Reduced prefrontal hemodynamic response in pediatric autism spectrum disorder measured with near-infrared spectroscopy

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by impairments in social and communicative functioning and the presence of restricted interests and repetitive behaviors [1]. Studies using neuropsychological measures have revealed an association between ASD and inattention. ASD can be characterized by a short attention span, and impulsivity and inattention symptoms are common [2]. Furthermore, individuals with ASD are typically impaired on neurocognitive measures of sustained and selective attention [3]. There is evidence for fronto-striatal, parietal, and cerebellar abnormalities in ASD during selective and flexible attention [4, 5]. In addition to attentional difficulties, many studies have indicated that individuals with ASD exhibit impairments of executive function [6, 7]. A wealth of data indicates that the prefrontal cortex plays a major role in executive function.

Multi-channel near-infrared spectroscopy (NIRS) enables the noninvasive detection of neural activity near the surface of the brain using near-infrared light [8, 9]. NIRS measures alterations in oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) concentrations in micro-blood vessels on the brain surface. Local increases in the concentration of oxy-Hb and decreases in the concentration of deoxy-Hb are indicators of cortical activity [8, 10]. In addition, changes in the concentration of oxy-Hb have been associated with changes in regional cerebral blood volume, using a combination of positron emission tomography (PET) and NIRS measurements [11, 12]. NIRS is a neuroimaging modality that, according to Matsuo et al. [13], is especially suitable for psychiatric patients for the following reasons. First, because NIRS is relatively insensitive to motion artifacts, it can be used in experiments where motion is expected, such as those involving vocalization. Second, NIRS can be used to examine participants while seated in a natural position, with minimal environmental distraction. Third, NIRS has cheaper running costs than other neuroimaging modalities and is simple to set up and use. Fourth, the high temporal resolution of NIRS is useful for characterizing the time course of prefrontal activity in people with psychiatric disorders [14, 15]. Accordingly, NIRS has been used to assess brain function in people with many psychiatric disorders, including schizophrenia, bipolar disorder, depression, obsessive–compulsive disorder, dementia, post traumatic stress disorder, Tourette’s disorder, attention-deficit/hyperactivity disorder, and ASD [13‐27].

Recent developments in NIRS have enabled noninvasive clarification of brain functions in pediatric psychiatric disorders. In pediatric ASD, reduced prefrontal hemodynamic activity has been reported in studies using NIRS measurement during self-face recognition and auditory tasks [28, 29]. Yasumura et al. [30] reported no significant differences in prefrontal hemodynamic activity between typically developing and ASD children (seven boys and four girls) measured with NIRS during the Stroop task. Similarly, Xiao et al. [31] reported no significant differences in prefrontal hemodynamic activity between typically developing controls and boys with ASD measured with 16-channel NIRS during the Stroop task. However, it is difficult to accurately measure the dorsolateral prefrontal hemodynamic activity using 16-channel NIRS, which is more suitable for measuring hemodynamic responses of the orbitofrontal and frontopolar cortex. The Stroop color-word task is one of the most commonly used methods for identifying attentional problems, as well as providing a test of executive function, and involves the dorsolateral prefrontal cortex. Moreover, sex differences in executive function in people with ASD have been reported in children and adolescents [32‐34]. Therefore, it may be valuable to examine the broader prefrontal hemodynamic response in male children with ASD, measured with 24-channel NIRS during the Stroop color-word task. We hypothesized that male children with ASD would exhibit reduced prefrontal hemodynamic responses in 24-channel NIRS during the Stroop color-word task. Thus, in the present study, we used 24-channel NIRS to examine the characteristics of prefrontal cerebral blood volume changes during the Stroop color-word task in male children with ASD and in age- and intelligence quotient (IQ)-matched healthy control males.

To the best of our knowledge, no previous studies have examined the broader prefrontal hemodynamic response in male children with ASD, measured with 24-channel NIRS during the Stroop color-word task. In the present study, the results revealed that oxy-Hb changes in 12 drug-naïve male children with ASD during the Stroop color-word task were significantly smaller than those in 12 healthy male children in the prefrontal cortex, particularly in the dorsolateral prefrontal cortex (Ch 12 and Ch 13). The present findings supported our hypothesis, in accord with the proposed prefrontal dysfunction in pediatric ASD identified by other imaging modalities, such as functional magnetic resonance imaging (fMRI) and single-photon emission computed tomography (SPECT). Previous SPECT studies reported localized areas of hypoperfusion, which may be correlated with focal reductions in function observed in the prefrontal lobes, cingulate gyrus, superior temporal gyrus, and mesial temporal lobes of individuals with ASD [43]. In ASD, fMRI studies of motor and cognitive interference inhibition and switching reported abnormalities in fronto-striato-parietal areas, including dorsolateral prefrontal cortex and ventrolateral prefrontal cortex [44, 45].

At Ch 12 and Ch 13, male children with ASD were associated with significantly smaller oxy-Hb changes than healthy children in the present study. Those channels were localized in the dorsolateral prefrontal cortex, whose hypoactivation was observed in ASD during cognitive control tasks involving inhibition [46], attention [47, 48], and working memory [49, 50]. Two previous studies used 16-channel NIRS during the Stroop task in ASD [30, 31]. However, accurately measuring dorsolateral prefrontal hemodynamic activity is difficult with 16-channel NIRS, which is more suitable for measuring the hemodynamic response of the orbitofrontal and frontopolar cortices. Thus, no significant differences were found between ASD children and typically developing controls in prefrontal hemodynamic activity measured with 16-channel NIRS during the Stroop task. In the current study, we used a 24-channel NIRS system rather than a 16-channel system. The results revealed that male children with ASD exhibited reduced dorsolateral prefrontal hemodynamic responses, measured with 24-channel NIRS during the Stroop color-word task.

In the present study, we used the Stroop color-word task because the prefrontal cortex is reported to be one of the regions most strongly related to Stroop interference [37]. Negoro et al. [26] examined brain activation in 20 healthy children during the Stroop color-word task, measured with NIRS. In that study, oxy-Hb changes indicated specific activation in the prefrontal cortex, and there were positive correlations between the SCWC and age (ages 6–13 years; mean 9.35 ± 2.13 years). The researchers concluded that prefrontal brain activation in healthy children during the Stroop color-word task is similar to that of healthy adults, measured using NIRS [51]. Similar results were obtained in the present study. In both groups, there were positive correlations between SCWC scores and age, and there were no correlations between SCWC scores and FIQ. This result was consistent with previous research on the Stroop that documented that children became progressively faster as they responded verbally to stimuli [52]. These data suggest that the Stroop color-word task used in the present study may be a useful task for children.

Several potential limitations of the present study should be taken into consideration. First, NIRS has several disadvantages compared with other modalities [53]: for example, NIRS enables measurement of Hb concentration changes only as relative values, not as absolute values. We used the Stroop color-word task with a clear baseline task to overcome these potential problems. In addition, we measured Hb concentration changes between the activation task and the baseline task, and performed the task three times to average out the potential effects of incidental changes, and prevent participants from becoming tired. The grand average waveforms of oxy-Hb concentration changes in the ASD group did not indicate a regional cerebral blood flow decrease during the activation task or a difference in blood flow between the baseline and activation tasks. Second, the spatial resolution for detecting hemodynamic responses from the scalp surface using NIRS is lower compared with fMRI, SPECT and PET. However, abnormal prefrontal hemodynamic responses in individuals with ASD are certainly detectible with NIRS. Third, several previous studies have shown that superficial hemodynamic changes, such as skin blood flow, can affect prefrontal NIRS hemoglobin signals [54, 55]. Thus, the present findings could have been influenced by skin blood flow. However, Sato et al. [56] conducted simultaneous NIRS, fMRI, and laser Doppler flowmeter measurements to determine whether prefrontal NIRS hemoglobin signals reflected cortical activity rather than superficial effects. They concluded that NIRS can be used to measure hemodynamic signals originating from prefrontal cortex activation. Fourth, only male children were included in the current study. ASD is more prevalent in males, and gender differences exist in clinical manifestation, cognitive deficits, and brain dysfunctions [32‐34, 57, 58]. Thus, our findings may not be generalizable to the female population. Nevertheless, the current finding of abnormal prefrontal hemodynamic responses in male children with ASD is valuable for extending current knowledge. Fifth, the sample size was small, although the 12 male children with ASD were drug-naïve and none had comorbid psychiatric, neurodevelopmental or neurological disorders. However, the required sample size was 11 when we calculated it as α error prob 0.05, power (1-β error prob) 0.8, and effect size 1.3 (effect size in previous studies [23, 26]: 1.3 to 1.6) before the start of this study. In this study, effect size was 1.4 to 1.5. This study is adequately powered (power (1-β error prob): 0.95 to 0.97). Future research with larger sample sizes will be needed to confirm the current findings.

To our knowledge, this is the first 24-channel NIRS study examining reduced prefrontal hemodynamic responses in male children with ASD during the Stroop color-word task. We found that oxy-Hb changes in 12 drug-naïve male children with ASD were significantly smaller than those in 12 healthy male children in the dorsolateral prefrontal cortex. In addition, 24-channel NIRS systems appears to be a very useful measurement modality for assessing the frontal function of ASD, as it enables non-invasive functional mapping of the cerebral cortex and has much shorter measurement times (about 5 min) compared with other functional brain imaging methodologies.