Understanding of Neuroanatomical Effects of Intrauterine Drug Exposure

INTRODUCTION

Approximately 159,900 infants were born with intrauterine illicit drug exposure in the United States in 2004 (1). Intrauterine drug exposure (IUDE) has been associated with a variety of different neurobehavioral and neuromotor findings in childhood. Infants with cocaine/polydrug exposure demonstrate longer latencies on auditory brain responses, variable state regulation, and motor abnormalities, when compared to non-drug exposed infants (2-8). Differences in attention, distractibility, and visual memory have been reported in infants with cocaine/polydrug exposure (3;9-12). Thus, intrauterine drug exposure is a significant public health challenge.

Neuroanatomical Effects of Illicit Drug Exposure on the Developing Brain.

Impairment of brain growth in children with intrauterine cocaine/polydrug exposure is documented in multiple studies (9;13;14). Disturbances of neuronal migration and differentiation have been reported in human infants exposed to cocaine during their gestation (15-18). The most common neurological anomaly found in children with cocaine/polydrug exposure is microcephaly (19). In one study by Butz, et al., mean birth head circumference for infants with only cocaine exposure was 1.71 standard deviations below the mean, while head circumference was 1.0 and 1.52 standard deviations below the mean for opiate only and cocaine and opiate exposed infants, respectively (20). Despite the evidence of risk for neuroanatomical abnormalities in children with IUDE, only two controlled volumetric MRI studies of children with IUDE have been published in the peer-reviewed literature to date and no studies associating neuropsychological deficits to anatomical MRI findings in children with IUDE.

METHODS

Subjects

The study cohort consisted of 46 children, of whom 22 subjects had IUDE (mean age 7.9 years, S.D. 0.7), the remaining children had no illicit drug exposure (mean age 8.2 years, S.D. 1.0). Children were identified as having illicit drug exposure by maternal self-report, prenatal medical records, maternal toxicology screens at delivery, and/or a positive infant urine toxicology screen within 24 hours of birth. Children with IUDE were matched by gestational age, gender and IQ with controls. All of the participants provided informed consent from parent/ legal guardian and assent from child after explanation of the study procedures.

MRI Techniques

Fast field echo (FFE) MRI sequences were acquired on all participants using a 1.5-Tesla Philips Gyroscan NT Integra with the parameters: TR=35 ms, TE=6 ms, flip angle=45 degrees, 256 X 256 matrix size, FOV=240 mm, slice thickness=1.5 mm. Images were analyzed in BrainImage using a fuzzy tissue segmentation algorithm (20) and a semi-automated parcellation method for which a revised Talairach stereotaxic grid specific for measurement in pediatric groups was used to subdivide the cerebrum into lobar and subcortical regions. As a first step, non-brain material was removed from the image stacks using a semi-automated edge detection process. Images were re-sliced converting the image stacks into cubic voxel datasets, followed by opening the stacks into a multiplanar visualization module, which allows standardization of positional normalization across subjects. Cerebral lobar and frontal sublobar (prefrontal, premotor, motor, anterior cingulate, and deep white matter) and parietal sublobar volumes were measured using a semi-automated approach based on the Talairach atlas. This method demonstrates high sensitivity and specificity for measuring these structures when compared with manually delineated “gold standards”(21;22). Tissue class (gray matter, white matter, CSF) segmentation was done using a probabilistic algorithm in BrainImage that creates three entire volume maps, reflecting the proportion of each tissue in each voxel. All image processing was performed by a research assistant masked to group assignments and diagnoses.

Statistical Analyses

Multivariate analysis of variance (MANOVA) tests were used to examine for effect of diagnosis (IUDE vs. controls). Analysis was applied in a sequential manner, from larger to smaller volumes (total cerebral volumes, lobar volumes and then sublobar frontal and parietal volumes). For each step, significance was set at a p < 0.05, Bonferroni corrected. To reduce the probability of type-I errors, post hoc tests, e.g. the Scheffe's test, were performed. RESULTS

In all levels of the brain, from total cerebral volume to parietal hemisphere components, the children with IUDE had brain volumes that were smaller than the non-exposed children. Statistically significant reductions in gray matter volumes were noted in the anterior cingulate cortex, bilaterally (mean difference on the right 1.2, p=0.0024 and mean difference on the left 0.99, p=0.0035), the right insula (mean difference 0.27, p<0.0001), and the right somatosensory cortex (mean difference 1.97, p=0.0024). DISCUSSION

The results of this study indicate that there are small, yet selective, reductions in brain volume associated with IUDE. Our findings revealed that children with IUDE show bilateral changes in the anterior cingulate cortex, a region involved in error-detection and self-monitoring. Research suggests that children with IUDE are at higher risk for having problems with attention and impulsivity than their non-drug exposed peers (9-11;23). Our imaging data appear to support the cognitive impairments reported in IUDE. Further research is warranted to evaluate the association between cerebral volume decreases and neurobehavioral deficits in children with IUDE.

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