Functional connectivity of the cortex of term and preterm infants and infants with Down's syndrome
Introduction
Multichannel near-infrared spectroscopy (NIRS) imaging is a method that allows noninvasive measurements of cortical hemodynamic changes that occur in response to activation in many cortical regions (see Ferrari and Quaresima, 2012, Obrig and Villringer, 2003 for a reviews). Because this technique does not require much physical restraint, it is particularly suited to studies of newborns and young infants (Peña et al., 2003, Taga et al., 2003). An increasing number of studies that have been conducted with NIRS have revealed the development of the functional activation of the cortex in early infancy (see Aslin, 2012, Gervain et al., 2011 for reviews; Taga et al., 2011, Watanabe et al., 2013). In addition to the stimulus-evoked responses, studies of the low-frequency spontaneous oscillations of cerebral hemodynamics of oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) changes during resting or sleeping states could provide rich information about the development of the cortex, especially the network properties of the functional connectivity of the cortex (see Sassaroli et al., 2012 for a review). A previous NIRS study of sleeping infants showed spatially synchronized spontaneous fluctuations in cerebral blood oxygenation in the occipital cortex, which suggested that these low-frequency oscillations might reflect the spontaneous activity of the developing cortex (Taga et al., 2000). A NIRS study on the spontaneous changes in the cerebral hemodynamics of sleeping infants has further revealed the development of global cortical networks during the first 6 months of life (Homae et al., 2010). A diffuse optical tomographic study of functional connectivity within the occipital regions in newborn infants has demonstrated that connectivity was absent in a stroke patient (White et al., 2012). In order to understand functional development and impairments of the cortex in newborns, measurements of spontaneous brain activity during sleeping have a great advantage because neither a stimulus nor a task is needed. While vast numbers of functional magnetic resonance imaging (fMRI) studies have described the resting-state functional networks of the brains of newborn and preterm infants (Doria et al., 2010, Fransson et al., 2007; see Smyser et al., 2011 for a review), NIRS allows quick and safe assessments of the functional connectivity of selected regions of the cortex, even at the bedside within the neonatal intensive care unit (NICU). In addition, NIRS has the advantage of being sensitive to both hemoglobin species (oxy- and deoxy-Hb), which provide information on vascular and metabolic dynamics (Obrig and Villringer, 2003, Sassaroli et al., 2012) and can be useful from a clinical point of view (Greisen et al., 2011).
It has been an important issue whether there are differences in the developmental trajectories of the brain between term- and preterm-born infants. Although structural differences have been reported in anatomical and MRI studies (Lubsen et al., 2011, Smyser et al., 2011), differences in functional connectivity have been controversial. While Doria et al. (2010) detected no differences in fMRI resting state networks between preterm infants at term age and normal term born controls, Smyser et al. (2010) reported the aberrant development of functional networks specifically thalamo-cortical connections in preterm infants. From a clinical point of view, it is important to detect any differences between term- and preterm-born infants, and NIRS is a promising tool to measure functional connectivity of the brain in infants who were admitted to NICU.
It has also remained unclear how chromosomal abnormalities affect the organization of the functional connectivity of the brain. Anatomical studies showed that there are smaller dendritic arborizations and fewer synapses in the prenatal brain of infants with Down's syndrome (DS) (Haydar and Reeves, 2012, Lubec and Engidawork, 2002, Purpura, 1974, Takashima et al., 1981, Wisniewski, 1990). These findings suggested that the functional connectivity of DS infants might not be well developed as compared with the one of typically developing infants. However, to the best of our knowledge, no one has described the early development of the functional connectivity of the brain of DS infants using noninvasive methods such as fMRI and NIRS.
Given the higher risks for the developmental disorders in preterm infants and the developmental delays observed in DS infants, it is important to reveal the status of the functional development of the cortex in each of them. In this study, we investigated how premature deliveries and chromosomal abnormalities affect the development of the functional connectivity of the cortex by measuring the spontaneous fluctuations of cortical hemodynamic signals with multichannel NIRS of term, preterm, and DS infants who were around term age. In addition, we investigated the phase differences in the time courses between oxy-Hb and deoxy-Hb signals in order to examine whether the local properties of hemodynamics reflected any pathological conditions.
Section snippets
Participants
We examined 48 infants who were admitted to the NICU of the University of Tokyo Hospital. The infants who were eligible for the study were around term age and scheduled to be discharged from the hospital within three days because of being without obvious clinical problems. Their gestational ages (GA) ranged between 23 weeks and 3 days to 40 weeks and 4 days. Seven infants with DS were included. We excluded 1 infant for technical reasons and 10 for other complex clinical reasons, including neonatal
Status of infants to be analyzed
Five infants were excluded from the following analysis because the amount of motion-artifact periods did not meet our criteria (see Data analysis). Although 2 infants woke up before we finished the measurements and their data were less than 6 min (5 min 12 s and 5 min 42 s), they were included. The final sample sizes were 12 participants in the term-or-late-preterm group, 15 in the early-preterm group, and 5 in the DS group. Information about the participants is listed in Table 1.
Connectivity
In order to
Discussion
The first finding of the present study was that the averaged functional connectivities among the cortical regions at around 40 weeks of gestation were not different between the term-or-late-preterm infants and the early-preterm infants. This suggested that the functional connectivity around term age was fully developed, even if the infants were born prematurely. This result was consistent with those of a fMRI study of resting-state networks in the preterm brain (Doria et al., 2010). Second, we
Conclusion
In the present paper, we demonstrated that NIRS can be used to measure the functional connectivity of the cortex and the local cerebral oxygenation dynamics at the bed side in the NICU. A measurement without stimulation during sleep had a great advantage in the clinic. While the previous studies that have used NIRS as a clinical tool to assess cerebral oxygenation in neonatology have focused on the accuracy of detecting the absolute values of cerebral blood flow, cerebral blood volume, and the
Acknowledgments
We would like to thank Dr. Keiji Goishi for planning the study and Mr. Hiroki Oohashi for preparing figures. The study was partly supported by a Grant-in-Aid for Scientific Research (No. 20670001 and No. 24119002) that was awarded to G.T.
Conflict of interest statement
The authors declare that there are no conflicts of interest.
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