A brain structural connectivity biomarker for autism spectrum disorder diagnosis in early childhood.

Background: Autism spectrum disorder (ASD) is associated with altered brain development, but it is unclear which specific structural changes may serve as potential diagnostic markers, particularly in young children at the age when symptoms become fully established. Furthermore, such brain markers need to meet the requirements of precision medicine and be accurate in aiding diagnosis at an individual rather than only a group level. Objective: This study aimed to identify and model brain-wide differences in structural connectivity using diffusion tensor imaging (DTI) in young ASD and typically developing (TD) children. Methods: A discovery cohort including 93 ASD and 26 TD children and two independent validation cohorts including 12 ASD and 9 TD children from three different cities in China were included. Brain-wide (294 regions) structural connectivity was measured using DTI (fractional anisotropy, FA) together with symptom severity and cognitive development. A connection matrix was constructed for each child for comparisons between ASD and TD groups. Pattern classification was performed on the discovery dataset and the resulting model was tested on the two independent validation datasets. Results: Thirty-three structural connections showed increased FA in ASD compared to TD children and associated with both autistic symptom severity and impaired general cognitive development. The majority (29/33) involved the frontal lobe and comprised five different networks with functional relevance to default mode, motor control, social recognition, language and reward. Overall, classification achieved very high accuracy of 96.77% in the discovery dataset, and 91.67% and 88.89% in the two independent validation datasets. Conclusions: Identified structural connectivity differences primarily involving the frontal cortex can very accurately distinguish novel individual ASD from TD children and may therefore represent a robust early brain biomarker which can address the requirements of precision medicine.

Anatomy-Guided Spatio-Temporal Graph Convolutional Networks (AG-STGCNs) for Modeling Functional Connectivity Between Gyri and Sulci Across Multiple Task Domains.

The cerebral cortex is folded as gyri and sulci, which provide the foundation to unveil anatomo-functional relationship of brain. Previous studies have extensively demonstrated that gyri and sulci exhibit intrinsic functional difference, which is further supported by morphological, genetic, and structural evidences. Therefore, systematically investigating the gyro-sulcal (G-S) functional difference can help deeply understand the functional mechanism of brain. By integrating functional magnetic resonance imaging (fMRI) with advanced deep learning models, recent studies have unveiled the temporal difference in functional activity between gyri and sulci. However, the potential difference of functional connectivity, which represents functional dependency between gyri and sulci, is much unknown. Moreover, the regularity and variability of the G-S functional connectivity difference across multiple task domains remains to be explored. To address the two concerns, this study developed new anatomy-guided spatio-temporal graph convolutional networks (AG-STGCNs) to investigate the regularity and variability of functional connectivity differences between gyri and sulci across multiple task domains. Based on 830 subjects with seven different task-based and one resting state fMRI (rs-fMRI) datasets from the public Human Connectome Project (HCP), we consistently found that there are significant differences of functional connectivity between gyral and sulcal regions within task domains compared with resting state (RS). Furthermore, there is considerable variability of such functional connectivity and information flow between gyri and sulci across different task domains, which are correlated with individual cognitive behaviors. Our study helps better understand the functional segregation of gyri and sulci within task domains as well as the anatomo-functional-behavioral relationship of the human brain.

Adversarial Learning Based Node-Edge Graph Attention Networks for Autism Spectrum Disorder Identification.

Graph neural networks (GNNs) have received increasing interest in the medical imaging field given their powerful graph embedding ability to characterize the non-Euclidean structure of brain networks based on magnetic resonance imaging (MRI) data. However, previous studies are largely node-centralized and ignore edge features for graph classification tasks, resulting in moderate performance of graph classification accuracy. Moreover, the generalizability of GNN model is still far from satisfactory in brain disorder [e.g., autism spectrum disorder (ASD)] identification due to considerable individual differences in symptoms among patients as well as data heterogeneity among different sites. In order to address the above limitations, this study proposes a novel adversarial learning-based node-edge graph attention network (AL-NEGAT) for ASD identification based on multimodal MRI data. First, both node and edge features are modeled based on structural and functional MRI data to leverage complementary brain information and preserved in the constructed weighted adjacent matrix for individuals through the attention mechanism in the proposed NEGAT. Second, two AL methods are employed to improve the generalizability of NEGAT. Finally, a gradient-based saliency map strategy is utilized for model interpretation to identify important brain regions and connections contributing to the classification. Experimental results based on the public Autism Brain Imaging Data Exchange I (ABIDE I) data demonstrate that the proposed framework achieves a classification accuracy of 74.7% between ASD and typical developing (TD) groups based on 1007 subjects across 17 different sites and outperforms the state-of-the-art methods, indicating satisfying classification ability and generalizability of the proposed AL-NEGAT model. Our work provides a powerful tool for brain disorder identification.

Decreased homotopic interhemispheric functional connectivity in children with autism spectrum disorder.

While several functional and structural changes occur in large-scale brain networks in autism spectrum disorder (ASD), reduced interhemispheric resting-state functional connectivity (rsFC) between homotopic regions may be of particular importance as a biomarker. ASD is an early-onset developmental disorder and neural alterations are often age-dependent. Although there is some evidence for homotopic interhemispheric rsFC alterations in language processing regions in ASD children, wider analyses using large data sets have not been performed. The present study, therefore, conducted a voxel-based homotopic interhemispheric rsFC analysis in 146 ASD and 175 typically developing children under-age 10 and examined associations with symptom severity in the autism brain imaging data exchange data sets. Given the role of corpus callosum (CC) in interhemispheric connectivity and reported CC volume changes in ASD we additionally examined whether there were parallel volumetric changes. Results demonstrated decreased homotopic rsFC in ASD children in the posterior cingulate cortex (PCC) and precuneus of the default mode network, the precentral gyrus of the mirror neuron system, and the caudate of the reward system. Homotopic rsFC of the PCC was associated with symptom severity. Furthermore, although no significant CC volume changes were found in ASD children, there was a significant negative correlation between the anterior CC volumes and homotopic rsFC strengths in the caudate. The present study shows that a reduced pattern of homotopic interhemispheric rsFC in ASD adults/adolescents is already present in children of 5-10 years old and further supports their potential use as a general ASD biomarker. LAY SUMMARY: Homotopic interhemispheric functional connectivity plays an important role in synchronizing activity between the two hemispheres and is altered in adults and adolescents with autism spectrum disorder (ASD). In the present study focused on children with ASD, we have observed a similar pattern of decreased homotopic connectivity, suggesting that alterations in homotopic interhemispheric connectivity may occur early in ASD and be a useful general biomarker across ages.

In the nose or on the tongue? Contrasting motivational effects of oral and intranasal oxytocin on arousal and reward during social processing.

Intranasal oxytocin exerts wide-ranging effects on socioemotional behavior and is proposed as a potential therapeutic intervention in psychiatric disorders. However, following intranasal administration, oxytocin could penetrate directly into the brain or influence its activity via increased peripheral concentrations crossing the blood-brain barrier or influencing vagal projections. In the current randomized, placebo-controlled, pharmaco-imaging clinical trial we investigated effects of 24IU oral (lingual) oxytocin spray, restricting it to peripherally mediated blood-borne and vagal effects, on responses to face emotions in 80 male subjects and compared them with 138 subjects treated intranasally with 24IU. Oral, but not intranasal oxytocin administration increased both arousal ratings for faces and associated brain reward responses, the latter being partially mediated by blood concentration changes. Furthermore, while oral oxytocin increased amygdala and arousal responses to face emotions, after intranasal administration they were decreased. Thus, oxytocin can produce markedly contrasting motivational effects in relation to socioemotional cues when it influences brain function via different routes. These findings have important implications for future therapeutic use since administering oxytocin orally may be both easier and have potentially stronger beneficial effects by enhancing responses to emotional cues and increasing their associated reward.

Intrinsic, dynamic and effective connectivity among large-scale brain networks modulated by oxytocin.

The neuropeptide oxytocin is a key modulator of social-emotional behavior and its intranasal administration can influence the functional connectivity of brain networks involved in the control of attention, emotion and reward reported in humans. However, no studies have systematically investigated the effects of oxytocin on dynamic or directional aspects of functional connectivity. The present study employed a novel computational framework to investigate these latter aspects in 15 oxytocin-sensitive regions using data from randomized placebo-controlled between-subject resting state functional MRI studies incorporating 200 healthy subjects. In order to characterize the temporal dynamics, the 'temporal state' was defined as a temporal segment of the whole functional MRI signal which exhibited a similar functional interaction pattern among brain regions of interest. Results showed that while no significant effects of oxytocin were found on brain temporal state related characteristics (including temporal state switching frequency, probability of transitions between neighboring states, and averaged dwell time on each state) oxytocin extensively (n = 54 links) modulated effective connectivity among the 15 regions. The effects of oxytocin were primarily characterized by increased effective connectivity both between and within emotion, reward, salience, attention and social cognition processing networks and their interactions with the default mode network. Top-down control over emotional processing regions such as the amygdala was particularly affected. Oxytocin also increased effective homotopic interhemispheric connectivity in almost all these regions. Additionally, the effects of oxytocin on effective connectivity were sex-dependent, being more extensive in males. Overall, these findings suggest that modulatory effects of oxytocin on both within- and between-network interactions may underlie its functional influence on social-emotional behaviors, although in a sex-dependent manner. These findings may be of particular relevance to potential therapeutic use of oxytocin in psychiatric disorders associated with social dysfunction, such as autism spectrum disorder and schizophrenia, where directionality of treatment effects on causal interactions between networks may be of key importance .

Oxytocin Differentially Modulates Amygdala Responses during Top-Down and Bottom-Up Aversive Anticipation.

The ability to successfully regulate negative emotions such as fear and anxiety is vital for mental health. Intranasal administration of the neuropeptide oxytocin (OXT) has been shown to reduce amygdala activity but to increase amygdala-prefrontal cortex connectivity during exposure to threatening stimuli suggesting that it may act as an important modulator of emotion regulation. The present randomized, between-subject, placebo-controlled pharmacological study combines the intranasal administration of OXT with functional magnetic resonance imaging (fMRI) during an explicit emotion regulation paradigm in 65 healthy male participants to investigate the modulatory effects of OXT on both bottom-up and top-down emotion regulation. OXT attenuates the activation in the posterior insular cortex and amygdala during anticipation of top-down regulation of predictable threat stimuli in participants with high trait anxiety. In contrast, OXT enhances amygdala activity during the bottom-up anticipation of unpredictable threat stimuli in participants with low trait anxiety. OXT may facilitate top-down goal-directed attention by attenuating amygdala activity in high anxiety individuals, while promoting bottom-up attention/vigilance to unexpected threats by enhancing amygdala activity in low anxiety individuals. OXT may thus have the potential to promote an adaptive balance between bottom-up and top-down attention systems depending on an individual's trait anxiety level.

Temporal Variability of Cortical Gyral-Sulcal Resting State Functional Activity Correlates With Fluid Intelligence.

The human cerebral cortex is highly convoluted as convex gyri and concave sulci. In the past decades, extensive studies have consistently revealed substantial differences between gyri and sulci in terms of genetics, anatomy, morphology, axonal fiber connections, and function. Although interesting findings have been reported to date to elucidate the functional difference between gyri and sulci, the temporal variability of functional activity, which could explain individual differences in learning and higher-order cognitive functions, and as well as differences in gyri and sulci, remains to be explored. The present study explored the temporal variability of cortical gyral-sulcal resting state functional activity and its association with fluid intelligence measures on the Human Connectome Project dataset. We found that the temporal variance of resting state fMRI BOLD signal was significantly larger in gyri than in sulci. We also found that the temporal variability of certain regions including middle frontal cortex, inferior parietal lobe and visual cortex was positively associated with fluid intelligence. Moreover, those regions were predominately located in gyri rather than in sulci. This study reports initial evidence for temporal variability difference of functional activity between gyri and sulci, and its association with fluid intelligence measures, and thus provides novel insights to understand the mechanism and functional relevance of gyri and sulci.

Changes in digestive enzyme activities during larval development of Chinese loach Paramisgurnus dabryanus (Dabry de Thiersant, 1872).

The digestive physiology of Chinese loach (Paramisgurnus dabryanus) was studied by assessing the specific and total activities of different pancreatic (trypsin, chymotrypsin, amylase and lipase), gastric (pepsin) and intestinal (alkaline phosphatase and leucine-aminopeptidase) enzymes from hatching to 40 days after hatching (DAH). Larvae were reared at 24.4 ± 0.4 °C and fed with rotifers from mouth opening (4 DAH) to 15 DAH, from 10 to 35 DAH with Cladocera and from 30 to 40 DAH with compound diet. Enzyme activities for trypsin, chymotrypsin, amylase and lipase were detected before the onset of exogenous feeding, indicating that these enzymes were genetically pre-programmed. Most of the pancreatic enzyme specific activities increased until 20 DAH and decreased thereafter. The pepsin activity of Chinese loach was firstly detected at 30 DAH, indicating the appearance of functional gastric gland. Alkaline phosphatase specific activity was detected from hatching onward, showed marked increase and reached the second peak at 20 DAH, while a gradual increase in specific leucine-aminopeptidase activity was observed until the end of the experiment. Accordingly, the larvae of Chinese loach possess a functional digestive system before the onset of exogenous feeding and the digestive capacity gradually increases as development progresses. The abrupt increase in intestinal enzyme activities between 10 and 20 DAH demonstrates onset of juvenile-like digestive mode in Chinese loach larvae. The increase in pepsin activity after 30 DAH indicates the shift from alkaline to acidic digestion in Chinese loach larvae, which may be considered as the onset of weaning.