Previous morphological studies indicated that development of the human prefrontal cortex (PFC) appears to continue into late adolescence. Although functional brain imaging studies have sought to determine the time course of functional development of the PFC, it is unclear whether the developmental change occurs after adolescence to adulthood and when it achieves a peak because of the narrow or discontinuous range in the participant's age. Moreover, previous functional studies have not focused on the anterior frontal region, that is, the frontopolar regions (BA9/10). Thus, the present study investigated the developmental change in frontopolar PFC activation associated with letter fluency task by using near-infrared spectroscopy (NIRS), in subjects from preschool children to adults. We analyzed the relative concentration of hemoglobin (ΔHb) in the prefrontal cortex measured during the activation task in 48 typically-developing children and adolescents and 22 healthy adults. Consistent with prior morphological studies, we found developmental change with age in the children/adolescents. Moreover, the average Δoxy-Hb in adult males was significantly larger than that in child/adolescent males, but was not true for females. These data suggested that functional development of the PFC continues into late adolescence. Although the developmental change of the frontopolar PFC was independent of gender from childhood to adolescence, in adulthood a gender difference was shown.

Funding: This study was supported by Health and Labour Sciences Research Grants for Comprehensive Research on Disability, Health and Welfare (H23-Seishin-Ippan-002 to YK and RT), and Grant-in-Aid for Scientific Research on Innovative Areas (Adolescent Mind & Self-Regulation: 23118001, & 23118004 to KK), MEXT, Japan. A part of this study was also the result of “Development of biomarker candidates for social behavior” carried out under the Strategic Research Program for Brain Sciences by the MEXT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Introduction

The pattern of development and maturation of the human prefrontal cortex (PFC) from childhood through early adulthood is an important research question in neuroscience. The activity of the catechol-o-methyltransferase (COMT) enzyme that modulates dopamine levels in the PFC increases from the neonate through to adulthood [1], consistent with the critical role of dopamine in modulating normal PFC function [2]. Previous morphological studies have used postmortem brains and MRI to indicate that development appears to continue into late adolescence in terms of synaptic density [3], gray matter volume [4], [5] and cortical thickness [6].

Functional brain imaging studies have also sought to determine the time course of functional development of the PFC, although the findings have been equivocal. A positron emission tomography (PET) study showed that glucose metabolism at 4 years and 9–10 years was at a high plateau and after 9–10 years began to decline and gradually reaches adult values by 16–18 years [7]. Some functional MRI (fMRI) studies showed that the activation of the dorsolateral PFC (DLPFC) increased with age during the declarative memory task for 8–24 year-olds [8], and that the greater activation in adults than in adolescents during the Stroop task for 7–22 year-olds [9]. Others indicated that DLPFC was more active in children (9–12 year-olds) than in adults (20–30 year-olds) in the go/no-go task [10], and that adolescents (14–17 year-olds) showed greater activation than children (8–13 year-olds) and adults (18–30 year-olds) in the saccade task [11]. The ventrolateral PFC (VLPFC) was activated in adults only during the go/no-go task, but not in children (8–12 year-olds) [12], while children (8–13 year-olds) demonstrated greater activation than adults (19–48 year-olds) in the verbal fluency task [13]. In a near-infrared spectroscopy (NIRS) study, both adults and preschool children (5–6 year-olds) increased oxyhemoglobin (oxyHb) in the lateral PFC (LPFC) during the working memory task and the activation of LPFC was larger and broader in children than in adults, although children were not directly compared with adults [14]. Another study using the Stroop task, however, showed that the oxyHb responses in the young adults were greater and faster than those in children (7–13 year-olds), and reported that the DLPFC activation increased with age [15]. To summarize the above findings, previous studies have been mixed regarding in which life stage (childhood, adolescence, adulthood) the LPFC activation becomes largest.

The disagreement in functional brain imaging studies might be attributed to participant's age, task demands or the experimental paradigm, such as event-related design or blocked design. Since few studies included participants with a broad range in age from childhood to adulthood, it is unclear whether the developmental change occurs between adolescence and adulthood and when it achieves its peak. Moreover, although previous studies have investigated the anterior frontal region, that is, the frontopolar regions (BA9/10), they have not focused on it. The frontopolar regions have a higher-order integrative prefrontal function [16] and comparative studies of humans and apes [17] suggested that they have enlarged and become specialized during hominid evolution. The frontopolar regions might coordinate VLPFC and DLPFC functions in order to achieve task goals or maximize task performance [18]–[20], and might evaluate internally generated information [21]. Because the frontopolar cortex is located in the vicinity of air-filled spaces of the nasal cavity, the corresponding magnetic susceptibility differences at air–tissue or bone–tissue interfaces result in severe distortions and regional signal losses in long-TE gradient-echo images, particularly for ultrafast imaging techniques such as echo-planar imaging in a high magnetic field. Therefore, such observation without signal losses in the frontopolar PFC might be one of the reasons for the superiority of NIRS.

NIRS is one of the most promising noninvasive functional neuroimaging tools to allow comparative evaluation of cortical hemodynamic response for children and individuals with psychiatric disorders. NIRS can measure the signals reflecting relative concentrations change of oxy-hemoglobin (Δoxy-Hb) and deoxy-hemoglobin (Δdeoxy-Hb), which are assumed to reflect regional cerebral blood volume (rCBV). While fMRI and PET have an excellent spatial resolution, they are limited in that they require a large apparatuse that prevents their use in bedside settings for diagnostic and treatment purposes. In contrast, NIRS is a neuroimaging modality that, for the following reasons is especially suitable for assessing the PFC of infants [22], children [14], [15] and psychiatric disorders [23]–[28] because NIRS is relatively insensitive to motion artifacts, it can be applied to experiments that might cause some motion of the subjects, such as vocalization. Second, the subject can be examined in a natural sitting position, without any surrounding distraction. Third, the cost is much lower than other neuroimaging modalities and the set-up is very easy. Fourth, as the test-retest reliability at weekly and monthly intervals has demonstrated [29], [30], NIRS can be applied to longitudinal assessment following intervention. Fifth, the high temporal resolution of NIRS is useful in characterizing the time course of prefrontal activity [23]–[25].

By simultaneous measurements with other methodologies, it has been shown that the Δoxy-Hb measured by NIRS correlates with the rCBF change in 15H2O PET [31] and the blood oxygenation level-dependent [32] signal in fMRI [33]. In other fMRI studies [32], [34], [35], in which the Δoxy-Hb was not analyzed, the Δdeoxy-Hb in NIRS has been correlated with the BOLD signal.

Moreover, previous studies showed that the verbal fluency test is a valid cognitive activation task to evaluate ΔHb in PFC using NIRS [24]–[26], [28], [31]. In NIRS studies recording the ΔHb during several tasks for the same subject group, the smaller-than-normal Δoxy-Hb during the cognitive tasks involving primarily the PFC, such as the letter fluency test and the random number generation task, was task specific in schizophrenia, i.e., this was not evident during other tasks, such as the sequential finger-to-thumb task [36], or the finger tapping task [24]. These findings suggested that the Δoxy-Hb reflected the neural activation but not general or nonspecific factors, such as impaired vascular responsiveness irrespective of neural activation or optical pathlength.

Thus, the present study investigated the developmental change in frontopolar PFC activation associated with the letter fluency task by using NIRS, in a group of subjects that included preschool children to adults.