Research ArticleSpinal Cord Injury

Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates

See allHide authors and affiliations

Science Translational Medicine  26 Aug 2015:
Vol. 7, Issue 302, pp. 302ra134
DOI: 10.1126/scitranslmed.aac5811
  • Fig. 1. Functional recovery correlates with SCI laterality in humans.

    (A) MR images representing a symmetrical and a lateralized SCI. (B) SCI laterality was measured as the relative difference between motor scores (ASIA) of the left and right sides, termed LI. The histogram shows the distribution of LI across 437 individuals with a cervical SCI (EMSCI database). The shaded area indicates individuals with asymmetric motor deficits. (C) Motor scores around 2 weeks after lesion for patients with LI <0.5 and LI ≥0.5. (D) Gain in motor scores in the chronic compared to subacute stage of SCI for each range of LI. Horizontal bars indicate the median, and upper and lower bars correspond to the 75 and 25% percentile of data, respectively; error bars correspond to the 90 and 10% percentiles of the data (n = 437). *P < 0.05, analysis of variance (ANOVA) followed by Turkey’s post hoc test. n.s., not significant.

  • Fig. 2. Recovery of motor responses in leg muscles after motor cortex stimulation in quadriplegic patients.

    (A) Schematic overview of experiments. Motor responses were recorded in the left and right tibialis anterior muscles after transcranial magnetic stimulation (TMS) applied over the motor cortex. (B) Representative electromyographic (EMG) traces of left and right motor responses at early and chronic time points after SCI for a patient with symmetrical versus asymmetrical deficits. (C) Mean gains in the amplitude of the motor responses on the less and more affected sides in patients with a low versus high LI. (D) Latency of motor responses from the less and more affected sides in patients with a low versus high LI. For (C) and (D), *P < 0.05, **P < 0.01, unpaired Student’s t test. Data are means ± SEM (n = 34). MEP, motor-evoked potential; a.u., arbitrary units.

  • Fig. 3. Humans and monkeys show greater recovery of locomotion compared to rats after lateralized SCI.

    (A to C) Decomposition of lower limb motion during stance and swing together with successive limb endpoint trajectories during locomotion on a treadmill. Representative data are shown for a human patient (A), monkey (B), and rat (C) before the injury (or healthy) and at early and chronic time points after SCI. The vectors indicate the direction and amplitude of foot acceleration at swing onset. The EMG activity of the soleus and tibialis anterior muscles is shown at the bottom. The shared areas indicate the duration of the stance phases. At early time points, hemiplegic patients were recorded in the gait orthosis Lokomat. (D) Principal component (PC) analysis was applied on dimensionless parameters (n = 101), characterizing gait patterns of rats, monkeys, and humans. Least-squares spheres are traced to help visualize gait clusters and thus emphasize time- and species-dependent gait recovery. (E) Individual (lines) and mean three-dimensional (3D) distances between noninjured gait clusters and those measured at the early and late time points. *P < 0.05, **P < 0.01, *** P < 0.001, ANOVA. Data are means ± SEM (n indicated in figure).

  • Fig. 4. Humans, but not rats, recover the ability to traverse a horizontal ladder after lateralized SCI.

    (A and B) Decomposition of lower limb motion during locomotion along the equally spaced rungs of a horizontal ladder. Foot placement was measured as the relative positioning of the ipsilesional foot with respect to two successive rung positions (red dots). The number of occurrences per 5% bin is reported together with the percentage of accurate, slipped, and missed placements. (C) PC analysis performed using the same conventions as in Fig. 3D: 101 kinematic parameters measured for the ipsilesional leg before the injury (or healthy) and at the chronic stage of SCI. Individual (lines) and averaged 3D distance between noninjured data points and those measured at late time points. ***P < 0.001, ANOVA. Data are means ± SEM (n = 4 humans, 15 rats).

  • Fig. 5. Monkeys and humans show greater recovery of hand function compared to rats.

    (A to C) Upper limb endpoint trajectories during reach and retrieval. Failures of item retrieval are displayed in dark red, seen after SCI in rats and monkeys but not in humans. Averaged EMG activity (± SEM in gray) of the extensor digitorum communis and flexor digitorum muscles is shown during successive retrievals before the injury (or healthy) and at chronic time points after SCI in humans (A), monkeys (B), and rats (C). (D) Percent of successful object retrieval for each subject. *P < 0.05, ***P < 0.001, ANOVA. Data are means ± SEM [n indicated in (A) to (C)].

  • Fig. 6. Monkeys show greater reorganization of corticospinal tract (CST) fibers compared to rats.

    Corticospinal projection patterns were measured in rats and monkeys terminated at early (n = 8 rats and 3 monkeys) or chronic (n = 7 rats and 9 monkeys) time points after SCI. (A and B) Diagrams illustrating anatomical experiments. (C to F) Heat maps and representative images and reconstructions taken from boxed and numbered areas, illustrating sprouting of corticospinal axons in spinal segments below the lesion (CC, central canal). Scale bars, 100 μm for monkeys and 40 μm (insets: 10 μm) for rats. (G and H) Fiber density distribution, ipsilesional corticospinal axon density at C8, and number of corticospinal fibers crossing the spinal cord midline per analyzed section at C8 in intact animals and at early and chronic time points after SCI. *P < 0.05, ANOVA. Data are means ± SEM (n = 8 monkeys; 9 rats for chronic subjects). (I and J) Serial reconstruction of a single corticospinal axon. (K and L) Representative confocal images of respective area in (I) or (J), showing 3D colocalization of dextran-conjugated Alexa Fluor 488 (D-A488) and synaptophysin in monkeys, and biotin dextran amine (BDA) and synaptophysin in rats, demonstrating the presence of synaptic terminals onto corticospinal fibers below the hemisection. Scale bars, 2 and 4 μm for monkeys and rats, respectively.

  • Fig. 7. Syndromic analysis linking reorganization of corticospinal tract function and functional recovery.

    We used subsets of variables that were collected from rats and monkeys or from rats and humans for direct cross-species comparisons. (A) Bivariate correlation matrix showing robust correlations between anatomical and functional parameters. (B) An NLPCA was applied on all the parameters measured in rats and humans and in rats and monkeys. The data variance explained by PC1 and PC2 is reported. Color- and size-coded arrows indicate the direction and correlation (red, positive; blue, negative) between the parameters and each PC. Ipsilesional and contralesional refer to the origin of the corticospinal tract. (C) Mean scores on PC1 for both analyses and on PC2 for human versus rat. Each dot represents an individual subject. ***P < 0.001, **P < 0.01, unpaired two-tailed t tests. Data are means ± SEM (n indicated in figure).

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/7/302/302ra134/DC1

    Materials and Methods

    Fig. S1. Clinical cases and experimental models of Brown-Séquard syndrome.

    Fig. S2. Kinematics analysis uncovers similar patterns of locomotor deficits and compensation across species.

    Fig. S3. Humans and monkeys, but not rats, recover hand kinematics and muscle activation patterns.

    Fig. S4. Spinal cord decussating corticospinal fibers below the injury establishes synaptic contacts with neurons projecting to lumbar segments in monkeys.

    Fig. S5. Increased density of corticospinal fibers above the hemisection in both rats and monkeys.

    Fig. S6. Increased density of corticospinal tract fibers originating from the ipsilesional motor cortex fibers in segments below the hemisection in both rats and monkeys.

    Fig. S7. Density of 5-hydroxytryptamine fibers below the hemisection remains unchanged in both monkeys and rats.

    Fig. S8. The motor cortex fails to regain access to motoneurons below the hemisection in rats.

    Table S1. Computed gait parameters.

    Movie S1. Recovery of locomotion in monkeys and humans compared to rats after a lateral hemisection of the spinal cord.

    Movie S2. Recovery of hand function in monkeys and humans compared to rats after a lateral hemisection of the spinal cord.

  • Supplementary Material for:

    Pronounced species divergence in corticospinal tract reorganization and functional recovery after lateralized spinal cord injury favors primates

    Lucia Friedli, Ephron S. Rosenzweig, Quentin Barraud, Martin Schubert, Nadia Dominici, Lea Awai, Jessica L. Nielson, Pavel Musienko, Yvette Nout-Lomas, Hui Zhong, Sharon Zdunowski, Roland R. Roy, Sarah C. Strand, Rubia van den Brand, Leif A. Havton, Michael S. Beattie, Jacqueline C. Bresnahan, Erwan Bézard, Jocelyne Bloch, V. Reggie Edgerton, Adam R. Ferguson, Armin Curt, Mark H. Tuszynski, Grégoire Courtine*

    *Corresponding author. E-mail: gregoire.courtine{at}epfl.ch

    Published 26 August 2015, Sci. Transl. Med. 7, 302ra134 (2015)
    DOI: 10.1126/scitranslmed.aac5811

    This PDF file includes:

    • Materials and Methods
    • Fig. S1. Clinical cases and experimental models of Brown-Séquard syndrome.
    • Fig. S2. Kinematics analysis uncovers similar patterns of locomotor deficits and compensation across species.
    • Fig. S3. Humans and monkeys, but not rats, recover hand kinematics and muscle activation patterns.
    • Fig. S4. Spinal cord decussating corticospinal fibers below the injury establishes synaptic contacts with neurons projecting to lumbar segments in monkeys.
    • Fig. S5. Increased density of corticospinal fibers above the hemisection in both rats and monkeys.
    • Fig. S6. Increased density of corticospinal tract fibers originating from the ipsilesional motor cortex fibers in segments below the hemisection in both rats and monkeys.
    • Fig. S7. Density of 5-hydroxytryptamine fibers below the hemisection remains unchanged in both monkeys and rats.
    • Fig. S8. The motor cortex fails to regain access to motoneurons below the hemisection in rats.
    • Table S1. Computed gait parameters.
    • Legends for movies S1 and S2

    [Download PDF]

    Other Supplementary Material for this manuscript includes the following:

    • Movie S1 (.mp4 format). Recovery of locomotion in monkeys and humans compared to rats after a lateral hemisection of the spinal cord.
    • Movie S2 (.mp4 format). Recovery of hand function in monkeys and humans compared to rats after a lateral hemisection of the spinal cord.

Navigate This Article