• fear;
  • near-infrared spectroscopy;
  • neuroimaging;
  • pervasive developmental disorders;
  • prefrontal cortex


  1. Top of page
  2. Abstract

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.


  1. Top of page
  2. Abstract


Fourteen patients with PDD (mean age, 31.6 ± 5.0 years; six men, eight women) and 14 age- and sex-matched healthy control subjects (mean age, 31.5 ± 4.8 years; six men, eight women) were enrolled (Table 1). The patients were outpatients or inpatients of the Department of Psychiatry of Tokushima University Hospital. The healthy subjects were college students and hospital personnel, and their acquaintances. PDD patients were diagnosed by two trained psychiatrists according to DSM-IV-TR criteria: autistic disorder, n = 6; Asperger syndrome, n = 3; and PDD not otherwise specified, n = 5. Six of the PDD patients were taking psychotropic drugs at the time of the examination, including antidepressants, antipsychotics, and/or benzodiazepines (Table 2). These patients, however, did not meet DSM-IV-TR criteria for any psychotic, affective, or anxiety disorder. All subjects were right-handed, as assessed on the Edinburgh Handedness Inventory.13 None of the subjects had any history of alcohol or substance abuse or dependence, neurological illness, traumatic brain injury, or treatment with electroconvulsive therapy. Intellectual ability in the PDD patients was assessed on either the Wechsler Adult Intelligence Scale Revised (WAIS-R) or its third edition (WAIS-III). Three intelligence quotients (IQ) were calculated: verbal (VIQ), performance (PIQ), and full-scale (FSIQ).

Table 1.  Subject characteristics (mean ± SD)
 Age (years)Sex M/FHandedness R/LYears of educationFSIQVIQPIQEIQAQSTAI-stateSTAI-trait
  1. t-test; Wechsler Adult Intelligence Scale–Revised or 3rd edn.

  2. AQ, autism spectrum quotient; EIQ, estimated intelligence quotient (on Japanese Adult Reading Test); FSIQ, full-scale intelligence quotient; PDD, pervasive developmental disorder; PIQ, performance intelligence quotient; STAI, State–Trait Anxiety Inventory; VIQ, verbal intelligence quotient.

PDD31.6 ± 5.06/814/013.9 ± 2.7101.1 ± 13.6103.1 ± 14.798.9 ± 18.0 34.8 ± 7.140.9 ± 18.159.0 ± 11.9
Control31.5 ± 4.86/814/018.5 ± 2.1   115.5 ± 6.114.3 ± 7.034.1 ± 8.137.7 ± 7.6
 P < 0.01  P < 0.01 P < 0.01
Table 2.  PDD patient data
Patient no.Age (years)SexFSIQVIQPIQAQSubtypeMedication
  • Wechsler Adult Intelligence Scale–Revised or 3rd edn.

  • AQ, autism spectrum quotient; As, Asperger disorder; Au, autistic disorder; FSIQ, full-scale intelligence quotient; PDD, pervasive developmental disorder; PDDNOS, pervasive developmental disorder not otherwise specified; PIQ, performance intelligence quotient; VIQ, verbal intelligence quotient.

 140F1039711437PDDNOSNo medication
 226F891086437AuAmoxapine 50 mg, Paroxetine 30 mg, Etizolam 1.5 mg, Tofisopam 150 mg
 325M11010311831AsFluvoxamine 150 mg
 438F1011079343PDDNOSNo medication
 533M1021119032AuOlanzapine 5 mg
 634M1191319933AsZopiclone 7.5 mg, Flunitrazepam 1 mg
 728M78689743AuFluvoxamine 50 mg
 835F96979641AuParoxetine 50 mg, Aripiprazole 12 mg
 932F10910511517PDDNOSNo medication
1033M90939041PDDNOSNo medication
1128M989210837AuNo medication
1235F12011612126PDDNOSNo medication
1332F81986537AsNo medication
1423F11911711432AuNo medication

The control subjects completed the Japanese Adult Reading Test (JART). This is a Japanese version of the National Adult Reading Test, which is a widely used measure of premorbid IQ in English-speaking patients with dementia.14 The JART score provides an estimate of IQ (EIQ). Mental retardation was thus excluded in all control subjects. In addition, all subjects were asked to complete the State-Trait Anxiety Inventory (STAI), which measures transient and enduring levels of anxiety.15 They were also asked to complete the Japanese version of the Autism-Spectrum Quotient (AQ)16,17 to measure traits associated with the autistic spectrum. Written informed consent was obtained from all participants prior to inclusion, and the study was approved by the Ethics Committee of Tokushima University Hospital.

Facial expression stimuli

Static facial expression stimuli were selected from a standard Japanese set of faces (ATR International),18 given that Moriguchi et al. have shown that Japanese individuals have difficulty in recognizing the facial expressions of Caucasian people.19 This face database includes images of the basic facial expressions of 60 male and 60 female Japanese models. The faces are classified according to six categories of expression and three levels of emotional intensity (33%, mild; 67%, moderate; 100%, intense), or to a neutral category with a 0% emotional intensity. Fearful faces of 100% intensity and neutral faces were selected for use in this experiment. These were expressed by 10 models (four female, six male). The size of the face stimuli was 22 × 16 cm, which subtended an angle of 20.8° horizontally and 15.2° vertically at a viewing distance of 60 cm.

NIRS measurement

The NIRS measurement was performed using the ETG4000, a 24-channel NIRS system (Hitachi Medical, Tokyo, Japan), which uses two wavelengths of near-infrared light (695 and 830 nm). The absorption of light was measured, and changes in oxyHb and deoxyHb concentrations were then calculated according to the Beer–Lambert law using the difference in absorption between the two wavelengths. The distance between the injector and the detector was 3.0 cm. The machine took measurements at points located 2–3 cm beneath the scalp, that is, on the surface of the cerebral cortices. The NIRS probes were placed symmetrically and bilaterally over the frontal region. The probes measured the relative changes in oxyHb and deoxyHb concentrations at 12 measurement points within a 6 × 6-cm area of the left and right hemispheres, respectively. The lowest probes were positioned along the Fp1–Fp2 line in accordance with the International 10/20 Electrode Placement System for electroencephalography. The distances from the midline to the most medial and the most lateral probes were 1.5 cm and 7.5 cm, respectively.

The procedure was based on that described by Marumo et al.20 The emotional task consisted of a 30-s pre-task period, a 60-s task period, and a 70-s post-task period. During the pre-task and post-task periods, neutral faces were presented in a random order at 2-s intervals. During the task period, fearful faces were presented in a random order at 2-s intervals. This procedure was performed only once.

The time resolution of the NIRS machine was set at 0.1 s. OxyHb and deoxyHb changes were analyzed using first-order correction to exclude task-unrelated changes during the task. The obtained data were analyzed using the integral mode: the pre-task baseline was determined as the mean across 10 s just before the task period; the post-task baseline was determined as the mean from 10 s to 20 s after the task period; and linear fitting was performed on the data between two baselines.

The subject sat on a comfortable chair and viewed the faces on a computer screen. A response button was placed in their right hand. They were instructed to press the button during the pre-task, task and post-task period as quickly as possible to indicate whether the presented face was male or female. This helped the subjects to concentrate on the faces, and facilitate implicit responses to fearful faces.

Data analysis and statistics

According to the aforementioned measurement parameters for the integral mode, the peak change in oxyHb and deoxyHb concentration during the task was recorded for each subject. Four areas were defined to allow investigation of the individual effects of the task parameters within different regions of NIRS measurement: area 1 with channels 1, 2, 3, 4, 6, and 8; area 2 with channels 5, 7, 9, 10, 11, and 12; area 3 with channels 15, 18, 20, 21, 23, and 24; and area 4 with channels 13, 14, 16, 17, 19, and 22. Areas 1–4 represented approximately the left dorsolateral PFC, the left ventromedial PFC, the right ventromedial PFC, and the right dorsolateral PFC, respectively (Fig. 1). The average of the peak change in oxyHb and deoxyHb concentration in each area was calculated.


Figure 1. Grand average waveform of hemoglobin concentration changes during the implicit processing of fearful faces for (a) controls (n = 14) and (b) pervasive developmental disorder (PDD) patients (n = 14). Red, oxygenated hemoglobin (oxyHb); blue, deoxygenated hemoglobin (deoxyHb); green, totalHb. Red arrow, task period. (c) Optodes over the bilateral frontal region. They measured the relative changes in oxyHb and deoxyHb concentrations at 12 measurement points within a 6 × 6-cm area of the left and right hemispheres, respectively.

Download figure to PowerPoint

All results were analyzed using SPSS version 18.0 (SPSS, Tokyo, Japan). Student's t-test was used to compare behavioral data (age, education, AQ score, STAI-state or -trait data). Data concerning changes in oxyHb and deoxyHb concentration were analyzed using two-way analysis of variance (ANOVA) and the following variables: diagnosis (PDD patients and controls), and area (areas 1–4).

For each subject in the control group, a correlational analysis was performed for oxyHb or deoxyHb change and age, education, EIQ, AQ score, and STAI-state or -trait data. For each PDD patient, a correlational analysis was performed for oxyHb or deoxyHb change and age, education, FSIQ, VIQ, PIQ, AQ score, and STAI-state or -trait data. Either Spearman's or Pearson's correlation was used, depending on the normality of the distribution of the variables, which was determined using the Kolmogorov–Smirnov test. Each correlational analysis was conducted only when the 2 × 2 ANOVA for changes in oxyHb or deoxyHb concentration indicated a significant main effect.


  1. Top of page
  2. Abstract

Psychological data

There was a significant difference between the two study groups in the number of years of education (PDD patients, 13.9 ± 2.7 years; controls, 18.5 ± 2.1 years; P < 0.01). The JART EIQ score for controls was 115.5 ± 6.1, and the WAIS-R or -III FSIQ score for the PDD patients was 101.1 ± 13.6. A significant difference between the two study groups was observed in the AQ score (PDD patients, 34.8 ± 7.1; controls, 14.3 ± 7.0; P < 0.01) and in the STAI-trait score (PDD patients, 59.0 ± 11.9; controls, 37.7 ± 7.6; P < 0.01), but not in the STAI-state score (PDD patients, 40.9 ± 18.1; controls, 34.1 ± 8.1; P = 0.21; Table 1).

NIRS data

Grand average waveform of Hb concentration changes during the task is shown in Figure 1. During the emotional activation task, the 2 × 2 ANOVA for changes in oxyHb concentration indicated a significant main effect for the variable ‘diagnosis’ (F = 11.44, d.f. = 1, P = 0.001). PDD patients (0.100 ± 0.058 mmol/L·mm) had a significantly less pronounced increase in oxyHb concentration than controls (0.152 ± 0.100 mmol/L·mm; Fig. 2). Neither the main effect for the variable ‘area’ (F = 2.068, d.f. = 3, P = 0.109), nor the interaction diagnosis × area were significant (F = 0.482, d.f. = 3, P = 0.695). In contrast, the 2 × 2 ANOVA for changes in deoxyHb concentration indicated no significant main effect for the variable ‘diagnosis’ (F = 1.327, d.f. = 1, P = 0.252), ‘area’ (F = 0.364, d.f. = 3, P = 0.779), and the interaction diagnosis × area (F = 0.349, d.f. = 3, P = 0.790). There was no significant difference between PDD patients (0.057 ± 0.063 mmol/L·mm) and controls (0.044 ± 0.046 mmol/L·mm).


Figure 2. Pervasive developmental disorder (PDD) patients had significantly reduced oxygenated hemoglobin (oxyHb) changes in the prefrontal cortex compared to healthy controls during the implicit processing task of fearful expression. Data are average of all 24 channels. *P = 0.001.

Download figure to PowerPoint

In control subjects, there were no significant correlations between oxyHb change and age (r = −0.121, P = 0.681), education (r = −0.183, P = 0.531), EIQ (r = 0.013, P = 0.964), AQ (r = 0.392, P = 0.166), STAI-state (r = 0.295, P = 0.306), or STAI-trait (r = 0.243, P = 0.403).

In PDD patients, significant correlations were found between oxyHb change and FSIQ (r = −0.561, P = 0.037) and VIQ (r = −0.761, P = 0.002), but not between oxyHb change and age (r = −0.075, P = 0.798), education (r = −0.046, P = 0.875), PIQ (r = −0.029, P = 0.922), AQ (r = 0.109, P = 0.711), STAI-state (r = 0.157, P = 0.400), or STAI-trait (r = 0.387, P = 0.255).


  1. Top of page
  2. Abstract

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.


  1. Top of page
  2. Abstract

This work was supported by a Grants-in-Aid for Scientific Research from the Japanese Ministry of Education, Culture, Sports, Science and Technology.


  1. Top of page
  2. Abstract
  • 1
    American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 4th edn, text revision. American Psychiatric Press, Washington, DC, 2000.
  • 2
    Schultz RT. Developmental deficits in social perception in autism: The role of the amygdala and fusiform face area. Int. J. Dev. Neurosci. 2005; 23: 125141.
  • 3
    Kanwisher N. Domain specificity in face perception. Nat. Neurosci. 2000; 3: 759763.
  • 4
    Damasio AR. Descartes' Error : Emotion, Reason, and the Human Brain. Penguin, London, 2005.
  • 5
    Critchley HD, Daly EM, Bullmore ET et al. The functional neuroanatomy of social behaviour: Changes in cerebral blood flow when people with autistic disorder process facial expressions. Brain 2000; 123 (Pt 11): 22032212.
  • 6
    Ashwin C, Baron-Cohen S, Wheelwright S, O'Riordan M, Bullmore ET. Differential activation of the amygdala and the ‘social brain’ during fearful face-processing in Asperger syndrome. Neuropsychologia 2007; 45: 214.
  • 7
    Pelphrey KA, Morris JP, McCarthy G, Labar KS. Perception of dynamic changes in facial affect and identity in autism. Soc. Cogn. Affect. Neurosci. 2007; 2: 140149.
  • 8
    Ogai M, Matsumoto H, Suzuki K et al. fMRI study of recognition of facial expressions in high-functioning autistic patients. Neuroreport 2003; 14: 559563.
  • 9
    Dapretto M, Davies MS, Pfeifer JH et al. Understanding emotions in others: Mirror neuron dysfunction in children with autism spectrum disorders. Nat. Neurosci. 2006; 9: 2830.
  • 10
    Jöbsis FF. Noninvasive, infrared monitoring of cerebral and myocardial oxygen sufficiency and circulatory parameters. Science 1977; 198: 12641267.
  • 11
    Kuwabara H, Kasai K, Takizawa R et al. Decreased prefrontal activation during letter fluency task in adults with pervasive developmental disorders: A near-infrared spectroscopy study. Behav. Brain Res. 2006; 172: 272277.
  • 12
    Kawakubo Y, Kuwabara H, Watanabe K et al. Impaired prefrontal hemodynamic maturation in autism and unaffected siblings. PLoS ONE 2009; 4: e6881.
  • 13
    Oldfield RC. The assessment and analysis of handedness: The Edinburgh inventory. Neuropsychologia 1971; 9: 97113.
  • 14
    Matsuoka K, Uno M, Kasai K, Koyama K, Kim Y. Estimation of premorbid IQ in individuals with Alzheimer's disease using Japanese ideographic script (Kanji) compound words: Japanese version of National Adult Reading Test. Psychiatry Clin. Neurosci. 2006; 60: 332339.
  • 15
    Spielberger CD, Gorsuch RL, Lushene RE. State-Trait Anxiety Inventory. Consulting Psychologists Press, Palo Alto, CA, 1970.
  • 16
    Baron-Cohen S, Wheelwright S, Skinner R, Martin J, Clubley E. The autism-spectrum quotient (AQ): Evidence from Asperger syndrome/high-functioning autism, males and females, scientists and mathematicians. J. Autism Dev. Disord. 2001; 31: 517.
  • 17
    Wakabayashi A, Tojo Y, Baron-Cohen S, Wheelwright S. The Autism-Spectrum Quotient (AQ) Japanese version: Evidence from high-functioning clinical group and normal adults. Shinrigaku Kenkyu 2004; 75: 7884.
  • 18
    Kamachi M, Bruce V, Mukaida S, Gyoba J, Yoshikawa S, Akamatsu S. Dynamic properties influence the perception of facial expressions. Perception 2001; 30: 875887.
  • 19
    Moriguchi Y, Ohnishi T, Kawachi T et al. Specific brain activation in Japanese and Caucasian people to fearful faces. Neuroreport 2005; 16: 133136.
  • 20
    Marumo K, Takizawa R, Kawakubo Y, Onitsuka T, Kasai K. Gender difference in right lateral prefrontal hemodynamic response while viewing fearful faces: A multi-channel near-infrared spectroscopy study. Neurosci. Res. 2009; 63: 8994.
  • 21
    Dalton KM, Nacewicz BM, Johnstone T et al. Gaze fixation and the neural circuitry of face processing in autism. Nat. Neurosci. 2005; 8: 519526.
  • 22
    Luna B, Minshew NJ, Garver KE et al. Neocortical system abnormalities in autism: An fMRI study of spatial working memory. Neurology 2002; 59: 834840.
  • 23
    Ring HA, Baron-Cohen S, Wheelwright S et al. Cerebral correlates of preserved cognitive skills in autism: A functional MRI study of embedded figures task performance. Brain 1999; 122 (Pt 7): 13051315.
  • 24
    Silk TJ, Rinehart N, Bradshaw JL et al. Visuospatial processing and the function of prefrontal-parietal networks in autism spectrum disorders: A functional MRI study. Am. J. Psychiatry 2006; 163: 14401443.
  • 25
    Schmitz N, Rubia K, Daly E, Smith A, Williams S, Murphy DG. Neural correlates of executive function in autistic spectrum disorders. Biol. Psychiatry 2006; 59: 716.
  • 26
    Müller RA, Kleinhans N, Kemmotsu N, Pierce K, Courchesne E. Abnormal variability and distribution of functional maps in autism: An FMRI study of visuomotor learning. Am. J. Psychiatry 2003; 160: 18471862.
  • 27
    Castelli F, Frith C, Happé F, Frith U. Autism, Asperger syndrome and brain mechanisms for the attribution of mental states to animated shapes. Brain 2002; 125: 18391849.
  • 28
    Happé F, Ehlers S, Fletcher P et al. ‘Theory of mind’ in the brain. Evidence from a PET scan study of Asperger syndrome. Neuroreport 1996; 8: 197201.
  • 29
    Sugihara G, Ouchi Y, Nakamura K, Sekine Y, Mori N. Advances in neuroimaging research on Asperger syndrome. Nippon Rinsho 2007; 65: 449452.
  • 30
    Brühl AB, Kaffenberger T, Herwig U. Serotonergic and noradrenergic modulation of emotion processing by single dose antidepressants. Neuropsychopharmacology 2010; 35: 521533.
  • 31
    Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB. Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch. Gen. Psychiatry 2005; 62: 282288.