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 estab-lished.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,clas-sification 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.

Use of electroacupuncture and transcutaneous electrical acupoint stimulation in reproductive medicine:a group consensus

Abstract： With the rapid development of assisted reproductive technology, various reproductive disorders have been effectively addressed. Acupuncture-like therapies, including electroacupuncture （EA） and transcutaneous electrical acupoint stimulation （TEAS）, become more popular world-wide. Increasing evidence has demonstrated that EA and TEAS are effective in treating gynecological disorders, especially infertility. This present paper describes how to select acupoints for the treatment of infertility from the view of theories of traditional Chinese medicine and how to determine critical parameters of electric pulses of ENTEAS based on results from animal and clinical studies. It summarizes the principles of clinical application of EA/rEAS in treating various kinds of reproductive disorders, such as polycystic ovary syndrome （PCOS）, pain induced by oocyte retrieval, diminished ovarian reserve, embryo transfer, and oligosperrnia/ asthenospermia. The possible underlying mechanisms mediating the therapeutic effects of EA/TEAS in reproductive medicine are also examined.

Responses of Primary Afferent Fibers to Acupuncture-Like Peripheral Stimulation at Different Frequencies:Characterization by Single-Unit Recording in Rats

The pain-relieving effect of acupuncture is known to involve primary afferent nerves(PANs) via their roles in signal transmission to the CNS.Using single-unit recording in rats,we characterized the generation and transmission of electrical signals in Aβ and Aδ fibers induced by acupuncture-like stimuli.Acupuncture-like signals were elicited in PANs using three techniques:manual acupuncture(MAc),emulated acupuncture(EAc),and electro-acupuncture(EA)-like peripheral electrical stimulation(PES).The discharges evoked by MAc and EAc were mostly in a burst pattern with average intra-burst and inter-burst firing rates of 90 Hz and 2 Hz,respectively.The frequency of discharges in PANs was correlated with the frequency of PES.The highest discharge frequency was 246 Hz in Aβ fibers and 180 Hz in Aδ fibers.Therefore,EA in a dense-disperse mode(at alternating frequency between 2 Hz and 15 Hz or between 2 Hz and 100 Hz) best mimics MAc.Frequencies of EA output>250 Hz appear to be obsolete for pain relief.

Involvement of Opioid Peptides in the Analgesic Effect of Spinal Cord Stimulation in a Rat Model of Neuropathic Pain

Spinal cord stimulation(SCS)-induced analgesia was characterized,and its underlying mechanisms were examined in a spared nerve injury model of neuropathic pain in rats.The analgesic effect of SCS with moderate mechanical hypersensitivity was increased with increasing stimulation intensity between the 20%and 80%motor thresholds.Various frequencies(2,15,50,100,10000 Hz,and 2/100 Hz dense-dispersed)of SCS were similarly effective.SCS-induced analgesia was maintained without tolerance within 24 h of continuous stimulation.SCS at 2 Hz significantly increased methionine enkephalin content in the cerebrospinal fluid.The analgesic effect of 2 Hz was abolished byμorκopioid receptor antagonist.The effect of 100 Hz was prevented by aκantagonist,and that of 10 kHz was blocked by any of theμ,δ,orκreceptor antagonists,suggesting that the analgesic effect of SCS at different frequencies is mediated by different endorphins and opioid receptors.

Development of an Autism Subtyping Questionnaire Based on Social Behaviors

Autism spectrum disorder can be differentiated into three subtypes （aloof, passive, and active-but-odd） based on social behaviors according to the Wing Subgroups Questionnaire （WSQ）. However, the correlations between the scores on some individual items and the total score are poor. In the present study, we translated the WSQ into Chinese, modified it, validated it in autistic and typically- developing Chinese children, and renamed it the Beijing Autism Subtyping Questionnaire （BASQ）. Our results demonstrated that the BASQ had improved validity and reliability, and differentiated autistic children into these three subtypes more precisely. We noted that the autistic symptoms tended to be severe in the aloof, moderate in the passive, and mild in the active-but-odd subtypes. The modified questionnaire may facilitate etiological studies and the selection of therapeutic regimes.

Genes Related to Oxytocin and Arginine-Vasopressin Pathways:Associations with Autism Spectrum Disorders

Autism spectrum disorder（ASD） is a highly heritable neurodevelopmental disorders characterized by impaired social interactions, communication de？cits, and repetitive behavior. Although the mechanisms underlying its etiology and manifestations are poorly understood,several lines of evidence from rodent and human studies suggest involvement of the evolutionarily highly-conserved oxytocin（OXT） and arginine-vasopressin（AVP）, as these neuropeptides modulate various aspects of mammalian social behavior. As far as we know, there is no comprehensive review of the roles of the OXT and AVP systems in the development of ASD from the genetic aspect. In this review, we summarize the current knowledge regarding associations between ASD and single-nucleotide variants of the human OXT-AVP pathway genes OXT, AVP, AVP receptor 1a（AVPR1a）, OXT receptor（OXTR）, theoxytocinase/vasopressinase（LNPEP）, and ADP-ribosyl cyclase（CD38）.

A Volumetric and Functional Connectivity MRI Study of Brain Arginine-Vasopressin Pathways in Autistic Children

Dysfunction of brain-derived arginine-vasopressin（AVP） systems may be involved in the etiology of autism spectrum disorder（ASD）. Certain regions such as the hypothalamus, amygdala, and hippocampus are known to contain either AVP neurons or terminals and may play an important role in regulating complex social behaviors.The present study was designed to investigate the concomitant changes in autistic behaviors, circulating AVP levels, and the structure and functional connectivity（FC） of speci？c brain regions in autistic children compared with typically developing children（TDC） aged from 3 to5 years. The results showed：（1） children with ASD had a signi？cantly increased volume in the left amygdala and left hippocampus, and a signi？cantly decreased volume in the bilateral hypothalamus compared to TDC, and these were positively correlated with plasma AVP level.（2） Autistic children had a negative FC between the left amygdala and the bilateral supramarginal gyri compared to TDC. The degree of the negative FC between amygdala and supramarginal gyrus was associated with a higher score on the clinical autism behavior checklist.（3） The degree of negative FC between left amygdala and left supramarginal gyrus was associated with a lowering of the circulating AVP concentration in boys with ASD.（4） Autistic children showed a higher FC between left hippocampus and right subcortical area compared to TDC.（5） The circulating AVP was negatively correlated with the visual and listening response score of the childhood autism rating scale.These results strongly suggest that changes in structure and FC in brain regions containing AVP may be involved in the etiology of autism.

Plasma Oxytocin and Arginine-Vasopressin Levels in Children with Autism Spectrum Disorder in China: Associations with Symptoms

Autism spectrum disorder（ASD） is defined by impairments of social interaction and the presence of obsessive behaviors. The ＇＇twin＇＇ nonapeptides oxytocin（OXT） and arginine-vasopressin（AVP） are known to play regulatory roles in social behaviors. However, the plasma levels and behavioral relevance of OXT and AVP in children with ASD have seldom been investigated. It is also unknown whether their mothers have abnormal plasma peptide levels. Here, using well-established methods of neuropeptide measurement and a relatively large sample size, we determined the plasma levels of the two neuropeptides in 85 normal children, 84 children with ASD, and 31 mothers from each group of children.As expected, children with ASD had lower plasma OXT levels than gender-matched controls（P = 0.028）. No such difference was found for plasma AVP concentrations. Correlation analysis showed that ASD children with higher plasma OXT concentrations tended to have less impairment of verbal communication（Rho =-0.22,P = 0.076）, while those with higher plasma AVP levels tended to have lower levels of repetitive use of objects（Rho =-0.231, P = 0.079）. Unlike the findings in children, maternal plasma OXT levels showed no group difference. However, plasma AVP levels in the mothers of ASD children tended to be lower than in the mothers of normal children（P = 0.072）. In conclusion, our results suggest that the OXT system is dysregulated in children with ASD, and that OXT and AVP levels in plasma seem to be associated with specific autistic symptoms. The plasma levels of OXT or AVP in mothers and their ASD children did not seem to change in the same direction.