Indirect evidence for altered dopaminergic neurotransmission in very premature-born adults

Abstract

While animal models indicate altered brain dopaminergic neurotransmission after premature birth, corresponding evidence in humans is scarce due to missing molecular imaging studies. To overcome this limitation, we studied dopaminergic neurotransmission changes in human prematurity indirectly by evaluating the spatial co-localization of regional alterations in blood oxygenation fluctuations with the distribution of adult dopaminergic neurotransmission. The study cohort comprised 99 very premature-born (<32 weeks of gestation and/or birth weight below 1500 g) and 107 full-term born young adults, being assessed by resting-state functional MRI (rs-fMRI) and IQ testing. Normative molecular imaging dopamine neurotransmission maps were derived from independent healthy control groups. We computed the co-localization of local (rs-fMRI) activity alterations in premature-born adults with respect to term-born individuals to different measures of dopaminergic neurotransmission. We performed selectivity analyses regarding other neuromodulatory systems and MRI measures. In addition, we tested if the strength of the co-localization is related to perinatal measures and IQ. We found selectively altered co-localization of rs-fMRI activity in the premature-born cohort with dopamine-2/3-receptor availability in premature-born adults. Alterations were specific for the dopaminergic system but not for the used MRI measure. The strength of the co-localization was negatively correlated with IQ. In line with animal studies, our findings support the notion of altered dopaminergic neurotransmission in prematurity which is associated with cognitive performance.

Keywords: Blood oxygenation fluctuations; amplitude of low frequency fluctuations; dopamine PET; dopaminergic neurotransmission; premature birth; resting-state fMRI.

FIGURE 1

Work flow for cross‐sample spatial‐RC analysis. First, a mean fALFF map is generated from the individual fALFF maps of the full‐term‐born control. Second, individual fALFF reference‐contrast maps are generated for each subject from the VP/VLBW group by subtracting individual fALFF maps from the mean fALFF map of the full‐term‐born controls. Third, the association between fALFF reference‐contrast maps and normative dopamine transmission PET maps are tested by implementing a cross‐sample spatial multiple linear regression model. This procedure yielded the outcome measure of individual spatial‐RCs per VP/VLBW individual and PET map. Fourth, exact orthogonal permutation‐based p‐values (with 10,000 permutations) were computed. The threshold for statistical significance was set to p < .05. D1R, dopamine‐1‐receptor; fALFF, fractional amplitude of low frequency blood fluctuations; FT, full‐term; spatial‐RC, spatial regression coefficient; VP/VLBW, very preterm and/or very low birth weight.

FIGURE 2

Significant spatial‐RCs in premature‐born adults and their relationship to birth weight. (a) Each dot represents an individual spatial‐RC value of the VP/VLBW group based on cross‐sample spatial regression analysis between fALFF reference‐contrast maps of a premature‐born adult and a given normative dopaminergic neurotransmission PET map. Error bars represent the parametric 95% confidence interval of the mean spatial RC. (b) Associations between spatial‐RCs and IQ‐values are shown as scatter plots. IQ is plotted on the y‐axes and spatial‐RCs on the x‐axes. Linear regression lines, 90% confidence interval bands, correlation coefficients r and p‐values were added. D1R, dopamine‐1‐receptor; D2/3R, dopamine‐2/3‐receptor; DAT, Dopamine transporter; fALFF, fractional amplitude of low‐frequency fluctuations; FT, full‐term; IQ, intelligence quotient; VP/VLBW, very preterm and/or very low birth weight.