Lower glial metabolite levels in brains of young children with prenatal nicotine exposure

Abstract

Many pregnant women smoke cigarettes during pregnancy, but the effect of nicotine on the developing human brain is not well understood, especially in young children. This study aims to determine the effects of prenatal nicotine exposure (PNE) on brain metabolite levels in young (3-4 years old) children, using proton magnetic resonance spectroscopy ((1)H MRS). Twenty-six children with PNE and 24 nicotine-unexposed children (controls) were evaluated with a structured examination, a battery of neuropsychological tests, and MRI/(1)H MRS (without sedation). Concentrations of N-acetyl compounds (NA), total creatine (tCR), choline-containing compounds (CHO), myo-inositol (MI), and glutamate+glutamine (GLX) were measured in four brain regions. Children with PNE had similar performance to controls on neuropsychological testing. However, compared to controls, the PNE group had lower MI (repeated measures ANOVA-p = 0.03) and tCr levels (repeated measures ANOVA-p = 0.003), especially in the basal ganglia of the girls (-19.3%, p = 0.01). In contrast, GLX was elevated in the anterior cingulate cortex of the PNE children (+9.4%, p = 0.03), and those with the highest GLX levels had the poorest performance on vocabulary (r = -0.67; p < 0.001) and visual motor integration (r = -0.53; p = 0.01). The amount of prenatal nicotine exposure did not correlate with metabolite concentrations. These findings suggest that PNE may lead to subclinical abnormalities in glial development, especially in the basal ganglia, and regionally specific changes in other neurometabolites. These alterations were not influenced by the amount of nicotine exposure prenatally. However, the effects of PNE on energy metabolism may be sex specific, with greater alterations in girls.

Fig. 1

Top left: axial MR images showing the placement of the four voxels: (1) anterior cingulate cortex (ACC), which contains primarily gray matter at the anterior and medial portions of both cingulate cortices across both hemispheres and above the anterior portion of the head of caudate; (2) frontal white matter (FWM), which is confined to white matter in the right frontal lobe at the same level as the ACC; (3) right basal ganglia (BG), which contains the central portions of the putamen, the globus pallidus, and some portion of the body of the caudate; and (4) thalamus (THAL), which is confined to the gray matter structure and spans across both hemispheres, posterior to the BG voxel. Bottom left: representative MR spectrum from the frontal white matter, showing well-defined peaks for each of the brain metabolites measured (NA N-acetylaspartate, GLX glutamate+glutamine, tCr total creatine, CHO choline-containing compounds, MI myo-inositol). The solid line shows the fitted spectrum from LCModel. Right panel: brain metabolite concentrations in the four brain regions (also see Table 2) are shown for each of the metabolites of interest. The brackets indicate metabolite values that are significantly different, or show a trend for significance, between the two groups. Lower tCr and MI, and to a lesser extent CHO and NA, are found in the basal ganglia of the PNE children compared to the unexposed controls. Total creatine and trends for NA are also lower in the THAL. However, in the anterior cingulate cortex region, GLX and to a lesser extent CHO are elevated in the PNE children relative to the controls

Fig. 2

Graphs show dependence of the metabolite concentrations on age and sex. Left: older PNE children show higher, but older non-PNE children show lower, ACC–choline concentrations with age (age×PNE interaction, p=0.02). Middle: older PNE children show lower thalamic GLX levels, while the opposite is true in non-PNE children (age×PNE interaction, p=0.05). Right: graph shows lower tCr in the basal ganglia of the girls, but not boys with PNE (boys—n=18; girls—n=7) compared to those unexposed to nicotine (boys—n=10; girls—n=12), resulting in a sex by PNE interaction (p=0.003)

Fig. 3

Negative relationships of ACC-GLX levels with vocabulary (EOWPVT-R score, left scatter plot) and with visual motor integration (right scatter plot) are observed in the PNE group, but not in the non-exposed children. The ANCOVA p value reflects the significance of the interaction between PNE status and ACC GLX on outcome measures