A functional magnetic resonance imaging study of the long-term influences of early indomethacin exposure on language processing in the brains of prematurely born children

Abstract

Background: Previous studies have demonstrated that indomethacin lowers the incidence and decreases the severity of intraventricular hemorrhage, as well as improves the cognitive outcome, in prematurely born male infants.

Objective: The purpose of this work was to use functional magnetic resonance imaging to test the hypothesis that neonatal indomethacin treatment would differentially affect brain activation across genders in school-aged, prematurely born children during performance of a language task.

Methods: Forty-seven prematurely born children (600-1250-g birth weight) and 24 matched term control subjects were evaluated using a functional magnetic resonance imaging passive language task and neurodevelopmental assessments that included the Wechsler Intelligence Scale for Children-III and the Peabody Picture Vocabulary Test-Revised. Neural activity was assessed during both phonologic and semantic processing in the functional magnetic resonance imaging protocol.

Results: Neurodevelopmental assessments demonstrated significant differences in full-scale, verbal, and performance intelligence quotient, as well as Peabody Picture Vocabulary Test scores, between the preterm and term control subjects. Rates of perinatal complications did not differ significantly across preterm treatment groups, but male preterm subjects randomly assigned to saline tended to have lower Peabody Picture Vocabulary Test-Revised scores than did all of the other preterm groups. During phonological processing, a significant treatment-by-gender effect was demonstrated in 3 brain regions: the left inferior parietal lobule, the left inferior frontal gyrus (Broca's area), and the right dorsolateral prefrontal cortex.

Conclusions: These data demonstrate a differential effect of indomethacin administration early in postnatal life on the subsequent development of neural systems that subserve language functioning in these male and female preterm infants.

FIGURE 1

Semantic (A) and phonologic (B) contrast group average activation maps. All 71 subjects are included. The voxel-wise threshold is P < .01, and the significance level for the regions is indicated by the color bar. The semantic task is characterized by both positive and negative signal changes. Negative signal changes, shown in blue and aqua, are seen in the bilateral parietal (BA 40) and insular cortex and in the left IFG (BA 47). This implies that the signal in these regions was highest while listening to scrambled speech compared with both low-pass filtered speech and with the original, unaltered speech. Positive activations in the semantic contrast, shown in red and yellow, reflect meaningful linguistic processing and are seen in the posterior superior and middle temporal gyri (BA 22, Wernicke's area) and a more anterior section of the superior temporal gyrus (BA 12).

FIGURE 2

Map of areas exhibiting a treatment-by-gender interaction effect on the phonologic task, in a preliminary whole-brain voxel-wise analysis of variance, include the left IPL (BA 40), the left IFG or Broca's area (BA 44), and the right DLPF (BA 46). For this treatment-by-gender map, all significant regions are shown in red, the voxel-wise threshold is P < .01, and the cluster-size corrected is P < .05.

FIGURE 3

Least-squares mean ± SEM for selected fixed effects. These graphs represent regions in which the fixed-effects analyses demonstrate treatment-by-gender effects for the phonologic processing task and show percent signal change adjusted for age at scan and VIQ. A, Left IPL (P = .0002); B, Left IFG (P = .0011); and C, Right DLPF (P = .0002).