Diffuse reduction of white matter connectivity in cerebral palsy with specific vulnerability of long range fiber tracts

Abstract

Cerebral palsy (CP) is a heterogeneous group of non-progressive motor disorders caused by injury to the developing fetal or infant brain. Although the defining feature of CP is motor impairment, numerous other neurodevelopmental disabilities are associated with CP and contribute greatly to its morbidity. The relationship between brain structure and neurodevelopmental outcomes in CP is complex, and current evidence suggests that motor and developmental outcomes are related to the spatial pattern and extent of brain injury. Given that multiple disabilities are frequently associated with CP, and that there is increasing burden of neurodevelopmental disability with increasing motor severity, global white matter (WM) connectivity was examined in a cohort of 17 children with bilateral CP to test the hypothesis that increased global WM damage will be seen in the group of severely affected (Gross Motor Function Classification Scale (GMFCS) level of IV) as compared to moderately affected (GMFCS of II or III) individuals. Diffusion tensor tractography was performed and the resulting fibers between anatomically defined brain regions were quantified and analyzed in relation to GMFCS levels. Overall, a reduction in total WM connectivity throughout the brain in severe versus moderate CP was observed, including but not limited to regions associated with the sensorimotor system. Our results also show a diffuse and significant reduction in global inter-regional connectivity between severity groups, represented by inter-regional fiber count, throughout the brain. Furthermore, it was also observed that there is a significant difference (p = 0.02) in long-range connectivity in patients with severe CP as compared to those with moderate CP, whereas short-range connectivity was similar between groups. This new finding, which has not been previously reported in the CP literature, demonstrates that CP may involve distributed, network-level structural disruptions.

Keywords: Cerebral palsy; Diffusion tensor imaging; Network disruption; Structural connectome; Tractography.

Fig. 1

Primary data images containing (A) T2 (baseline b0), (B) diffusion weighted (b = 1000), (C) colored FA, and (D) tractography from a representative subject (GMFCS II, age = 1.73).

Fig. 2

Inter-regional whole-brain connectivity analysis reveals a diffuse pattern of nodes and edges with significantly reduced connectivity in severe versus moderate CP. A total of 63 nodes (ROIs) are depicted as spheres. The sphere is placed at the center of mass of the ROI, with a radius proportional to the average number of connections across individuals associated with that region. Red-yellow nodes show significantly reduced total connectivity to all other brain regions in severe versus moderate CP (p < 0.05, corrected for multiple comparisons). The color gradient of the nodes denotes the significance level of the difference in total connectivity between groups; red nodes indicating the most significantly different between groups. Gray nodes show insignificant differences in total connectivity between groups. Cool-colored edges (connections) between nodes indicate significantly reduced mutual connectivities in the severe CP group as compared to moderate CP group (p < 0.05, corrected for multiple comparisons). The color gradient of the edges denotes the significance level of the difference in connectivity between groups; dark blue edges being the most significantly different between groups. Nodes marked with an asterisk (*) indicate ROIs with significant GM volume reduction in severe versus moderate CP. All connectivity measures are normalized by total WM volume in each individual.

Fig. 3

A: Global WM volume is reduced in severe versus moderate CP (p = 0.01); B: Corrected fiber volume (normalized by global WM volume) is reduced in severe vs. moderate CP (p = 0.01). Error bars represent standard errors.

Fig. 4

Long-range mutual connectivity is reduced in severe versus moderate CP. A significant difference (p = 0.02) long-range connectivities (≥ 40 mm) is observed in severe versus moderate CP, while the short-range connectivities (< 40 mm in length) remain similar between groups. Connectivity measures were normalized by total WM volume in each individual. Error bars represent standard errors.