Vestibular asymmetry as the cause of idiopathic scoliosis: a possible answer from Xenopus

Abstract

Human idiopathic scoliosis is characterized by severe deformations of the spine and skeleton. The occurrence of vestibular-related deficits in these patients is well established but it is unclear whether a vestibular pathology is the common cause for the scoliotic syndrome and the gaze/posture deficits or if the latter behavioral deficits are a consequence of the scoliotic deformations. A possible vestibular origin was tested in the frog Xenopus laevis by unilateral removal of the labyrinthine endorgans at larval stages. After metamorphosis into young adult frogs, X-ray images and three-dimensional reconstructed micro-computer tomographic scans of the skeleton showed deformations similar to those of scoliotic patients. The skeletal distortions consisted of a curvature of the spine in the frontal and sagittal plane, a transverse rotation along the body axis and substantial deformations of all vertebrae. In terrestrial vertebrates, the initial postural syndrome after unilateral labyrinthectomy recovers over time and requires body weight-supporting limb proprioceptive information. In an aquatic environment, however, this information is absent. Hence, the lesion-induced asymmetric activity in descending spinal pathways and the resulting asymmetric muscular tonus persists. As a consequence the mostly cartilaginous skeleton of the frog tadpoles progressively deforms. Lack of limb proprioceptive signals in an aquatic environment is thus the element, which links the Xenopus model with human scoliosis because a comparable situation occurs during gestation in utero. A permanently imbalanced activity in descending locomotor/posture control pathways might be the common origin for the observed structural and behavioral deficits in humans as in the different animal models of scoliosis.

Figure 1.

Postural deficits after a UL. A, Top view of a stage 56 larval Xenopus laevis after removal of the left labyrinth (arrow), illustrating the induced bending of the body/tail. B–E, Top and front views of a stage 65 young adult control frog (B, C) and after UL (D, E). F, Schematic drawing depicting the organization of descending vestibulo-spinal/vestibulo-reticulo-spinal, spinal motor activity, contraction of axial musculature, and relative orientation of cartilaginous skeletal elements in controls (F₁) and after a UL on the left side (F₂).

Figure 2.

Skeletal deformations in young adult Xenopus after a UL. A–F, X-ray images of stage 65–66 young adult control frogs (A, B) and of frogs that received a UL on the left side at larval stage 58 (C, D); Cobb angle measurements (B, D) of the spine and deformation matching grid application on X-ray skeletal images of normal (E) and UL frogs (F); black arrows indicate the side of lesion and absent endorgans. G, Cobb angles and changes in the deformation cost of controls and pre-metamorphic and post-metamorphic Xenopus frogs with a UL. H, relation between Cobb angle (angle of spine curvature) and the deformation cost. Scale bars: C, E, F, 10 mm. Post-met, Post-metamorphosis (stage 65–66); Pre-met, pre-metamorphosis (stage 57–59). Skull r., Skull roof; Sac, saccule; Scap, scapula. **p ≤ 0.001, Mann–Whitney U test; error bars are SE.

Figure 3.

3D quantification of the skeletal geometry in young adult Xenopus (stage 65–66). A, B, 3D reconstructed micro-CT scans of the vertebral column in a young adult control frog (A) and a frog that received a UL at pre-metamorphic stage 56 (B). C, Optical extraction of 3 vertebrae (v2, v5, v8) and 3D grid of the deformation in a young adult UL frog. D, Plane and axis of rotation of v2, v5, and v8 in the coronal plane; α indicates the rotation of the actual frontal plane (red) of the vertebra relative to the theoretical coronal plane (green); β indicates the rotation of the vertebral axis (green) relative to the dorsoventral axis (blue). E, F, Quantification of vertebrae (v1-8) symmetry in a young adult control frog (E, upper row) and in a frog that received a UL at pre-metamorphic stage 56 (E, lower row); blue dots indicate the outline of the right and red dots the left half of the vertebra which was optically flipped and superimposed on the right half (F). G, Normalized degree of asymmetry (0, perfect symmetry between right and left side of the vertebra; 1, complete asymmetry) of individual vertebrae (v1-8) in a young adult control frog (in red) and three frogs that received a UL at pre-metamorphic stage 56–58; the blue line indicates the mean of the 3 UL frog; error bars are SE; dashed lines indicate the level of the vertebra along the rostro-caudal extent of the spine shown in the background.