Oxytocin-induced increases in cytokines and clinical effect on the core social features of autism: Analyses of RCT datasets.

Although oxytocin may provide a novel therapeutics for the core features of autism spectrum disorder (ASD), previous results regarding the efficacy of repeated or higher dose oxytocin are controversial, and the underlying mechanisms remain unclear. The current study is aimed to clarify whether repeated oxytocin alter plasma cytokine levels in relation to clinical changes of autism social core feature. Here we analyzed cytokine concentrations using comprehensive proteomics of plasmas of 207 adult males with high-functioning ASD collected from two independent multi-center large-scale randomized controlled trials (RCTs): Testing effects of 4-week intranasal administrations of TTA-121 (A novel oxytocin spray with enhanced bioavailability: 3U, 6U, 10U, or 20U/day) and placebo in the crossover discovery RCT; 48U/day Syntocinon or placebo in the parallel-group verification RCT. Among the successfully quantified 17 cytokines, 4 weeks TTA-121 6U (the peak dose for clinical effects) significantly elevated IL-7 (9.74, 95 % confidence interval [CI] 3.59 to 15.90, False discovery rate corrected P (PFDR) < 0.001), IL-9 (56.64, 20.46 to 92.82, PFDR < 0.001) and MIP-1b (18.27, 4.96 to 31.57, PFDR < 0.001) compared with placebo. Inverted U-shape dose-response relationships peaking at TTA-121 6U were consistently observed for all these cytokines (IL-7: P < 0.001; IL-9: P < 0.001; MIP-1b: P = 0.002). Increased IL-7 and IL-9 in participants with ASD after 4 weeks TTA-121 6U administration compared with placebo was verified in the confirmatory analyses in the dataset before crossover (PFDR < 0.001). Furthermore, the changes in all these cytokines during 4 weeks of TTA-121 10U administration revealed associations with changes in reciprocity score, the original primary outcome, observed during the same period (IL-7: Coefficient = -0.05, -0.10 to 0.003, P = 0.067; IL-9: -0.01, -0.02 to -0.003, P = 0.005; MIP-1b: -0.02, -0.04 to -0.007, P = 0.005). These findings provide the first evidence for a role of interaction between oxytocin and neuroinflammation in the change of ASD core social features, and support the potential role of this interaction as a novel therapeutic seed. Trial registration: UMIN000015264, NCT03466671/UMIN000031412.

Effect of a novel nasal oxytocin spray with enhanced bioavailability on autism: a randomized trial.

Although intranasal oxytocin is expected to be a novel therapy for the core symptoms of autism spectrum disorder, which has currently no approved medication, the efficacy of repeated administrations was inconsistent, suggesting that the optimal dose for a single administration of oxytocin is not optimal for repeated administration. The current double-blind, placebo-controlled, multicentre, crossover trial (ClinicalTrials.gov Identifier: NCT03466671) was aimed to test the effect of TTA-121, a new formulation of intranasal oxytocin spray with an enhanced bioavailability (3.6 times higher than Syntocinon® spray, as assessed by area under the concentration-time curve in rabbit brains), which enabled us to test a wide range of multiple doses, on autism spectrum disorder core symptoms and to determine the dose-response relationship. Four-week administrations of TTA-121, at low dose once per day (3 U/day), low dose twice per day (6 U/day), high dose once per day (10 U/day), or high dose twice per day (20 U/day), and 4-week placebo were administered in a crossover manner. The primary outcome was the mean difference in the reciprocity score (range: 0-14, higher values represent worse outcomes) on the Autism Diagnostic Observation Schedule between the baseline and end point of each administration period. This trial with two administration periods and eight groups was conducted at seven university hospitals in Japan, enrolling adult males with high-functioning autism spectrum disorder. Enrolment began from June 2018 and ended December 2019. Follow-up ended March 2020. Of 109 males with high-functioning autism spectrum disorder who were randomized, 103 completed the trial. The smallest P-value, judged as the dose-response relationship, was the contrast with the peak at TTA-121 6 U/day, with inverted U-shape for both the full analysis set (P = 0.182) and per protocol set (P = 0.073). The Autism Diagnostic Observation Schedule reciprocity score, the primary outcome, was reduced in the TTA-121 6 U/day administration period compared with the placebo (full analysis set: P = 0.118, mean difference = -0.5; 95% CI: -1.1 to 0.1; per protocol set: P = 0.012, mean difference = -0.8; 95% CI: -1.3 to -0.2). The per protocol set was the analysis target population, consisting of all full analysis set participants except those who deviated from the protocol. Most dropouts from the full analysis set to the per protocol set occurred because of poor adherence to the test drug (9 of 12 in the first period and 8 of 15 in the second period). None of the secondary clinical and behavioural outcomes were significantly improved with the TTA-121 compared with the placebo in the full analysis set. A novel intranasal spray of oxytocin with enhanced bioavailability enabled us to test a wide range of multiple doses, revealing an inverted U-shape dose-response curve, with the peak at a dose that was lower than expected from previous studies. The efficacy of TTA-121 shown in the current exploratory study should be verified in a future large-scale, parallel-group trial.

Seeing motion of controlled object improves grip timing in adults with autism spectrum condition: evidence for use of inverse dynamics in motor control.

Previous studies (Haswell et al. in Nat Neurosci 12:970-972, 2009; Marko et al. in Brain J Neurol 138:784-797, 2015) reported that people with autism rely less on vision for learning to reach in a force field. This suggested a possibility that they have difficulties in extracting force information from visual motion signals, a process called inverse dynamics computation. Our recent study (Takamuku et al. in J Int Soc Autism Res 11:1062-1075, 2018) examined the ability of inverse computation with two perceptual tasks and found similar performances in typical and autistic adults. However, this tested the computation only in the context of sensory perception while it was possible that the suspected disability is specific to the motor domain. Here, in order to address the concern, we tested the use of inverse dynamics computation in the context of motor control by measuring changes in grip timing caused by seeing/not seeing a controlled object. The motion of the object was informative of its inertial force and typical participants improved their grip timing based on the visual feedback. Our interest was on whether the autism participants show the same improvement. While some autism participants showed atypical hand slowing when seeing the controlled object, we found no evidence of abnormalities in the inverse computation in our grip timing task or in a replication of the perceptual task. This suggests that the ability of inverse dynamics computation is preserved not only for sensory perception but also for motor control in adults with autism.

Impact of sleep problems on daytime function in school life: a cross-sectional study involving Japanese university students.

BACKGROUND: The aims of this study were 1) to clarify the prevalence of sleep problems (insomnia, insufficient sleep, and delayed sleep-wake phase) among Japanese university students; 2) to examine sociodemographic characteristics, lifestyle, and sleep-related symptoms in each sleep problem; and 3) to evaluate the association between the above-mentioned sleep problems and daytime dysfunction in school life. METHODS: Self-report questionnaire surveys were conducted at eight universities in Japan, and we received 1034 valid answers (78% female). The questionnaire consisted of socio-demographic characteristics, information on lifestyle, sleep pattern, sleep-related symptoms, and daytime dysfunction in school life. Groups with insomnia, behaviorally induced insufficient sleep syndrome (BIISS), delayed sleep-wake phase (DSWP), and BIISS + DSWP were defined. To identify the association between sleep problems and daytime dysfunction in school life, the generalized linear mixed effect model was conducted. RESULTS: Sleep duration on weekdays was 5.9 ± 1.2 h, and 38.2% of the students had a sleep duration < 6.0 h. About 16% of the students were categorized as evening-type individuals. More than half of the students (56.1%) had excessive daytime sleepiness. Insomnia was associated with tardiness (aOR: 0.8, 95%CI: 0.7-0.9) and falling asleep during class (aOR: 1.6: 95%CI: 1.4-2.0). BIISS was associated with tardiness (aOR: 1.5, 95%CI: 1.1-2.2) and interference with academic achievement (aOR: 1.9, 95%CI: 1.3-2.6). DSWP and BIISS + DSWP were associated with absence (aOR: 3.4, 95%CI: 2.2-5.1 / aOR: 4.2, 95%CI: 3.2-5.6), tardiness (aOR: 2.7, 95%CI: 1.8-4.1 / aOR: 2.2, 95%CI: 1.6-2.8), falling asleep during class (aOR: 2.6, 95%CI: 1.4-4.8 / aOR: 7.6, 95%CI: 3.3-17.2), and interference with academic achievement (aOR: 2.6, 95%CI: 1.7-3.9 / aOR: 2.1, 95%CI: 1.6-2.8). CONCLUSIONS: Students with DSWP and BIISS + DSWP were significantly associated with daytime dysfunction in school life, i.e. absence, tardiness, falling asleep during class and interference with academic achievement. Students displaying BIISS + DSWP were considered to have a relatively more serious condition compared with those with only insomnia, DSWP, or BIISS. It is therefore of utmost importance that university students aim to prevent DSWP and BIISS which were associated with daytime function in school life.

An fMRI study of reduced perceptual load-dependent modulation of task-irrelevant activity in adults with autism spectrum conditions.

Recent studies on selective attention have demonstrated that the perceptual load of a task determines the processing stage at which irrelevant sensory stimuli are filtered out. Although individuals with autism spectrum conditions (ASC) have been repeatedly reported to display several kinds of abnormal behavior related to attention deficits, the neural mechanisms underlying these deficits have not been well investigated within the framework of the load dependency of selective attention. The present study used functional magnetic resonance imaging (fMRI) to examine the brain responses of adults with high-functioning ASC to irrelevant visual distractors while performing a visual target detection task under high or low perceptual load. We observed that the increased perceptual load activated regions of the fronto-parietal attention network of controls and ASC comparably. On the other hand, the visual cortex activity evoked by visual distractors was less modulated by the increased perceptual load in ASC than in controls. Simple regression analyses showed that the degree of the modulation was significantly correlated with the severity of the autistic symptoms. We also observed reduced load-dependent modulation of the functional connectivity between the intraparietal and visual regions in the ASC group. These results revealed neural correlates for abnormal perceptual load-dependent engagement of visual attention in ASC, which may underlie aspects of cognitive and behavioral characteristics of these disorders.

Transdiagnostic and sex differences in cognitive profiles of autism spectrum disorder and attention-deficit/hyperactivity disorder.

An increasing number of studies have shown that autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) share symptoms and aetiologies. However, transdiagnostic comparisons between ASD and ADHD is complicated due to the sex differences within each condition. To clarify the similarities and differences in the cognitive functioning between ASD and ADHD, while considering potential sex differences, this study compared cognitive profiles assessed by the WAIS-III between the four groups created by orthogonally combining diagnosis and sex based on the data from 277 ASD males, 86 ASD females, 99 ADHD males and 64 ADHD females. The analysis revealed three major findings. First, performance IQ and perceptual organization index were higher in ADHD males than in ASD males and ADHD females. Second, Gaussian mixture model fitting revealed two clusters underlying the distribution of subindex scores. The percentage of being classified into the cluster that scored lower in all the subindices was higher in females than in males irrespective of diagnosis. Third, feature importance for classification of ASD and ADHD yielded by random forest classifier, a supervised machine learning algorithm, revealed that autism quotient was most informative feature in classifying ASD and ADHD in males, while the discrepancy between verbal and performance intelligence quotient was in females, indicating that the set of behavioral features contributing to classification differs between males and females. Thus, these findings indicate that sex as well as diagnosis is critical in determining the cognitive profiles of people with ASD and ADHD. LAY SUMMARY: The present study compared profiles of cognitive functions measured by Wechsler Adult Intelligence Scale between males and females with ASD and ADHD. The analyses revealed clear sex differences in cognitive functions in both ASD and ADHD and that the set of cognitive functions useful in classifying ASD and ADHD differed between males and females. Thus, biological sex seems to be a critical factor in determining the cognitive profiles of people with ASD and ADHD.

Automatic Classification of Adult Males With and Without Autism Spectrum Disorder by Non-contact Measurement of Autonomic Nervous System Activation.

People with autism spectrum disorder (ASD) exhibit atypicality in various domains of behavior. Previous psychophysiological studies have revealed an atypical pattern of autonomic nervous system (ANS) activation induced by psychosocial stimulation. Thus, it might be feasible to develop a novel assessment tool to evaluate the risk of ASD by measuring ANS activation in response to emotional stimulation. The present study investigated whether people with ASD could be automatically classified from neurotypical adults based solely on physiological data obtained by the recently introduced non-contact measurement of pulse wave. We video-recorded faces of adult males with and without ASD while watching emotion-inducing video clips. Features reflective of ANS activation were extracted from the temporal fluctuation of facial skin coloration and entered into a machine-learning algorithm. Though the performance was modest, the gradient boosting classifier succeeded in classifying people with and without ASD, which indicates that facial skin color fluctuation contains information useful for detecting people with ASD. Taking into consideration the fact that the current study recruited only high-functioning adults who have relatively mild symptoms and probably developed some compensatory strategies, ASD screening by non-contact measurement of pulse wave could be a promising assessment tool to evaluate ASD risk.

Lack of implicit visual perspective taking in adult males with autism spectrum disorders.

BACKGROUND: Some theorists have suggested that the ability of visual perspective-taking (VPT) constitutes a rudimentary process of social cognition, and as such, the ability of VPT in people with autism spectrum disorder (ASD) has been the focus of intensive research. AIM: The present study investigated whether adult males with ASD show signs of implicit VPT in first-level VPT tasks, in which participants were required to judge whether a target object can be seen from another's perspective, even when they are not explicitly required to take another's perspective. METHODS AND PROCEDURES: We examined whether the information from another's visual perspective interferes with visual processing from the participant's own perspective ("altercentric interference") using the reaction time as the main performance indicator in adult males with or without ASD. Eye movement patterns during VPT were analyzed for some participants. OUTCOMES AND RESULTS: The results revealed signs of altercentric interference in neurotypical adults, but not in adult males with ASD. CONCLUSIONS AND IMPLICATIONS: The results indicate the possibility that people with ASD may rely on a different strategy than neurotypical adults in completing a first-level VPT task.

White matter alterations in autism spectrum disorder and attention-deficit/hyperactivity disorder in relation to sensory profile.

BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) have high rates of co-occurrence and share atypical behavioral characteristics, including sensory symptoms. The present diffusion tensor imaging (DTI) study was conducted to examine whether and how white matter alterations are observed in adult populations with developmental disorders (DD) and to determine how brain-sensory relationships are either shared between or distinct to ASD and ADHD. METHODS: We collected DTI data from adult population with DD (a primary diagnosis of ASD: n = 105, ADHD: n = 55) as well as age- and sex-matched typically developing (TD) participants (n = 58). Voxel-wise fractional anisotropy (FA), mean diffusivity, axial diffusivity, and radial diffusivity (RD) were analyzed using tract-based spatial statistics. The severities of sensory symptoms were assessed using the Adolescent/Adult Sensory Profile (AASP). RESULTS: Categorical analyses identified voxel clusters showing significant effects of DD on FA and RD in the posterior portion of the corpus callosum and its extension in the right hemisphere. Furthermore, regression analyses using the AASP scores revealed that slopes in relationships of FA or RD with the degree of sensory symptoms were parallel between the two DDs in large parts of the affected corpus callosum regions. A small but significant cluster did exist showing difference in association between an AASP subscale score and RD across ASD and ADHD. LIMITATIONS: Wide age range of the participants may be oversimplified. CONCLUSIONS: These results indicate that white matter alteration and their relationships to sensory symptoms are largely shared between ASD and ADHD, with localized abnormalities showing significant between-diagnosis differences within DD.

Fourth finger dependence of high-functioning autism spectrum disorder in multi-digit force coordination.

A number of studies have reported that the digit ratio 2D:4D (length of the second finger divided by length of the fourth finger) is smaller (longer fourth digit) in autism spectrum disorder (ASD) than in typically developed (TD) controls. Because form and function are closely related in biological systems, we hypothesized that the 4D dominance occurs in not only finger morphology but also physical performance in ASD. Individuals with ASD and TD controls participated in a multi-digit force-producing task. Individuals with ASD showed a significant 4D dependence compared to TD controls in the task. We found a significant correlation between 4D dependence and scores of the standard diagnostic instrument across individuals with ASD. Our analysis of functional connectivity in resting-state functional MRI suggests that connectivity between the visual cortex and the cerebellum contributes to the 4D dependence. Collectively, these results extend the 2D:4D ratio beyond being a morphological marker to being involved in motor functions in the form of 4D dependence in a multi-digit force task.

Sunk Cost Effect in Individuals with Autism Spectrum Disorder.

The sunk cost effect, an interesting and well-known decision bias, is pervasive in real life and has been studied in various disciplines. In this study, we modified a task exemplifying the sunk cost effect and used it to evaluate this behavior in individuals with autism spectrum disorder (ASD). The control group exhibited a typical sunk cost effect in our task. We found that the sunk cost effect was lower in the ASD group than in the control group. The results agree with previous evidence of reduced sensitivity to context stimuli in individuals with ASD and extend this finding to the context of the sunk cost effect. Our findings are useful in addressing the practical implications on their socioeconomic behavior.

Inflexible daily behaviour is associated with the ability to control an automatic reaction in autism spectrum disorder.

Inflexible behaviours in people with autism spectrum disorder (ASD) broadly obstruct social communication. Meanwhile, flexibility implicates cognitive control to resolve socially conflicting situations; however, it remains unclear how people with ASD behave in the face of these conflicts in this respect. We used the ultimatum game (UG) and the implicit-association test (IAT) to examine goal-directed/economic flexibility, both of which involve conflict and cognitive control. In addition, we used the Detail and Flexibility Questionnaire (DFlex) to measure inflexible everyday behaviour with diminished cognitive control and attention shifting. We observed the decreased flexibility in participants with ASD (DFlex and IAT); further, their IAT scores positively correlated with DFlex. However, in the UG, contrary to our prediction, participants with ASD accepted unfair offers more frequently than TD. These results suggest that assessing the automatic/attention processing level with the IAT could be a useful approach to study behavioural flexibility among ASD compared with the UG, which might comprise multiple response strategies besides economic rationality. Overall, the severity of inflexible daily behaviours in people with ASD may be associated with a reduced flexible attitude at an automatic level, altered attention processing and decreased cognitive control.

Distinct contribution of IL-6, TNF-alpha, IL-1, and IL-10 to T cell-mediated spontaneous autoimmune arthritis in mice.

Cytokines play key roles in spontaneous CD4(+) T cell-mediated chronic autoimmune arthritis in SKG mice, a new model of rheumatoid arthritis. Genetic deficiency in IL-6 completely suppressed the development of arthritis in SKG mice, irrespective of the persistence of circulating rheumatoid factor. Either IL-1 or TNF-alpha deficiency retarded the onset of arthritis and substantially reduced its incidence and severity. IL-10 deficiency, on the other hand, exacerbated disease, whereas IL-4 or IFN-gamma deficiency did not alter the disease course. Synovial fluid of arthritic SKG mice contained high amounts of IL-6, TNF-alpha, and IL-1, in accord with active transcription of these cytokine genes in the afflicted joints. Notably, immunohistochemistry revealed that distinct subsets of synovial cells produced different cytokines in the inflamed synovium: the superficial synovial lining cells mainly produced IL-1 and TNF-alpha, whereas scattered subsynovial cells produced IL-6. Thus, IL-6, IL-1, TNF-alpha, and IL-10 play distinct roles in the development of SKG arthritis; arthritogenic CD4(+) T cells are not required to skew to either Th1 or Th2; and the appearance of rheumatoid factor is independent of joint inflammation. The results also indicate that targeting not only each cytokine but also each cell population secreting distinct cytokines could be an effective treatment of rheumatoid arthritis.

Cognitive profiles of adults with high-functioning autism spectrum disorder and those with attention-deficit/hyperactivity disorder based on the WAIS-III.

The cognitive profile differences between adult patients with autism spectrum disorder (ASD) and those with attention-deficit/hyperactivity disorder (ADHD) are not well characterized. We examined the cognitive profiles of adults having either ASD (n=120) or ADHD (n=76) with no intellectual disabilities (IQ≥70) using the Wechsler Intelligence Scale III (WAIS-III). Verbal Intelligence (VIQ) - Performance Intelligence (PIQ) difference discrepancies were detected between the two groups. Information subtest scores of the Verbal Comprehension index and Arithmetic and Digit Span subtests of the Freedom from Distractibility index were significantly higher in ASD than in ADHD, while the Picture Completion subtest was significantly lower in ASD. To our knowledge, this is the first study to evaluate the difference in the cognitive profiles of adults with ASD and those with ADHD based on the WAIS III with a large number of participants.

Altered effects of perspective-taking on functional connectivity during self- and other-referential processing in adults with autism spectrum disorder.

In interactive social situations, it is often crucial to be able to take another person's perspective when evaluating one's own or another person's specific trait; individuals with autism spectrum disorder (ASD) critically lack this social skill. To examine how perspective-dependent self- and other-evaluation processes modulate functional connectivity in ASD, we conducted a functional magnetic resonance imaging study in which 26 high-functioning adults with ASD and 24 typically developed (TD) controls were asked to decide whether an adjective describing a personality trait correctly described the participant himself/herself ("self") or the participant's mother ("other") by taking either the first (1P) or third person (3P) perspective. We observed that functional connectivity between the left sensorimotor cortex and the left middle cingulate cortex was enhanced in TD control individuals taking the 3P perspective, this enhancement was significantly reduced in ASD, and the degree of reduction was significantly correlated with the severity of autistic traits. Furthermore, the self-reference effect on functional connectivity between the left inferior frontal cortex and frontopolar cortices was significantly enhanced in TD control individuals taking the 3P perspective, whereas such effect was reversed in ASD. These findings indicate altered effects of perspective on the functional connectivity, which may underlie the deficits in social interaction and communication observed in individuals with ASD.

Attitudes toward risk and ambiguity in patients with autism spectrum disorder.

Although the ability to make optimal decisions under uncertainty is an integral part of everyday life, individuals with autism spectrum disorder (ASD) frequently report that they experience difficulties with this skill. In behavioral economics, researchers distinguish two types of uncertainty to understand decision-making in this setting: risk (known probabilities) and ambiguity (unknown probabilities). However, it remains unclear how individuals with ASD behave under risk and ambiguity, despite growing evidence of their altered decision-making under uncertainty. We therefore extended previous research by studying the attitudes of those with ASD toward risk and ambiguity in both positive and negative contexts (i.e., gain and loss). In gain contexts, no significant difference was observed between the groups in risk attitudes, but ambiguity aversion was attenuated in ASD. In loss contexts, ambiguity attitudes did not significantly differ between the groups, but the ASD participants were less risk-seeking compared with the controls. In addition, insensitivity to the context change under risk and ambiguity in ASD was both significantly associated with poor social skills. These results improve our understanding of altered decision-making under uncertainty by disentangling the attitudes toward risk and ambiguity in ASD individuals. Applying behavioral economic tools may provide insights into the mechanisms underlying behavioral disturbances in ASD.

Ocular Fixation Abnormality in Patients with Autism Spectrum Disorder.

We examined the factors that influence ocular fixation control in adults with autism spectrum disorder (ASD) including sensory information, individuals' motor characteristics, and inhibitory control. The ASD group showed difficulty in maintaining fixation especially when there was no fixation target. The fixational eye movement characteristics of individuals were consistent regardless of the presence or absence of a fixation target in the controls, but not in the ASD group. Additionally, fixation stability did not correlate with an ability to suppress reflexive saccades measured by an antisaccade task. These findings suggest that ASD adults have deficits in converting alternative sensory information, such as retinal signals in the peripheral visual field or extraretinal signals, to motor commands when the foveal information is unavailable.

Altered functional organization within the insular cortex in adult males with high-functioning autism spectrum disorder: evidence from connectivity-based parcellation.

BACKGROUND: The insular cortex comprises multiple functionally differentiated sub-regions, each of which has different patterns of connectivity with other brain regions. Such diverse connectivity patterns are thought to underlie a wide range of insular functions, including cognitive, affective, and sensorimotor processing, many of which are abnormal in autism spectrum disorder (ASD). Although past neuroimaging studies of ASD have shown structural and functional abnormalities in the insula, possible alterations in the sub-regional organization of the insula and the functional characteristics of each sub-region have not been examined in the ASD brain. METHODS: Resting-state functional magnetic resonance imaging (rs-fMRI) data were acquired from 36 adult males with ASD and 38 matched typically developed (TD) controls. A data-driven clustering analysis was applied to rs-fMRI data of voxels in the left and right insula to automatically group voxels with similar intrinsic connectivity pattern into a cluster. After determining the optimal number of clusters based on information theoretic measures of variation of information and mutual information, functional parcellation patterns in both the left and the right insula were compared between the TD and ASD groups. Furthermore, functional profiles of each sub-region were meta-analytically decoded using Neurosynth and were compared between the groups. RESULTS: We observed notable alterations in the anterior sector of the left insula and the middle ventral sub-region of the right insula in the ASD brain. Meta-analytic decoding revealed that whereas the anterior sector of the left insula contained two functionally differentiated sub-regions for cognitive, sensorimotor, and emotional/affective functions in TD brain, only a single functional cluster for cognitive and sensorimotor functions was identified in the anterior sector in the ASD brain. In the right insula, the middle ventral sub-region, which is primarily specialized for sensory- and auditory-related functions, showed a significant volumetric increase in the ASD brain compared with the TD brain. CONCLUSIONS: The results indicate an altered organization of sub-regions in specific parts of the left and right insula of the ASD brain. The alterations in the left and right insula may constitute neural substrates underlying abnormalities in emotional/affective and sensory functions in ASD.

Alterations of local spontaneous brain activity and connectivity in adults with high-functioning autism spectrum disorder.

BACKGROUND: Previous autism research has hypothesized that abnormalities of functional connectivity in autism spectrum disorder (ASD) may vary with the spatial distance between two brain regions. Although several resting-state functional magnetic resonance imaging (rsfMRI) studies have extensively examined long-range (or distant) connectivity in the adult ASD brain, short-range (or local) connectivity has been investigated in less depth. Furthermore, the possible relationship between functional connectivity and brain activity level during the resting state remains unclear. METHODS: We acquired rsfMRI data from 50 adults with high-functioning ASD and 50 matched controls to examine the properties of spontaneous brain activity using measures of local and distant connectivity together with a measure of the amplitude of brain activity, known as fractional amplitude of low-frequency fluctuation (fALFF). The two connectivity measures were calculated using a common graph-theoretic framework. We also examined the spatial overlaps between these measures and possible relationships of these disrupted functional measures with autistic traits assessed by the Autism-Spectrum Quotient (AQ). RESULTS: Compared to the controls, participants with ASD exhibited local over-connectivity in the right superior frontal gyrus and middle frontal gyrus, accompanied by local under-connectivity in the bilateral fusiform gyri (FG) and right middle temporal gyrus (MTG). On the other hand, we did not find any significant alterations in distant connectivity. Participants with ASD also exhibited reduced fALFF in the right middle occipital gyrus, lingual gyrus, and FG. Further conjunction and spatial overlap analyses confirmed that the spatial pattern of reduced fALFF substantially overlapped with that of local under-connectivity, demonstrating the co-occurrence of disrupted connectivity and spontaneous activity level in the right inferior occipital gyrus, posterior MTG (pMTG), and FG. Finally, within the ASD group, disrupted local connectivity in the right pMTG significantly correlated with the "social interaction" subscale score of the AQ. CONCLUSIONS: These findings revealed local functional disruptions in the occipital and temporal regions, especially the right FG and pMTG, in the form of co-occurrence of spontaneous brain activity level and local connectivity, which may underline social and communicative dysfunctions in adult ASD.

Light and Electron Microscopic Studies on Fertilization of Pelmatohydra Robusta I. Sperm Entry to a Specialized Region of the Egg.

Fertilization of a fresh water polyp, Pelmatohydra robusta, was studied by light and electron microscopy. A small depression was observed in the animal pole of the unfertilized egg. The egg pronucleus was always situated in close contact with the bottom of the depression. Microvilli which were covered with an egg coat consisting of filamentous components were observed on the egg surface. Microvilli and the egg coat were not detected on the surface of the depression. Sperm were associated with the egg plasma membrane and entered the egg only at the bottom of the depression. Excess sperm aggregated around the depression of inseminated eggs. After fertilization, the egg made a protrusion in the region where the egg pronucleus and sperm were in close contact with each other. A new egg coat was formed on the entire surface of the fertilized egg. The restriction of sperm-egg interactions to a specialized region of the hydra egg is discussed in connection with the micropyle of Pisces eggs and the animal dimple of Discoglossus (Anura) eggs.