Increased glutamate and glutamine levels and their relationship to astrocytes and dopaminergic transmissions in the brains of adults with autism.

Increased excitatory neuronal tones have been implicated in autism, but its mechanism remains elusive. The amplified glutamate signals may arise from enhanced glutamatergic circuits, which can be affected by astrocyte activation and suppressive signaling of dopamine neurotransmission. We tested this hypothesis using magnetic resonance spectroscopy and positron emission tomography scan with 11C-SCH23390 for dopamine D1 receptors in the anterior cingulate cortex (ACC). We enrolled 18 male adults with high-functioning autism and 20 typically developed (TD) male subjects. The autism group showed elevated glutamate, glutamine, and myo-inositol (mI) levels compared with the TD group (p = 0.045, p = 0.044, p = 0.030, respectively) and a positive correlation between glutamine and mI levels in the ACC (r = 0.54, p = 0.020). In autism and TD groups, ACC D1 receptor radioligand binding was negatively correlated with ACC glutamine levels (r = - 0.55, p = 0.022; r = - 0.58, p = 0.008, respectively). The enhanced glutamate-glutamine metabolism might be due to astroglial activation and the consequent reinforcement of glutamine synthesis in autistic brains. Glutamine synthesis could underly the physiological inhibitory control of dopaminergic D1 receptor signals. Our findings suggest a high neuron excitation-inhibition ratio with astrocytic activation in the etiology of autism.

Neural correlates of perceptual switching and their association with empathy and alexithymia in individuals with and without autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) often show limited empathy (poor recognition of others' emotions) and high alexithymia (poor recognition of own emotions and external thinking), which can negatively impact their social functioning. Previous experimental studies suggest that alterations in cognitive flexibility play key roles in the development of these characteristics in ASD. However, the underlying neural mechanisms that link cognitive flexibility and empathy/alexithymia are still largely unknown. In this study, we examined the neural correlates of cognitive flexibility via functional magnetic resonance imaging during perceptual task-switching in typical development (TD) adults and adults with ASD. We also investigated associations between regional neural activity and psychometric empathy and alexithymia scores among these populations. In the TD group, stronger activation of the left middle frontal gyrus was associated with better perceptual switching and greater empathic concern. Among individuals with ASD, stronger activation of the left inferior frontal gyrus was associated with better perceptual switching, greater empathy, and lower alexithymia. These findings will contribute to develop a better understanding of social cognition, and could be informative for the development of new ASD therapies.

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study.

Autism spectrum disorder (ASD) is a lifelong condition, and its underlying biological mechanisms remain elusive. The complexity of various factors, including inter-site and development-related differences, makes it challenging to develop generalizable neuroimaging-based biomarkers for ASD. This study used a large-scale, multi-site dataset of 730 Japanese adults to develop a generalizable neuromarker for ASD across independent sites and different developmental stages. Our adult ASD neuromarker achieved successful generalization for the US and Belgium adults and Japanese adults. The neuromarker demonstrated significant generalization for children and adolescents. We identified 141 functional connections (FCs) important for discriminating individuals with ASD from TDCs. Finally, we mapped schizophrenia (SCZ) and major depressive disorder (MDD) onto the biological axis defined by the neuromarker and explored the biological continuity of ASD with SCZ and MDD. We observed that SCZ, but not MDD, was located proximate to ASD on the biological dimension defined by the ASD neuromarker. The successful generalization in multifarious datasets and the observed relations of ASD with SCZ on the biological dimensions provide new insights for a deeper understanding of ASD.

Generalizable neuromarker for autism spectrum disorder across imaging sites and developmental stages: A multi-site study.

Autism spectrum disorder (ASD) is a lifelong condition, and its underlying biological mechanisms remain elusive. The complexity of various factors, including inter-site and development-related differences, makes it challenging to develop generalizable neuroimaging-based biomarkers for ASD. This study used a large-scale, multi-site dataset of 730 Japanese adults to develop a generalizable neuromarker for ASD across independent sites (U.S., Belgium, and Japan) and different developmental stages (children and adolescents). Our adult ASD neuromarker achieved successful generalization for the US and Belgium adults (area under the curve [AUC] = 0.70) and Japanese adults (AUC = 0.81). The neuromarker demonstrated significant generalization for children (AUC = 0.66) and adolescents (AUC = 0.71; all P<0.05, family-wise-error corrected). We identified 141 functional connections (FCs) important for discriminating individuals with ASD from TDCs. These FCs largely centered on social brain regions such as the amygdala, hippocampus, dorsomedial and ventromedial prefrontal cortices, and temporal cortices. Finally, we mapped schizophrenia (SCZ) and major depressive disorder (MDD) onto the biological axis defined by the neuromarker and explored the biological continuity of ASD with SCZ and MDD. We observed that SCZ, but not MDD, was located proximate to ASD on the biological dimension defined by the ASD neuromarker. The successful generalization in multifarious datasets and the observed relations of ASD with SCZ on the biological dimensions provide new insights for a deeper understanding of ASD.

Distinctive alterations in the mesocorticolimbic circuits in various psychiatric disorders.

AIM: Increasing evidence suggests that psychiatric disorders are linked to alterations in the mesocorticolimbic dopamine-related circuits. However, the common and disease-specific alterations remain to be examined in schizophrenia (SCZ), major depressive disorder (MDD), and autism spectrum disorder (ASD). Thus, this study aimed to examine common and disease-specific features related to mesocorticolimbic circuits. METHODS: This study included 555 participants from four institutes with five scanners: 140 individuals with SCZ (45.0% female), 127 individuals with MDD (44.9%), 119 individuals with ASD (15.1%), and 169 healthy controls (HC) (34.9%). All participants underwent resting-state functional magnetic resonance imaging. A parametric empirical Bayes approach was adopted to compare estimated effective connectivity among groups. Intrinsic effective connectivity focusing on the mesocorticolimbic dopamine-related circuits including the ventral tegmental area (VTA), shell and core parts of the nucleus accumbens (NAc), and medial prefrontal cortex (mPFC) were examined using a dynamic causal modeling analysis across these psychiatric disorders. RESULTS: The excitatory shell-to-core connectivity was greater in all patients than in the HC group. The inhibitory shell-to-VTA and shell-to-mPFC connectivities were greater in the ASD group than in the HC, MDD, and SCZ groups. Furthermore, the VTA-to-core and VTA-to-shell connectivities were excitatory in the ASD group, while those connections were inhibitory in the HC, MDD, and SCZ groups. CONCLUSION: Impaired signaling in the mesocorticolimbic dopamine-related circuits could be an underlying neuropathogenesis of various psychiatric disorders. These findings will improve the understanding of unique neural alternations of each disorder and will facilitate identification of effective therapeutic targets.

Intergroup bias in punishing behaviors of adults with autism spectrum disorder.

Groups are essential elements of society, and humans, by nature, commonly manifest intergroup bias (i.e., behave more positively toward an ingroup member than toward an outgroup member). Despite the growing evidence of various types of altered decision-making in individuals with autism spectrum disorder (ASD), their behavior under the situation involving group membership remains largely unexplored. By modifying a third-party punishment paradigm, we investigated intergroup bias in individuals with ASD and typical development (TD). In our experiment, participants who were considered as the third party observed a dictator game wherein proposers could decide how to distribute a provided amount of money while receivers could only accept unconditionally. Participants were confronted with two different group situations: the proposer was an ingroup member and the recipient was an outgroup member (IN/OUT condition) or the proposer was an outgroup member and the recipient was an ingroup member (OUT/IN condition). Participants with TD punished proposers more severely when violating social norms in the OUT/IN condition than in IN/OUT condition, indicating that their decisions were influenced by the intergroup context. This intergroup bias was attenuated in individuals with ASD. Our findings deepen the understanding of altered decision-making and socioeconomic behaviors in individuals with ASD.

Depression induced by low-frequency repetitive transcranial magnetic stimulation to ventral medial frontal cortex in monkeys.

The medial frontal cortex (MFC), especially its ventral part, has long been of great interest with respect to the pathology of mood disorders. A number of human brain imaging studies have demonstrated the abnormalities of this brain region in patients with mood disorders, however, whether it is critically and causally involved in the pathogenesis of such disorders remains to be fully elucidated. In this study, we examined how the suppression of neural activity in the ventral region of the MFC (vMFC) affects the behavioral and physiological states of monkeys by using repetitive transcranial magnetic stimulation (rTMS). By using low-frequency rTMS (LF-rTMS) as an inhibitory intervention, we found that LF-rTMS targeting the vMFC temporarily induced a depression-like state in monkeys, which was characterized by a reduced movement activity level, impaired sociability, and decreased motivation level, as well as increased plasma cortisol level. On the other hand, no such significant changes in behavioral and physiological states were observed when targeting the other MFC regions, dorsal or posterior. We further found that the administration of an antidepressant agent, ketamine, ameliorated the abnormal behavioral and physiological states induced by the LF-rTMS intervention. These findings causally indicate the involvement of the vMFC in the regulation of mood and the validity of the LF-rTMS-induced dysfunction of the vMFC as a nonhuman primate model of depression.

Decision flexibilities in autism spectrum disorder: an fMRI study of moral dilemmas.

People make flexible decisions across a wide range of contexts to resolve social or moral conflicts. Individuals with autism spectrum disorder (ASD) frequently report difficulties in such behaviors, which hinders the flexibility in changing strategies during daily activities or adjustment of perspective during communication. However, the underlying mechanisms of this issue are insufficiently understood. This study aimed to investigate decision flexibility in ASD using a functional magnetic resonance imaging task that involved recognizing and resolving two types of moral dilemmas: cost-benefit analysis (CBA) and mitigating inevitable misconducts (MIM). The CBA session assessed the participants' pitting of result-oriented outcomes against distressful harmful actions, whereas the MIM session assessed their pitting of the extenuation of a criminal sentence against a sympathetic situation of defendants suffering from violence or disease. The behavioral outcome in CBA-related flexibility was significantly lower in the ASD group compared to that of the typical development group. In the corresponding CBA contrast, activation in the left inferior frontal gyrus was lower in the ASD group. Meanwhile, in the MIM-related flexibility, there were no significant group differences in behavioral outcome or brain activity. Our findings add to our understanding of flexible decision-making in ASD.

Local and Transient Changes of Sleep Spindle Density During Series of Prefrontal Repetitive Transcranial Magnetic Stimulation in Patients With a Major Depressive Episode.

The neuromodulatory effects of brain stimulation therapies notably involving repetitive transcranial magnetic stimulation (rTMS) on nocturnal sleep, which is critically disturbed in major depression and other neuropsychiatric disorders, remain largely undetermined. We have previously reported in major depression patients that prefrontal rTMS sessions enhanced their slow wave activity (SWA) power, but not their sigma power which is related to sleep spindle activity, for electrodes located nearby the stimulation site. In the present study, we focused on measuring the spindle density to investigate cumulative effects of prefrontal rTMS sessions on the sleep spindle activity. Fourteen male inpatients diagnosed with medication-resistant unipolar or bipolar depression were recruited and subjected to 10 daily rTMS sessions targeting the left dorsolateral prefrontal cortex (DLPFC). All-night polysomnography (PSG) data was acquired at four time points: Adaptation, Baseline, Post-1 (follow-up after the fifth rTMS session), and Post-2 (follow-up after the tenth rTMS session). Clinical and cognitive evaluations were longitudinally performed at Baseline, Post-1, and Post-2 time points to explore associations with the spindle density changes. The PSG data from 12 of 14 patients was analyzed to identify sleep spindles across the sleep stages II-IV at four electrode sites: F3 (frontal spindle near the stimulation site), F4 (contralateral homologous frontal region), P3 (parietal spindle in the hemisphere ipsilateral to the stimulation site), and P4 (contralateral parietal region). Statistical analysis by two-way ANOVA revealed that spindle density at F3 increased at Post-1 but decreased at Post-2 time points. Moreover, the local and transient increase of spindle density at F3 was associated with the previously reported SWA power increase at F3, possibly reflecting a shared mechanism of thalamocortical synchronization locally enhanced by diurnal prefrontal rTMS sessions. Clinical and cognitive correlations were not observed in this dataset. These findings suggest that diurnal rTMS sessions transiently modulate nocturnal sleep spindle activity at the stimulation site, although clinical and cognitive effects of the local changes warrant further investigation.

Neural correlates of shared sensory symptoms in autism and attention-deficit/hyperactivity disorder.

Symptoms of autism spectrum disorder and attention-deficit/hyperactivity disorder often co-occur. Among these, sensory impairment, which is a core diagnostic feature of autism spectrum disorder, is often observed in children with attention-deficit/hyperactivity disorder. However, the underlying mechanisms of symptoms that are shared across disorders remain unknown. To examine the neural correlates of sensory symptoms that are associated with autism spectrum disorder and attention-deficit/hyperactivity disorder, we analysed resting-state functional MRI data obtained from 113 people with either autism spectrum disorder or attention-deficit/hyperactivity disorder (n = 78 autism spectrum disorder, mean age = 29.5; n = 35 attention-deficit/hyperactivity disorder, mean age = 31.2) and 96 neurotypical controls (mean age = 30.6, range: 20-55 years) using a cross-sectional study design. First, we used a multi-dimensional approach to examine intrinsic brain functional connectivity related to sensory symptoms in four domains (i.e. low registration, sensation seeking, sensory sensitivity and sensation avoidance), after controlling for age, handedness and head motion. Then, we used a partial least squares correlation to examine the link between sensory symptoms related to intrinsic brain functional connectivity and neurodevelopmental symptoms measured using the Autism Spectrum Quotient and Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale, regardless of diagnosis. To test whether observed associations were specific to sensory symptoms related to intrinsic brain functional connectivity, we conducted a control analysis using a bootstrap framework. The results indicated that transdiagnostic yet distinct intrinsic brain functional connectivity neural bases varied according to the domain of the examined sensory symptom. Partial least squares correlation analysis revealed two latent components (latent component 1: q < 0.001 and latent component 2: q < 0.001). For latent component 1, a set of intrinsic brain functional connectivity was predominantly associated with neurodevelopmental symptom-related composite score (r = 0.64, P < 0.001), which was significantly correlated with Conners' Adult Attention-Deficit/Hyperactivity Disorder Rating Scale total T scores (r = -0.99, q < 0.001). For latent component 2, another set of intrinsic brain functional connectivity was positively associated with neurodevelopmental symptom-related composite score (r = 0.58, P < 0.001), which was eventually positively associated with Autism Spectrum Quotient total scores (r = 0.92, q < 0.001). The bootstrap analysis showed that the relationship between intrinsic brain functional connectivity and neurodevelopmental symptoms was relative to sensory symptom-related intrinsic brain functional connectivity (latent component 1: P = 0.003 and latent component 2: P < 0.001). The current results suggest that sensory symptoms in individuals with autism spectrum disorder and those with attention-deficit/hyperactivity disorder have shared neural correlates. The neural correlates of the sensory symptoms were associated with the severity of both autism spectrum disorder and attention-deficit/hyperactivity disorder symptoms, regardless of diagnosis.

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.

Binding of Dopamine D1 Receptor and Noradrenaline Transporter in Individuals with Autism Spectrum Disorder: A PET Study.

Although previous studies have suggested the involvement of dopamine (DA) and noradrenaline (NA) neurotransmissions in the autism spectrum disorder (ASD) pathophysiology, few studies have examined these neurotransmissions in individuals with ASD in vivo. Here, we investigated DA D1 receptor (D1R) and noradrenaline transporter (NAT) binding in adults with ASD (n = 18) and neurotypical controls (n = 20) by utilizing two different PET radioligands, [11C]SCH23390 and (S,S)-[18F]FMeNER-D2, respectively. We found no significant group differences in DA D1R (striatum, anterior cingulate cortex, and temporal cortex) or NAT (thalamus and pons) binding. However, in the ASD group, there were significant negative correlations between DA D1R binding (striatum, anterior cingulate cortex and temporal cortex) and the "attention to detail" subscale score of the Autism Spectrum Quotient. Further, there was a significant positive correlation between DA D1R binding (temporal cortex) and emotion perception ability assessed by the neurocognitive battery. Associations of NAT binding with empathic abilities and executive function were found in controls, but were absent in the ASD group. Although a lack of significant group differences in binding might be partly due to the heterogeneity of ASD, our results indicate that central DA and NA function might play certain roles in the clinical characteristics of ASD.

Transdiagnostic subtyping of males with developmental disorders using cortical characteristics.

BACKGROUND: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are biologically heterogeneous and often co-occur. As within-diagnosis heterogeneity and overlapping diagnoses are challenging for researchers and clinicians, identifying biologically homogenous subgroups, independent of diagnosis, is an urgent need. METHODS: MRI data from 148 adult males with developmental disorders (99 primary ASD, mean age = 31.7 ± 8.0, 49 primary ADHD; mean age = 31.7 ± 9.6) and 105 neurotypical controls (NTC; mean age = 30.6 ± 6.8) were analyzed. We extracted mean cortical thickness (CT) and surface area (SA) values using a functional atlas. Then, we conducted HeterogeneitY through DiscRiminant Analysis (HYDRA) to transdiagnostically cluster and classify individuals. Differences in diagnostic likelihood and clinical symptoms between subtypes were tested. Sensitivity analyses tested the stability of the number of subtypes and their membership by excluding 13 participants diagnosed with both ASD and ADHD and by using a different atlas. RESULTS: In relation to both CT and SA, HYDRA identified two subtypes. The likelihood of ASD or ADHD was not significantly different from the chance of belonging to any of these two subtypes. Clinical characteristics did not differ between subtypes in either CT or SA based analyses. The high consistency in membership was replicated when utilizing a different atlas or excluding people with dual diagnoses in CT (dice coefficients > 0.94) and in SA (>0.88). CONCLUSION: Although the brain-derived subtypes do not match diagnostic groups, individuals with developmental disorders were successfully and stably subtyped using either CT or SA.

Orbitofrontal Sulcogyral Pattern as a Transdiagnostic Trait Marker of Early Neurodevelopment in the Social Brain.

Objective. To systematically assess previous findings on the orbitofrontal sulcogyral pattern in psychiatric disorders and to address the utility of this pattern as a transdiagnostic trait marker of early neurodevelopment in the social brain. Methods. An online literature search was conducted using the PubMed database from inception to August 2019. Studies included in this review were based on the Chiavaras's original classification method of this H-shaped sulcus (type I, II, and III), intermediate orbital sulcus (IOS), and posterior orbital sulcus (POS). Results. Twenty-six studies were included in the review. Sixteen studies (62%) focused on schizophrenia spectrum (Sz) disorders, and the remaining studies focused on autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), history of extremely preterm and extremely low birth weight, bipolar disorder (BD), panic disorder, obsessive-compulsive disorder, cannabis users, and pathological gambling. In Sz, compared with healthy controls, the orbitofrontal sulcogyral pattern was decreased in type I, increased in type II and III, and there were fewer numbers of IOS and POS reported, although specificity in sex and hemispheric dominance was not consistent. BD and neurodevelopmental disorders in ASD and ADHD showed a similar pattern of alteration to that observed in the Sz. Conclusions. The present review of the orbitofrontal sulcogyral pattern indicated that type I expression might reflect a neurodevelopmental protective marker, and type II and III expressions, as well as fewer numbers of IOS and POS, might reflect neurodevelopmental risk markers. These trait markers may be transdiagnostic among socially disabling diseases.

Impact of past experiences on decision-making in autism spectrum disorder.

People are often influenced by past costs in their current decision-making, thus succumbing to a well-known bias recognized as the sunk cost effect. A recent study showed that the sunk cost effect is attenuated in individuals with autism spectrum disorder (ASD). However, the study only addressed one situation of utilization decision by focusing on the choice between similar attractive alternatives with different levels of sunk costs. Thus, it remains unclear how individuals with ASD behave under sunk costs in different types of decision situations, particularly progress decisions, in which the decision-maker allocates additional resources to an initially chosen alternative. The sunk cost effect in progress decisions was estimated using an economic task designed to assess the effect of the past investments on current decision-making. Twenty-four individuals with ASD and 21 age-, sex-, smoking status-, education-, and intelligence quotient-level-matched typical development (TD) subjects were evaluated. The TD participants were more willing to make the second incremental investment if a previous investment was made, indicating that their decisions were influenced by sunk costs. However, unlike the TD group, the rates of investments were not significantly increased after prior investments in the ASD group. The results agree with the previous evidence of a reduced sensitivity to context stimuli in individuals with ASD and help us obtain a broader picture of the impact of sunk costs on their decision-making. Our findings will contribute to a better understanding of ASD and may be useful in addressing practical implications of their socioeconomic behavior.

Role of the right temporoparietal junction in intergroup bias in trust decisions.

Intergroup bias, which is the tendency to behave more positively toward an in-group member than toward an out-group member, is pervasive in real life. In particular, intergroup bias in trust decisions substantially influences multiple areas of life and thus better understanding of this tendency can provide significant insights into human social behavior. Although previous functional magnetic resonance imaging studies showed the involvement of the right temporoparietal junction (TPJ) in intergroup trust bias, a causal relationship between the two has rarely been explored. By combining repetitive transcranial magnetic stimulation and a newly developed trust game task, we investigated the causal role of the right TPJ in intergroup bias in trust decisions. In the trust game task, the counterpart's group membership (in-group or out-group) and reciprocity were manipulated. We applied either neuronavigated inhibitory continuous theta burst stimulation (cTBS) or sham stimulation over the right TPJ before performing the trust game task in healthy volunteers. After the sham stimulation, the participants' degrees of investments with in-group members were significantly higher than those with out-group members. However, after cTBS to the right TPJ, this difference was not observed. The current results extend previous findings by showing that the causal roles of the right TPJ can be observed in intergroup bias in trust decisions. Our findings add to our understanding of the mechanisms of human social behavior.

Egocentric biases and atypical generosity in autistic individuals.

Individuals with autism spectrum conditions (ASCs) often experience difficulty and confusion in acknowledging others' perspectives and arguably exhibit egocentricity. However, whether this egocentricity necessarily results in selfish behavior during social situations remains a matter of debate. To study this relationship, we used computerized visuospatial perspective-taking task (VPT) and social-discounting task (SDT), derived from cognitive psychology and behavioral economics, and examined egocentric and other-oriented judgments in participants with ASCs (mean age 29.0 ± 4.2 years) and a group of matched typically developing (TD) controls (30.8 ± 8.5). The response time in VPT showed altered perspective-taking in the ASCs group compared with the TD group that involved in enhanced self-other intrusion and condition-insensitive response. Regardless of self/other perspective judgments, responses were relatively slower and consistent in duration in the ASCs group compared with the TD group. Social discounting was attenuated rather than steep discounting in the ASCs group. Their discounting was comparatively more consistent, irrespective of the task condition (i.e., self-other closeness-level). In effect, ASCs group exhibited more generous decisions than the TD group in this task. Finally, those with more egocentric perspective intrusion in VPT paradoxically showed more generous behaviors in SDT in the ASCs group. Our findings suggest that having ASCs does not always exhibit selfish behavior during interpersonal communication. Reduced flexibility in distinguishing self/other perspective and shifting decision-rules might account for this unique relationship between egocentricity and apparently generous behaviors. These results extend the recent suggestion that more careful attention should be paid to the idea of egocentricity in individuals with ASCs. Autism Res 2019. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: We aimed to examine whether seeing the world from another person's point of view and being generous toward other people are related in autistic and nonautistic people. We used a visual perspective-taking task and a social task in which individuals made decisions about how to divide a sum of money with others. Our results suggest that being autistic does not always make someone bad at seeing the world from another's viewpoint, and that autistic people may make fairer social decisions toward unfamiliar people because of lower bias.

Cortical surface architecture endophenotype and correlates of clinical diagnosis of autism spectrum disorder.

AIM: Prior structural magnetic resonance imaging studies demonstrated atypical gray matter characteristics in siblings of individuals with autism spectrum disorder (ASD). However, they did not clarify which aspect of gray matter is related to the endophenotype (i.e., genetic vulnerability) of ASD. Further, because they did not enroll siblings of typically developing (TD) people, they may have underestimated the difference between individuals with ASD and their unaffected siblings. The current study aimed to address these gaps. METHODS: We recruited 30 pairs of adult male siblings (15 pairs with an ASD endophenotype and 15 pairs without) and focused on four gray matter parameters: cortical volume and three surface-based parameters (cortical thickness, fractal dimension, and sulcal depth [SD]). First, we sought to identify a pattern of an ASD endophenotype, comparing the four parameters. Then, we compared individuals with ASD and their unaffected siblings in the cortical parameters to identify neural correlates for the clinical diagnosis accounting for the difference between TD siblings. RESULTS: A sparse logistic regression with a leave-one-pair-out cross-validation showed the SD as having the highest accuracy for the identification of an ASD endophenotype (73.3%) compared with the other three parameters. A bootstrapping analysis accounting for the difference in the SD between TD siblings showed a significantly large difference between individuals with ASD and their unaffected siblings in six out of 68 regions of interest. CONCLUSION: This proof-of-concept study suggests that an ASD endophenotype emerges in the SD and that neural bases for ASD diagnosis can be discerned from the endophenotype when accounting for the difference between TD siblings.

Machine learning approach to identify a resting-state functional connectivity pattern serving as an endophenotype of autism spectrum disorder.

Endophenotype refers to a measurable and heritable component between genetics and diagnosis, and the same endophenotype is present in both individuals with a diagnosis and their unaffected siblings. Determination of the neural correlates of an endophenotype and diagnosis is important in autism spectrum disorder (ASD). However, prior studies enrolling individuals with ASD and their unaffected siblings have generally included only one group of typically developing (TD) subjects; they have not accounted for differences between TD siblings. Thus, they could not differentiate the neural correlates for endophenotype from the clinical diagnosis. In this context, we enrolled pairs of siblings with an ASD endophenotype (individuals with ASD and their unaffected siblings) and pairs of siblings without this endophenotype (pairs of TD siblings). Using resting-state functional MRI, we first aimed to identify an endophenotype pattern consisting of multiple functional connections (FCs) then examined the neural correlates of FCs for ASD diagnosis, controlling for differences between TD siblings. Sparse logistic regression successfully classified subjects as to the endophenotype (area under the curve = 0.78, classification accuracy = 75%). Then, a bootstrapping approach controlling for differences between TD siblings revealed that an FC between the right middle temporal gyrus and right anterior cingulate cortex was substantially different between individuals with ASD and their unaffected siblings, suggesting that this FC may be a neural correlate for the diagnosis, while the other FCs represent the endophenotype. The current findings suggest that an ASD endophenotype pattern exists in FCs, and a neural correlate for ASD diagnosis is dissociable from this endophenotype. (250 words).