Nobumasa Kato

Voxel-based analysis of MRI reveals anterior cingulate gray-matter volume reduction in posttraumatic stress disorder due to terrorism.

MRI studies using the manual tracing method have shown a smaller-than-normal hippocampal volume in patients with posttraumatic stress disorder (PTSD). However, these studies have yielded inconsistent results, and brain structures other than the hippocampus have not been well investigated. A recently developed, fully automated method called voxel-based morphometry enables an exploration of structural changes throughout the brain by applying statistical parametric mapping to high-resolution MRI. Here we first used this technology in patients with PTSD. Participants were 9 victims of the Tokyo subway sarin attack with PTSD and 16 matched victims of the same traumatic event without PTSD. The voxel-based morphometry showed a significant gray-matter volume reduction in the left anterior cingulate cortex (ACC) in trauma survivors with PTSD compared with those without PTSD. The severity of the disorder was negatively correlated with the gray-matter volume of the left ACC in PTSD subjects. There were no significant differences in other gray-matter regions or any of the white-matter regions between two groups. The present study demonstrates evidence for structural abnormalities of ACC in patients with PTSD. Together with previous functional neuroimaging studies showing a dysfunction of this region, the present findings provide further support for the important role of ACC, which is pivotally involved in attention, emotional regulation, and conditioned fear, in the pathology of PTSD.

Atypical gaze patterns in children and adults with autism spectrum disorders dissociated from developmental changes in gaze behaviour

Eye tracking has been used to investigate gaze behaviours in individuals with autism spectrum disorder (ASD). However, traditional analysis has yet to find behavioural characteristics shared by both children and adults with ASD. To distinguish core ASD gaze behaviours from those that change with development, we examined temporo-spatial gaze patterns in children and adults with and without ASD while they viewed video clips. We summarized the gaze patterns of 104 participants using multidimensional scaling so that participants with similar gaze patterns would cluster together in a two-dimensional plane. Control participants clustered in the centre, reflecting a standard gaze behaviour, whereas participants with ASD were distributed around the periphery. Moreover, children and adults were separated on the plane, thereby showing a clear effect of development on gaze behaviours. Post hoc frame-by-frame analyses revealed the following findings: (i) both ASD groups shifted their gaze away from a speaker earlier than the control groups; (ii) both ASD groups showed a particular preference for letters; and (iii) typical infants preferred to watch the mouth rather than the eyes during speech, a preference that reversed with development. These results highlight the importance of taking the effect of development into account when addressing gaze behaviours characteristic of ASD.

Smaller amygdala volume and reduced anterior cingulate gray matter density associated with history of post-traumatic stress disorder

Although post-traumatic stress disorder (PTSD) may be seen to represent a failure to extinguish learned fear, significant aspects of the pathophysiology relevant to this hypothesis remain unknown. Both the amygdala and hippocampus are necessary for fear extinction occur, and thus both regions may be abnormal in PTSD. Twenty-five people who experienced the Tokyo subway sarin attack in 1995, nine who later developed PTSD and 16 who did not, underwent magnetic resonance imaging (MRI) with manual tracing to determine bilateral amygdala and hippocampus volumes. At the time of scanning, one had PTSD and eight had a history of PTSD. Results indicated that the group with a history of PTSD had significantly smaller mean bilateral amygdala volume than did the group that did not develop PTSD. Furthermore, left amygdala volume showed a significant negative correlation with severity of PTSD symptomatology as well as reduced gray matter density in the left anterior cingulate cortex. To our knowledge, this is the first observation of an association between PTSD and amygdala volume. Furthermore the apparent interplay between amygdala and anterior cingulate cortex represents support at the level of gross brain morphology for the theory of PTSD as a failure of fear extinction.

Mitigation of Sociocommunicational Deficits of Autism Through Oxytocin-Induced Recovery of Medial Prefrontal Activity: A Randomized Trial

IMPORTANCEnSociocommunicational deficits make it difficult for individuals with autism spectrum disorders (ASD) to understand communication content with conflicting verbal and nonverbal information. Despite growing prospects for oxytocin as a therapeutic agent for ASD, no direct neurobiological evidence exists for oxytocins beneficial effects on this core symptom of ASD. This is slowing clinical application of the neuropeptide.nnnOBJECTIVEnTo directly examine whether oxytocin has beneficial effects on the sociocommunicational deficits of ASD using both behavioral and neural measures.nnnDESIGN, SETTING, AND PARTICIPANTSnAt the University of Tokyo Hospital, we conducted a randomized, double-blind, placebo-controlled, within-subject-crossover, single-site experimental trial in which intranasal oxytocin and placebo were administered. A total of 40 highly functioning men with ASD participated and were randomized in the trial.nnnINTERVENTIONSnSingle-dose intranasal administration of oxytocin (24 IU) and placebo.nnnMAIN OUTCOMES AND MEASURESnUsing functional magnetic resonance imaging, we examined effects of oxytocin on behavioral neural responses of the participants to a social psychological task. In our previous case-control study using the same psychological task, when making decisions about social information with conflicting verbal and nonverbal contents, participants with ASD made judgments based on nonverbal contents less frequently with longer time and could not induce enough activation in the medial prefrontal cortex. Therefore, our main outcomes and measures were the frequency of the nonverbal information-based judgments (NVJs), the response time for NVJs, and brain activity of the medial prefrontal cortex during NVJs.nnnRESULTSnIntranasal oxytocin enabled the participants to make NVJs more frequently (P =u2009.03) with shorter response time (P =u2009.02). During the mitigated behavior, oxytocin increased the originally diminished brain activity in the medial prefrontal cortex (P <u2009.001). Moreover, oxytocin enhanced functional coordination in the area (P <u2009.001), and the magnitude of these neural effects was predictive of the behavioral effects (P ≤ .01).nnnCONCLUSIONS AND RELEVANCEnThese findings provide the first neurobiological evidence for oxytocins beneficial effects on sociocommunicational deficits of ASD and give us the initial account for neurobiological mechanisms underlying any beneficial effects of the neuropeptide.nnnTRIAL REGISTRATIONnumin.ac.jp/ctr Identifier: UMIN000002241 and UMIN000004393.

Reduced gray matter volume of pars opercularis is associated with impaired social communication in high-functioning autism spectrum disorders.

BACKGROUNDnRecent literature suggests that the inferior frontal gyrus, especially its posterior portion, has an important role in imitation and social reciprocity and in the pathophysiology of their disturbance in autism spectrum disorders (ASD). However, the structural abnormality of this region has not fully been clarified in subjects with ASD.nnnMETHODSnHere we obtained magnetic resonance images from 13 right-handed men with high-functioning ASD (Asperger disorder [n = 10] or autism [n = 3]) and from 11 age-, parental socioeconomic background-, and intelligence quotient-matched right-handed typical men. A reliable manual tracing methodology was employed to measure the gray matter volume of the pars opercularis, corresponding to Brodmann area 44, and the pars triangularis, corresponding to Brodmann area 45.nnnRESULTSnA significant gray matter volume reduction of both the pars opercularis and triangularis was found bilaterally in the subjects with ASD compared with the typical control subjects. The effect size seemed to be larger for pars opercularis (1.25) than for pars triangularis (.90). The reduced volume of right as well as total pars opercularis showed a significant association with the increased severity of social communication problems in the ASD group.nnnCONCLUSIONSnThe current findings support an important role of pars opercularis, a center of the mirror neuron system, in the pathophysiology of ASD.

A small number of abnormal brain connections predicts adult autism spectrum disorder

Although autism spectrum disorder (ASD) is a serious lifelong condition, its underlying neural mechanism remains unclear. Recently, neuroimaging-based classifiers for ASD and typically developed (TD) individuals were developed to identify the abnormality of functional connections (FCs). Due to over-fitting and interferential effects of varying measurement conditions and demographic distributions, no classifiers have been strictly validated for independent cohorts. Here we overcome these difficulties by developing a novel machine-learning algorithm that identifies a small number of FCs that separates ASD versus TD. The classifier achieves high accuracy for a Japanese discovery cohort and demonstrates a remarkable degree of generalization for two independent validation cohorts in the USA and Japan. The developed ASD classifier does not distinguish individuals with major depressive disorder and attention-deficit hyperactivity disorder from their controls but moderately distinguishes patients with schizophrenia from their controls. The results leave open the viable possibility of exploring neuroimaging-based dimensions quantifying the multiple-disorder spectrum.

Altered Network Topologies and Hub Organization in Adults with Autism: A Resting-State fMRI Study

Recent functional magnetic resonance imaging (fMRI) studies on autism spectrum condition (ASC) have identified dysfunctions in specific brain networks involved in social and non-social cognition that persist into adulthood. Although increasing numbers of fMRI studies have revealed atypical functional connectivity in the adult ASC brain, such functional alterations at the network level have not yet been fully characterized within the recently developed graph-theoretical framework. Here, we applied a graph-theoretical analysis to resting-state fMRI data acquired from 46 adults with ASC and 46 age- and gender-matched controls, to investigate the topological properties and organization of autistic brain network. Analyses of global metrics revealed that, relative to the controls, participants with ASC exhibited significant decreases in clustering coefficient and characteristic path length, indicating a shift towards randomized organization. Furthermore, analyses of local metrics revealed a significantly altered organization of the hub nodes in ASC, as shown by analyses of hub disruption indices using multiple local metrics and by a loss of “hubness” in several nodes (e.g., the bilateral superior temporal sulcus, right dorsolateral prefrontal cortex, and precuneus) that are critical for social and non-social cognitive functions. In particular, local metrics of the anterior cingulate cortex consistently showed significant negative correlations with the Autism-Spectrum Quotient score. Our results demonstrate altered patterns of global and local topological properties that may underlie impaired social and non-social cognition in ASC.

Diminished Medial Prefrontal Activity behind Autistic Social Judgments of Incongruent Information

Individuals with autism spectrum disorders (ASD) tend to make inadequate social judgments, particularly when the nonverbal and verbal emotional expressions of other people are incongruent. Although previous behavioral studies have suggested that ASD individuals have difficulty in using nonverbal cues when presented with incongruent verbal-nonverbal information, the neural mechanisms underlying this symptom of ASD remain unclear. In the present functional magnetic resonance imaging study, we compared brain activity in 15 non-medicated adult males with high-functioning ASD to that of 17 age-, parental-background-, socioeconomic-, and intelligence-quotient-matched typically-developed (TD) male participants. Brain activity was measured while each participant made friend or foe judgments of realistic movies in which professional actors spoke with conflicting nonverbal facial expressions and voice prosody. We found that the ASD group made significantly less judgments primarily based on the nonverbal information than the TD group, and they exhibited significantly less brain activity in the right inferior frontal gyrus, bilateral anterior insula, anterior cingulate cortex/ventral medial prefrontal cortex (ACC/vmPFC), and dorsal medial prefrontal cortex (dmPFC) than the TD group. Among these five regions, the ACC/vmPFC and dmPFC were most involved in nonverbal-information-biased judgments in the TD group. Furthermore, the degree of decrease of the brain activity in these two brain regions predicted the severity of autistic communication deficits. The findings indicate that diminished activity in the ACC/vmPFC and dmPFC underlies the impaired abilities of individuals with ASD to use nonverbal content when making judgments regarding other people based on incongruent social information.

Changed preference for sweet taste in adulthood induced by perinatal exposure to bisphenol A-A probable link to overweight and obesity.

BACKGROUNDnThe preference of obesity has risen dramatically worldwide over the past decades. Some latest reports showed significant increase of obesity in men compared to women. Implication of environmental endocrine disruptors has been focused more and more. Numerous studies in vitro and vivo implied metabolic actions of bisphenol A (BPA), however much less consideration is given to the possibility of BPA exposure-induced change in gender-specific behaviors which result in obesity and overweight.nnnOBJECTIVESnTo examine whether perinatal exposure to BPA at relative dose to environmental levels can influence sweet preference of male and female rats and consequently lead to alteration in bodyweight.nnnMETHODSnRats perinatally exposed to BPA at doses of 0.01, 0.1 and 1.0 mg/L were tested sweet preference for 0.25%, 0.5% saccharin and 15% sucrose by two-bottle choice (water vs. saccharin/sucrose). The food intake, liquid consumption and bodyweight of each rat were monitored daily. At the end of the test, the fat percentage and tail blood pressure were measured.nnnRESULTSnSignificant sex difference of preference for 0.25% and 0.5% saccharin was shown in control and all BPA-treated groups (p < 0.001, female vs. male). 0.1 and 1.0 mg/L BPA treatment induced the increase of preference for 0.25% saccharin solution in males, but not in females. 0.1 mg/L BPA treatment increased sucrose preference in males at postnatal day (PND) 70 and 140 (p < 0.05 and p < 0.001, compared to control respectively) but decreased sucrose preference in females at PND 140 (p < 0.05, compared to control). The males treated by BPA showed overweight (p < 0.001), high fat percentage (p < 0.001) and tail blood pressure (p < 0.05) than control at PND 140.nnnCONCLUSIONnPerinatal exposure to a low dose of BPA could increase sweet preference of male rats. Calorie intake may be programmed during early life, leading to changes of body weight depending on the gender. Although further researches concerning the mechanism are required, the results of the present study are particularly important with regards to the more significant increasing prevalence of obesity in men and the environmental endocrine disruptors.

Impaired Prefrontal Hemodynamic Maturation in Autism and Unaffected Siblings

Background Dysfunctions of the prefrontal cortex have been previously reported in individuals with autism spectrum disorders (ASD). Previous studies reported that first-degree relatives of individuals with ASD show atypical brain activity during tasks associated with social function. However, developmental changes in prefrontal dysfunction in ASD and genetic influences on the phenomena remain unclear. In the present study, we investigated the change in hemoglobin concentration in the prefrontal cortex as measured with near-infrared spectroscopy, in children and adults with ASD during the letter fluency test. Moreover, to clarify the genetic influences on developmental changes in the prefrontal dysfunction in ASD, unaffected siblings of the ASD participants were also assessed. Methodology/Principal Findings Study participants included 27 individuals with high-functioning ASD, age- and IQ-matched 24 healthy non-affected siblings, and 27 unrelated healthy controls aged 5 to 39 years. The relative concentration of hemoglobin ([Hb]) in the prefrontal cortex was measured during the letter fluency task. For children, neither the [oxy-Hb] change during the task nor task performances differed significantly among three groups. For adults, the [oxy-Hb] increases during the task were significantly smaller in the bilateral prefrontal cortex in ASD than those in control subjects, although task performances were similar. In the adult siblings the [oxy-Hb] change was intermediate between those in controls and ASDs. Conclusion/Significance Although indirectly due to a cross-sectional design, the results of this study indicate altered age-related change of prefrontal activity during executive processing in ASD. This is a first near-infrared spectroscopy study that implies alteration in the age-related changes of prefrontal activity in ASD and genetic influences on the phenomena.