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Aim: The purpose of the present study was to investigate whether individuals with pervasive developmental disorders (PDD) show differential activation during an emotional activation task compared with age- and sex-matched controls, by measuring changes in the concentration of oxygenated (oxyHb) and deoxygenated (deoxyHb) hemoglobin, using near-infrared spectroscopy (NIRS).
Methods: Fourteen patients with PDD and 14 age- and sex-matched healthy controls participated in the study. The relative changes of concentrations of oxyHb and deoxyHb were measured on NIRS during an implicit processing task of fearful expression using Japanese standard faces.
Results: PDD patients had significantly reduced oxyHb changes in the prefrontal cortex (PFC) compared to healthy controls.
Conclusion: PFC dysfunction may exist in PDD.
PERVASIVE DEVELOPMENTAL DISORDERS (PDD) are neurally based psychiatric disorders that are characterized by restricted behaviors and interests, and developmental impairments in social interaction.1 One of the most characteristic impairments in social communication in PDD is the failure to perceive and respond to non-verbal conversational cues such as facial expression.2
In healthy humans, face perception elicits activation within the occipitotemporal regions, including the fusiform face area (FFA).3 These areas are involved in the processing of facial expressions of emotion and of salient parts of the face. Perceptual information from these areas is sent to the amygdala and the prefrontal cortex (PFC), which are involved in the appraisal of the emotional significance of stimuli and the guiding of social decisions and behavior.4 In PDD, studies using functional neuroimaging have reported hypoactivation of the FFA and the amygdala in a face processing task.5–7 Moreover, in a fearful face processing task, functional neuroimaging studies have shown frontal cortex dysfunction, involving the superior frontal gyrus and the medial frontal gyrus,7 the orbitofrontal cortex,6 the middle frontal gyrus,8 and the inferior frontal gyrus,9 but PFC activation associated with a fearful face processing task remains to be fully elucidated.
The PFC is easily accessible for measurement using near-infrared spectroscopy (NIRS), which is an optical imaging technique that allows non-invasive measurement of changes in the concentration of oxygenated (oxyHb) and deoxygenated (deoxyHb) hemoglobin in brain tissue.10 NIRS has several advantages over other imaging methods, because it is versatile, relatively inexpensive, and non-invasive. NIRS has been used in neuroimaging of several psychiatric disorders. To our knowledge, only two previous NIRS studies have investigated hemodynamic responses in PDD. Kuwabara et al. and Kawakubo et al. reported that the PDD group was associated with lower activation in PFC according to oxyHb concentration change as compared with the control group during a letter fluency task.11,12 The involvement of PFC function in PDD with emotional tasks, however, such as a fearful facial expression task, remains to be elucidated.
The aim of the present study was to investigate prefrontal hemodynamic change in PDD using NIRS during implicit processing of fearful expression. Based on previous studies using other neuroimaging techniques or tasks, we predicted that the PDD group would be associated with lower activation in PFC as compared with the control group.
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To the best of our knowledge, this is the first NIRS study to have evaluated prefrontal activation during an emotional paradigm in patients with PDD. PDD patients had less PFC activation during the implicit processing of fearful faces than controls. The present findings are consistent with those of previous studies using functional magnetic resonance imaging (fMRI), which found hypofrontality in patients with PDD compared to controls during implicit and explicit responses to fearful facial expressions.6–9 The present findings, however, differ from one recent study, which reported that PDD patients had increased PFC activation during facial discrimination tasks involving fearful faces.21 The participants were much younger and had a lower IQ than those of the present study, and age or intelligence may have influenced the results.
There are three possible interpretations of the present observation. First, PDD patients may be unable to perceive facial expression, although we did not examine whether they recognize the face as fearful expressions. Abnormal perception of faces has been demonstrated in PDD.2 A recent study using fMRI in PDD reported hypoactivation of the FFA, an important area for face perception, during the implicit processing of faces.5 Second, the normal affective response to fearful facial expression stimuli may be absent in PDD, although we did not examine affective response. Recent fMRI of PDD patients showed hypoactivation of the amygdala,6,7 which plays an important role in the response to fear conditioning during the processing of threatening facial stimuli. A third possible interpretation is that this reduced prefrontal blood volume change may be attributable to hypofrontality in PDD. Decreased hemodynamic responses in the PFC during the performance of spatial working memory, motor inhibition, visuomotor control tasks, mentalizing and theory of mind tasks have been reported in fMRI or positron emission tomography of PDD patients.22–28
We observed neither laterality nor localization of activation in the PFC of controls or PDD patients. Two fMRI studies of PDD during an implicit processing of fearful faces have reported differing patterns of brain activation in the frontal region.6,7 Pelphrey et al. demonstrated decreased activation in the right superior frontal gyrus and the left medial frontal gyrus in response to dynamic facial expression.7 Ashwin et al. reported decreased activation in the left orbitofrontal cortex in response to varying intensities of fearful expression.6 Differences in the methodology and tasks of these studies may explain their inconsistent results.
In the PDD patients, a negative correlation was found between oxyHb change in the PFC and the FSIQ or VIQ scores. In controls, no correlation was found between oxyHb change and the JART EIQ score. Although the precise reason for the negative correlation between IQ and PFC activation in PDD is unknown, higher functioning PDD patients have a more pronounced decrease in PFC activation. This negative correlation appears to exclude the possibility that decreased PFC activation in PDD is related to the lower IQ in PDD compared with the JART EIQ in controls.
The STAI-trait score, but not the STAI-state score, was significantly higher in patients with PDD than in controls. This indicates that the PDD patients experienced the same level of anxiety as controls at the time of measurement, even though greater susceptibility to anxiety is one PDD trait. The higher STAI-trait scores, however, do not explain the lower PFC activation in PDD, because there was no correlation in these patients between oxyHb change and STAI-trait score.
Unfortunately, we could not examine the gender difference because of the small sample size, although Marumo et al. found differences between male and female participants during stimulation with fearful faces in their NIRS study with healthy subjects.
The present results should be interpreted with caution. Continuous-wave NIRS cannot measure absolute concentrations of oxyHb, because change is measured relative to pre-task period. The present findings may therefore have been due to differences in prefrontal blood volume during the pre-task period. The decreased activation observed in PDD during the task, however, is unlikely to have been due to a saturated hemodynamic state in the pre-task period, because single-photon emission computed tomography has indicated significant hypoperfusion during the resting state in the frontal areas of PDD compared to controls.29
The present study had three important limitations. First, although NIRS is a reliable measure of cortical functions, it is not a reliable measure of the functions of deep white/gray matter structures. In addition, the spatial resolution of NIRS measurement is lower than that of other brain imaging methods such as fMRI. This lower spatial resolution may have prevented the identification of laterality and localization of activation in the PFC of both the controls and the PDD patients. Second, medication may have influenced the present findings. In view of the small sample size, it was not possible to compare medicated and non-medicated PDD patients. Brühl et al. reported that antidepressants increased activity in the PFC compared with placebo during emotional processing.30 The present PDD patients, however, had reduced PFC activation compared to healthy controls. Paulus et al. reported that benzodiazepines did not significantly attenuate blood oxygen level-dependent (BOLD)-fMRI signal in the PFC during emotion processing in healthy volunteers.31 No functional brain imaging study has evaluated the effect of antipsychotics during emotional processing. Only two patients in the present study were prescribed antipsychotics, and the dosages were <300 mg/day chlorpromazine equivalent. Thus, psychotropic medication did not appear to contribute to the present findings. Third, the reduced oxyHb change in the PDD group might have been due to the less active engagement in the task. Unfortunately, we could not rule out this possibility, because we failed to collect accurate data of the task performance, although gross observation found no apparent difference in the engagement in the task.
In summary, the change in oxyHb concentration during the implicit processing of fearful faces was significantly less pronounced in PDD patients than in healthy control subjects, suggesting that PDD patients show differential prefrontal regulation in the processing of fearful facial expression.