Development of BOLD signal hemodynamic responses in the human brain

Abstract

In the rodent brain the hemodynamic response to a brief external stimulus changes significantly during development. Analogous changes in human infants would complicate the determination and use of the hemodynamic response function (HRF) for functional magnetic resonance imaging (fMRI) in developing populations. We aimed to characterize HRF in human infants before and after the normal time of birth using rapid sampling of the blood oxygen level dependent (BOLD) signal. A somatosensory stimulus and an event related experimental design were used to collect data from 10 healthy adults, 15 sedated infants at term corrected post menstrual age (PMA) (median 41+1 weeks), and 10 preterm infants (median PMA 34+4 weeks). A positive amplitude HRF waveform was identified across all subject groups, with a systematic maturational trend in terms of decreasing time-to-peak and increasing positive peak amplitude associated with increasing age. Application of the age-appropriate HRF models to fMRI data significantly improved the precision of the fMRI analysis. These findings support the notion of a structured development in the brain's response to stimuli across the last trimester of gestation and beyond.

Fig. 1

Identified clusters of functional activation following passive motor stimulation of the right hand, in a 32 + 3 PMA week preterm infant (top row: figures a,b,c); a term equivalent (PMA 41 + 1 weeks) infant (middle row: figures d,e,f), and a healthy 24 year old adult (bottom row: figures g,h,i). A thresholded statistical map with a corrected cluster significance of p < 0.05 has been overlaid on the subject T2-weighted image.

Fig. 2

Peristimulus timeseries plots for the (a) adult; (b) term equivalent infant; (c) preterm infant groups. Stimulation occurred at time point 0, lasting a total of 1 s. The mean % BOLD signal change (relative to the pre-stimulus signal) at each timepoint (circles) is shown fitted with a double gamma probability distribution function. Error bars represent 2 SEM. (d) A decrease in the time to peak of the HRF, and an increase in peak amplitude is seen with increasing age.

Fig. 3

(a) A significant difference was seen between both the preterm and term infant groups and adult subjects in the amplitude of the HRF positive peak. (Boxplots: box represents 25th and 75th centiles and central line the group median; outliers denoted by ‘+’ symbol; Mann–Whitney–Wilcoxon test with Holm–Bonferroni correction for multiple comparisons, p < 0.05*, p < 0.01**)). (b) The ratio of the negative HRF undershoot to the amplitude of the positive peak was significantly deeper in the term infant group in comparison to both the preterm and adult groups. (c) A significant maturational trend towards a reduction in the time taken to achieve the positive HRF peak was identified across the three patient groups. (d) In the neonatal subjects only, an inverse exponential relationship between increasing post-menstrual age (in weeks) and the time to the HRF peak (in seconds) was identified (r² = 0.6479; dashed lines represent 95% population confidence intervals).

Fig. 4

Preterm infant group (top row): (a) A large cluster of positive activation was identified in the contralateral somatosensory cortex when an age-specific HRF model was convolved into the GLM analysis in a group of 6 preterm infants; (b) this was not seen when the analysis was repeated using the canonical adult t-test analysis was performed on the statistical maps derived from the lower level analyses. Term equivalent infant group (bottom row): (d) Significant clusters of functional activity were identified when both age-specific and (e) canonical adult HRF models were convolved into the GLM analysis of 6 infants at term corrected PMA; (f) There was no significant difference between the two forms of analysis on a paired t-test analysis.

Fig. 5

Example peristimulus timeseries data derived from clusters of activation (inset pictures, red) identified following passive motor stimulation of the right hand. (a) In a preterm infant, the age-specific HRF can be seen to greatly improve the model fit (green), as the peak in contrast occurs much later than would be predicted using the adult HRF (blue). (Error bars represent 1SD from the mean) (b) In an infant at term corrected PMA, the age-specific HRF improves the model fit (red), by incorporating the deeper undershoot period seen following the positive peak.