Filled bars show monosynaptic and open bars disynaptic responses. The left column shows the incidence of EPSPs. The middle column shows the mean amplitudes of EPSPs, where present. The right column indicates the product of amplitude and incidence, which measures the overall strength of input from a given pathway (connection strength). Statistical tests were performed using Fisher’s exact test (incidence) and a Monte Carlo resampling method (amplitude and amplitude × incidence product). Asterisks mark significant differences between control and lesioned animals (*P < 0.05; **P < 0.01).