Impaired language pathways in tuberous sclerosis complex patients with autism spectrum disorders

Abstract

The purpose of this study was to examine the relationship between language pathways and autism spectrum disorders (ASDs) in patients with tuberous sclerosis complex (TSC). An advanced diffusion-weighted magnetic resonance imaging (MRI) was performed on 42 patients with TSC and 42 age-matched controls. Using a validated automatic method, white matter language pathways were identified and microstructural characteristics were extracted, including fractional anisotropy (FA) and mean diffusivity (MD). Among 42 patients with TSC, 12 had ASD (29%). After controlling for age, TSC patients without ASD had a lower FA than controls in the arcuate fasciculus (AF); TSC patients with ASD had even a smaller FA, lower than the FA for those without ASD. Similarly, TSC patients without ASD had a greater MD than controls in the AF; TSC patients with ASD had even a higher MD, greater than the MD in those without ASD. It remains unclear why some patients with TSC develop ASD, while others have better language and socio-behavioral outcomes. Our results suggest that language pathway microstructure may serve as a marker of the risk of ASD in TSC patients. Impaired microstructure in language pathways of TSC patients may indicate the development of ASD, although prospective studies of language pathway development and ASD diagnosis in TSC remain essential.

Keywords: arcuate fasciculus; diffusion tensor imaging; neuroanatomy; tractography; white matter.

Figure 1.

Schematic of the selection method for AF segments. Tracts shown are those for 1 control subject. Regions were automatically mapped onto all subjects, with region 1 in the white matter near Broca's territory, region 2 in the white matter near Geschwind's territory, and region 3 in the white matter near Wernicke's territory. The anterior segment was selected by choosing streamlines that passed through regions 1 and 2, but not region 3. The long segment was selected by choosing streamlines that passed through regions 1 and 3 (and which may pass through region 2 as well, but are not required to do so). The posterior segment was selected by choosing streamlines that passed through regions 2 and 3, but not region 1.

Figure 2.

The segments of the AF and selection regions in patients and controls. Left side: segments of the AF in patients and controls. Green = anterior segment, red = long segment, yellow = posterior segment. Right side: ROIs used to select segments of AF. (A) A 13-year-old patient with ASD. (B) A 12-year-old patient without ASD. (C) A 12-year-old control subject. The ROIs and AF segments are superimposed on a color-map of the principal diffusion directions: green represents the anterior-to-posterior diffusion direction, blue superior to inferior, and red medial to lateral.

Figure 3.

The long segment MD progression by age. Controls (blue) have a lower MD at all ages than patients without ASD (red), and patients with ASD (green). Controls have a lower MD than patients without ASD, although the difference is small (P = 0.026). Controls have a much lower MD than patients with ASD (P < 0.000001). Patients without ASD also have a much lower MD than those with ASD (P = 0.0005).

Figure 4.

The predicted FA values at age 1 for controls and patients. The predicted FA values at age 1 for controls (blue), patients without ASD (red), and patients with ASD (green). The predicted FA values at age 1 do not reflect a set of patients at age 1, but rather are predictions of the FA at age 1 based on the regression models for the 3 groups. For the anterior segment, only the patients with ASD have a different FA from controls (P = 0.00082). The patients with ASD also have a significantly lower FA than those without ASD (P = 0.047). For the long segment, the controls are significantly different from both patients without ASD (P = 0.045) and with ASD (P = 0.00017). The patients with ASD again had a significantly lower FA than those without ASD (P = 0.02). Similarly, for the posterior segment, control FA values are different from patients without ASD (P = 0.010) and with ASD (P = 0.000045). Patients with ASD had a significantly lower FA than those without ASD (P = 0.02). Error bars represent standard error of the intercept from the regression analysis. *P < 0.05; ***P < 0.001.