literature review in autism

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• Exp Neurobiol
• v.25(1); 2016 Feb

A Short Review on the Current Understanding of Autism Spectrum Disorders

Hye ran park.

1 Department of Neurosurgery, Seoul National University Hospital, Seoul 03080, Korea.

Jae Meen Lee

Hyo eun moon, dong soo lee.

2 Department of Nuclear Medicine, Seoul National University College of Medicine, Seoul 03080, Korea.

Bung-Nyun Kim

3 Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul 03080, Korea.

Jinhyun Kim

4 Center for Functional Connectomics, Korea Institute of Science and Technology (KIST), Seoul 02792, Korea.

Dong Gyu Kim

Sun ha paek.

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by a deficit in social behaviors and nonverbal interactions such as reduced eye contact, facial expression, and body gestures in the first 3 years of life. It is not a single disorder, and it is broadly considered to be a multi-factorial disorder resulting from genetic and non-genetic risk factors and their interaction. Genetic studies of ASD have identified mutations that interfere with typical neurodevelopment in utero through childhood. These complexes of genes have been involved in synaptogenesis and axon motility. Recent developments in neuroimaging studies have provided many important insights into the pathological changes that occur in the brain of patients with ASD in vivo. Especially, the role of amygdala, a major component of the limbic system and the affective loop of the cortico-striatothalamo-cortical circuit, in cognition and ASD has been proved in numerous neuropathological and neuroimaging studies. Besides the amygdala, the nucleus accumbens is also considered as the key structure which is related with the social reward response in ASD. Although educational and behavioral treatments have been the mainstay of the management of ASD, pharmacological and interventional treatments have also shown some benefit in subjects with ASD. Also, there have been reports about few patients who experienced improvement after deep brain stimulation, one of the interventional treatments. The key architecture of ASD development which could be a target for treatment is still an uncharted territory. Further work is needed to broaden the horizons on the understanding of ASD.

INTRODUCTION

Autism spectrum disorder (ASD) is a set of neurodevelopmental disorders characterized by a lack of social interaction, verbal and nonverbal communication in the first 3 years of life. The distinctive social behaviors include an avoidance of eye contact, problems with emotional control or understanding the emotions of others, and a markedly restricted range of activities and interests [ 1 ]. The current prevalence of ASD in the latest large-scale surveys is about 1%~2% [ 2 , 3 ]. The prevalence of ASD has increased in the past two decades [ 4 ]. Although the increase in prevalence is partially the result of changes in DSM diagnostic criteria and younger age of diagnosis, an increase in risk factors cannot be ruled out [ 5 , 6 ]. Studies have shown a male predominance; ASD affects 2~3 times more males than females [ 2 , 3 , 7 ]. This diagnostic bias towards males might result from under-recognition of females with ASD [ 8 ]. Also, some researchers have suggested the possibility that the female-specific protective effects against ASD might exist [ 9 ].

A Swiss psychiatrist, Paul Eugen Bleuler used the term "autism" to define the symptoms of schizophrenia for the first time in 1912 [ 10 ]. He derived it from the Greek word αὐτὀς (autos), which means self. Hans Asperger adopted Bleuler's terminology "autistic" in its modern sense to describe child psychology in 1938. Afterwards, he reported about four boys who did not mix with their peer group and did not understand the meaning of the terms 'respect' and 'polite', and regard for the authority of an adult. The boys also showed specific unnatural stereotypic movement and habits. Asperger describe this pattern of behaviors as "autistic psychopathy", which is now called as Asperger's Syndrome [ 11 ]. The person who first used autism in its modern sense is Leo Kanner. In 1943, he reported about 8 boys and 3 girls who had "an innate inability to form the usual, biologically provided affective contact with people", and introduced the label early infantile autism [ 12 ]. Hans Asperger and Leo Kanner have been considered as those who designed the basis of the modern study of autism.

Most recently, the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) adopted the term ASD with a dyadic definition of core symptoms: early-onset of difficulties in social interaction and communication, and repetitive, restricted behaviors, interests, or activities [ 13 ]. Atypical language development, which had been included into the triad of ASD, is now regarded as a co-occurring condition.

As stated earlier, the development of the brain in individuals with ASD is complex and is mediated by many genetic and environmental factors, and their interactions. Genetic studies of ASD have identified mutations that interfere with typical neurodevelopment in utero through childhood. These complexes of genes have been involved in synaptogenesis and axon motility. Also, the resultant microstructural, macrostructural, and functional abnormalities that emerge during brain development create a pattern of dysfunctional neural networks involved in socioemotional processing. Microstructurally, an altered ratio of short- to long-diameter axons and disorganization of cortical layers are observed. Macrostructurally, MRI studies assessing brain volume in individuals with ASD have consistently shown cortical and subcortical gray matter overgrowth in early brain development. Functionally, resting-state fMRI studies show a narrative of widespread global underconnectivity in socioemotional networks, and task-based fMRI studies show decreased activation of networks involved in socioemotional processing. Moreover, electrophysiological studies demonstrate alterations in both resting-state and stimulus-induced oscillatory activities in patients with ASD [ 14 ].

The well-conserved sets of genes and genetic pathways were implicated in ASD, many of which contribute toward the formation, stabilization, and maintenance of functional synapses. Therefore, these genetic aspects coupled with an in-depth phenotypic analysis of the cellular and behavioral characteristics are essential to unraveling the pathogenesis of ASD. The number of genes already discovered in ASD holds the promise to translate the knowledge into designing new therapeutic interventions. Also, the fundamental research using animal models is providing key insights into the various facets of human ASD. However, a better understanding of the genetic, molecular, and circuit level aberrations in ASD is still needed [ 15 ].

Neuroimaging studies have provided many important insights into the pathological changes that occur in the brain of patients with ASD in vivo. Importantly, ASD is accompanied by an atypical path of brain maturation, which gives rise to differences in neuroanatomy, functioning, and connectivity. Although considerable progress has been made in the development of animal models and cellular assays, neuroimaging approaches allow us to directly examine the brain in vivo, and to probably facilitate the development of a more personalized approach to the treatment of ASD [ 16 ].

ASD is not a single disorder. It is now broadly considered to be a multi-factorial disorder resulting from genetic and non-genetic risk factors and their interaction.

Genetic causes including gene defects and chromosomal anomalies have been found in 10%~20% of individuals with ASD [ 17 , 18 ]. Siblings born in families with an ASD subject have a 50 times greater risk of ASD, with a recurrence rate of 5%~8% [ 19 ]. The concordance rate reaches up to 82%~92% in monozygotic twins, compared with 1%~10% in dizygotic twins. Genetic studies suggested that single gene mutations alter developmental pathways of neuronal and axonal structures involved in synaptogenesis [ 20 , 21 , 22 ]. In the cases of related with fragile X syndrome and tuberous sclerosis, hyperexcitability of neocortical circuits caused by alterations in the neocortical excitatory/inhibitory balance and abnormal neural synchronization is thought to be the most probable mechanisms [ 23 , 24 ]. Genome-wide linkage studies suggested linkages on chromosomes 2q, 7q, 15q, and 16p as the location of susceptibility genes, although it has not been fully elucidated [ 25 , 26 ]. These chromosomal abnormalities have been implicated in the disruption of neural connections, brain growth, and synaptic/dendritic morphology [ 27 , 28 , 29 ]. Metabolic errors including phenylketonuria, creatine deficiency syndromes, adenylosuccinate lyase deficiency, and metabolic purine disorders are also account for less than 5% of individuals with ASD [ 30 ]. Recently, the correlation between cerebellar developmental patterning gene ENGRAILED 2 and autism was reported [ 31 ]. It is the first genetic allele that contributes to ASD susceptibility in as many as 40% of ASD cases. Other genes such as UBE3A locus, GABA system genes, and serotonin transporter genes have also been considered as the genetic factors for ASD [ 18 ].

Diverse environmental causative elements including pre-natal, peri-natal, and post-natal factors also contribute to ASD [ 32 ]. Prenatal factors related with ASD include exposure to teratogens such as thalidomide, certain viral infections (congenital rubella syndrome), and maternal anticonvulsants such as valproic acid [ 33 , 34 ]. Low birth weight, abnormally short gestation length, and birth asphyxia are the peri-natal factors [ 34 ]. Reported post-natal factors associated with ASD include autoimmune disease, viral infection, hypoxia, mercury toxicity, and others [ 33 , 35 , 36 ]. Table 1 summarizes the known and putative ASD-related genes and environmental factors contributing to the ASD.

In recent years, some researchers suggest that ASD is the result of complex interactions between genetic and environmental risk factors [ 37 ]. Understanding the interaction between genetic and environmental factors in the pathogenesis of ASD will lead to optimal treatment strategy.

Clinical features and Diagnosis

ASD is typically noticed in the first 3 years of life, with deficits in social behaviors and nonverbal interactions such as reduced eye contact, facial expression, and body gestures [ 1 ]. Children also manifest with non-specific symptoms such as unusual sensory perception skills and experiences, motor clumsiness, and insomnia. Associated phenomena include mental retardation, emotional indifference, hyperactivity, aggression, self-injury, and repetitive behaviors such as body rocking or hand flapping. Repetitive, stereotyped behaviors are often accompanied by cognitive impairment, seizures or epilepsy, gastrointestinal complaints, disturbedd sleep, and other problems. Differential diagnosis includes childhood schizophrenia, learning disability, and deafness [ 38 , 39 ].

ASD is diagnosed clinically based on the presence of core symptoms. However, caution is required when diagnosing ASD because of non-specific manifestations in different age groups and individual abilities in intelligence and verbal domains. The earliest nonspecific signs recognized in infancy or toddlers include irritability, passivity, and difficulties with sleeping and eating, followed by delays in language and social engagement. In the first year of age, infants later diagnosed with ASD cannot be easily distinguished from control infants. However, some authors report that about 50% of infants show behavioral abnormalities including extremes of temperament, poor eye contact, and lack of response to parental voices or interaction. At 12 months of age, individuals with ASD show atypical behaviors, across the domains of visual attention, imitation, social responses, motor control, and reactivity [ 40 ]. There is also report about atypical language trajectories, with mild delays at 12 months progressing to more severe delays by 24 months [ 40 ]. By 3 years of age, the typical core symptoms such as lack of social communication and restricted/repetitive behaviors and interests are manifested. ASD can be easily differentiated from other psychosocial disorders in late preschool and early school years.

Amygdala and ASD

The frontal and temporal lobes are the markedly affected brain areas in the individuals with ASD. In particular, the role of amygdala in cognition and ASD has been proved in numerous neuropathological and neuroimaging studies. The amygdala located the medial temporal lobe anterior to the hippocampal formation has been thought to have a strong association with social and aggressive behaviors in patients with ASD [ 41 , 42 ]. The amygdala is a major component of the limbic system and affective loop of the cortico-striato-thalamo-cortical circuit [ 43 ].

The amygdala has 2 specific functions including eye gaze and face processing [ 44 ]. The lesion of the amygdala results in fear-processing, modulation of memory with emotional content, and eye gaze when looking at human face [ 45 , 46 , 47 ]. The findings in individuals with amygdala lesion are similar to the phenomena in ASD. The amygdala receives highly processed somatosensory, visual, auditory, and all types of visceral inputs. It sends efferents through two major pathways, the stria terminalis and the ventral amygdalofugal pathway.

The amygdala comprises a collection of 13 nuclei. Based on histochemical analyses, these 13 nuclei are divided into three primary subgroups: the basolateral (BL), centromedial (CM), and superficial groups [ 42 ]. The BL group attributes amygdala to have a role as a node connecting sensory stimuli to higher social cognition level. It links the CM and superficial groups, and it has reciprocal connection with the orbitofrontal cortex, anterior cingulate cortex (ACC), and the medial prefrontal cortex (mPFC) [ 48 ]. The BL group contains neurons responsive to faces and actions of others, which is not found in the other two groups of amygdala [ 49 , 50 ]. The CM group consists of the central, medial, cortical nuclei, and the periamygdaloid complex. It innervates many of the visceral and autonomic effector regions of the brain stem, and provides a major output to the hypothalamus, thalamus, ventral tegmental area, and reticular formation [ 51 ]. The superficial group includes the nucleus of the lateral olfactory tract [ 42 ].

Neurochemistrial studies revealed high density of benzodiazepine/GABAa receptors and a substantial set of opiate receptors in the amygdala. It also includes serotonergic, dopaminergic, cholinergic, and noradrenergic cell bodies and pathways [ 52 ]. Since some patients with temporal epilepsy and aggressive behavior experienced improvement in aggressiveness after bilateral stereotactic ablation of basal and corticomedial amygdaloid nuclei, the role of amygdala in emotional processing, especially rage processing has been investigated [ 53 , 54 , 55 , 56 ]. Some evidences for the amygdala deficit in patients with ASD have been suggested. Post-mortem studies found the pathology in the amygdala of individuals with ASD compared to age- and sex-matched controls [ 57 , 58 , 59 ]. Small neuronal size and increased cell density in the cortical, medial, and central nuclei of the amygdala were detected in ASD patients.

Several studies proposed the use of an animal model to confirm the evidence for the association between amygdala and ASD [ 60 , 61 ]. Despite the limitation which stems from the need to prove higher order cognitive disorder, the studies suggested that disease-associated alterations in the temporal lobes during experimental manipulations of the amygdala in animals have produced some symptoms of ASD [ 62 ]. Especially, the Kluver-Bucy syndrome, which is caused by bilateral damage to the anterior temporal lobes in monkeys, has characteristic manifestations similar to ASD [ 63 , 64 ]. Monkeys with the Kluver-Bucy syndrome shows absence of social chattering, lack of facial expression, absence of emotional reactions, repetitive abnormal movement patterns, and increased aggression. Sajdyk et al. performed experiments on rats and discovered that physiological activation of the BL nucleus of the amygdala by blocking tonic GABAergic inhibition or enhancing glutamate or the stress-associated peptide corticotropin-releasing factor (CRF)-mediated excitation caused reduction in social behaviors [ 65 ]. On the contrary, lesioning of the amygdala or blocking amygdala excitability with glutamate antagonist increased dyadic social interactions [ 60 ]. Besides animals, humans who underwent lesioning of the amygdala showed impairments in social judgment. This phenomenon is called acquired ASD [ 66 , 67 , 68 ]. The pattern of social deficits was similar in idiopathic and acquired ASD [ 69 ]. Felix-Ortiz and Tye sought to understand the role of projections from the BL amygdala to the ventral hippocampus in relation to behavior. Their study using mice showed that the BLS-ventral hippocampus pathway involved in anxiety plays a role in the mediation of social behavior as well [ 70 ].

The individuals with temporal lobe tumors involving the amygdala and hippocampus provide another evidence of the correlation between the amygdala and ASD. Some authors reported that patients experienced autistic symptoms after temporal lobe was damaged by a tumor [ 71 , 72 ]. Also, individuals with tuberous sclerosis experienced similar symptoms including facial expression due to a temporal lobe hamartoma [ 73 ].

Although other researchers failed to find structural abnormalities in the mesial temporal lobe of autistic subjects by performing magnetic resonance imaging (MRI) studies [ 74 , 75 , 76 ], recent development in neuroimaging has facilitated the investigation of amygdala pathology in ASD. Studies using structural MRI estimated volumes of the amygdala and related structures in individuals with ASD and age-, gender, and verbal IQ-matched healthy controls [ 77 ]. Increase in bilateral amygdala volume and reduction in hippocampal and parahippocampal gyrus volumes were noted in individuals with ASD. Also, the lateral ventricles and intracranial volumes were significantly increased in the autistic subjects; however, overall temporal lobe volumes were similar between the ASD and control groups.

There was a significant difference in the whole brain voxel-based scans of individuals with ASD and control groups [ 78 ]. Individuals with ASD showed decreased gray matter volume in the right paracingulate sulcus, the left occipito-temporal cortex, and the left inferior frontal sulcus. On the contrary, the gray matter volume in the bilateral cerebellum was increased. Otherwise, they showed increased volume in the left amygdala/periamygdaloid cortex, the right inferior temporal gyrus, and the middle temporal gyrus.

Recently, the development of functional neuroimaging also provided some evidence for the correlation between amygdala deficit and ASD. A study using Technetium-99m (Tc-99m) single-photon emission computed tomography (SPECT) found that regional cerebral blood flow (rCBF) was decreased in the bilateral insula, superior temporal gyri, and left prefrontal cortices in individuals with ASD compared to age- and gender-matched controls with mental retardation [ 79 ]. Also, the authors found that rCBF in both the right hippocampus and amygdala was correlated with a behavioral rating subscale.

On proton magnetic resonance spectroscopy (MRS) in the right hippocampal-amygdala region and the left cerebellar hemisphere, autistic subjects showed decreased level of N-acetyl aspartate (NAA) in both areas [ 80 ]. There was no difference in the level of the other metabolites, such as creatine and choline. This study implies that a decreased level of NAA might be associated with neuronal hypofunction or immature neurons.

These findings support the claim that amygdala might be a key structure in the development of ASD and a target for the management of the disease.

Prefrontal cortex and ASD

Frontal lobe has been considered as playing an important role in higher-level control and a key structure associated with autism. Individuals with frontal lobe deficit demonstrate higher-order cognitive, language, social, and emotion dysfunction, which is deficient in autism [ 81 ]. Recently, neuroimaging and neuropsychological studies have attempted to delineate distinct regions of prefrontal cortex supporting different aspects of executive function. Some authors have reported that the excessive rates of brain growth in infants with ASD, which is mainly contributed by the increase of frontal cortex volume [ 82 , 83 ]. Especially, the PFC including Brodmann areas 8, 9, 10, 11, 44, 45, 46, and 47 has been noted for the structure related with ASD [ 84 ]. The PFC is cytoarchitectonically defined as the presence of a cortical granular layer IV [ 85 ], and anatomically refers to the regions of the cerebral cortex that are anterior to premotor cortex and the supplementary motor area [ 86 ]. The PFC has extensive connections with other cortical, subcortical and brain stem sites [ 87 ]. It receives inputs from the brainstem arousal systems, and its function is particularly dependent on its neurochemical environment [ 88 ].

The PFC is broadly divided into the medial PFC (mPFC) and the lateral PFC (lPFC). The mPFC is further divided into four distinct regions: medial precentral cortex, anterior cingulate cortex, prelimbic and infralimbic prefrontal cortex [ 89 ]. While the lPFC is thought to support cognitive control process [ 90 ], the mPFC has reciprocal connections with brain regions involved in emotional processing (amygdala), memory (hippocampus) and higher-order sensory regions (within temporal cortex) [ 91 ]. This involvement of mPFC in social cognition and interaction implies that mPFC might be a key region in understanding self and others [ 92 ].

The mPFC involves in fear learning and extinction by reciprocal synaptic connections with the basolateral amygdala [ 93 , 94 ]. It is believed that the mPFC regulates and controls amygdala output and the accompanying behavioral phenomena [ 95 , 96 ]. Previous authors investigated how memory processing is regulated by interactions between BLA and mPFC by means of functional disconnection [ 97 , 98 ]. Disturbed communication within amygdala-mPFC circuitry caused deficits in memory processing. These informations provide support for a role of the mPFC in the development of ASD.

Nucleus Accumbens and ASD

Besides amygdala, nucleus accumbens (NAc) is also considered as the key structure which is related with the social reward response in ASD. NAc borders ventrally on the anterior limb of the internal capsule, and the lateral subventricular fundus of the NAc is permeated in rostral sections by internal capsule fiber bundles. The rationale for NAc to be considered as the potential target of DBS for ASD is its predominant role in modulating the processing of reward and pleasure [ 99 ]. Anticipation of rewarding stimuli recruits the NAc as well as other limbic structures, and the experience of pleasure activates the NAc as well as the caudate, putamen, amygdala, and VMPFC [ 100 , 101 , 102 ]. It is well known that dysfunction of NAc regarding rewarding stimuli in subjects with depression. Bewernick et al. demonstrated antidepressant effects of NAc-DBS in 5 of the 10 patients suffering from severe treatment-resistant depression [ 103 ].

Two groups reported about the neural basis of social reward processing in ASD. Schmitz et al. examined responses to a task that involved monetary reward. They investigated the neural substrates of reward feedback in the context of a sustained attention task, and found increased activation in the left anterior cingulate gyrus and left mid-frontal gyrus on rewarded trials in ASD [ 104 ]. Scott-Van Zeeland et al. investigated the neural correlates of rewarded implicit learning in children with ASD using both social and monetary rewards. They found diminished ventral striatal response during social, but not monetary, rewarded learning [ 105 ]. According to them, activity within the ventral striatum predicted social reciprocity within the control group, but not within the ASD group.

Anticipation of pleasurable stimuli recruits the NAc, whereas the experience of pleasure activates VMPFC [ 106 ]. NAc is activated by incentive motivation to reach salient goals [ 106 ]. Increased activation in the left anterior cingulate gyrus and left mid-frontal gyrus was noted during both the anticipatory and consummatory phase of the reward response [ 104 , 107 , 108 ]. However, the activity within the ventral striatum was decreased in autistic subjects, which caused impairment in social reciprocity [ 105 ].

These findings indicate that reward network function in ASD is contingent on both the temporal phase of the response and the type of reward processed, suggesting that it is critical to assess the temporal chronometry of responses in a study of reward processing in ASD. NAc might be one of the candidates as a target of DBS which is introduced as below.

Various educational and behavioral treatments have been the mainstay of the management of ASD. Most experts agree that the treatment for ASD should be individualized. Treatment of disabling symptoms such as aggression, agitation, hyperactivity, inattention, irritability, repetitive and self-injurious behavior may allow educational and behavioral interventions to proceed more effectively [ 109 ].

Increasing interest is being shown in the role of various pharmacological treatments. Medical management includes typical antipsychotics, atypical antipsychotics, antidepressants, selective serotonin reuptake inhibitors, α2-adrenergic agonists, β-adrenergic antagonist, mood stabilizers, and anticonvulsants [ 110 , 111 ]. So far, there has been no agent which has been proved effective in social communication [ 112 ]. A major factor in the choice of pharmacologic treatment is awareness of specific individual physical, behavioral or psychiatric conditions comorbid with ASD, such as obsessive-compulsive disorder, schizophrenia, mood disorder, and intellectual disability [ 113 ]. Antidepressants were the most commonly used agents followed by stimulants and antipsychotics. The high prevalence of comorbidities is reflected in the rates of psychotropic medication use in people with ASD. Antipsychotics were effective in treating the repetitive behaviors in children with ASD; however, there was not sufficient evidence on the efficacy and safety in adolescents and adults [ 114 ]. There are also alternative options including opiate antagonist, immunotherapy, hormonal agents, megavitamins and other dietary supplements [ 109 , 113 ].

However, the autistic symptoms remain refractory to medication therapy in some patients [ 115 ]. These individuals have severely progressed disease and multiple comorbidities causing decreased quality of life [ 44 , 110 ]. Interventional therapy such as deep brain stimulation (DBS) may be an alternative therapeutic option for these patients.

Two kinds of interventions have been used for treating ASD; focused intervention practices and comprehensive treatments [ 116 ]. The focused intervention practices include prompting, reinforcement, discrete trial teaching, social stories, or peer-mediated interventions. These are designed to produce specific behavioral or developmental outcomes for individual children with ASD, and used for a limited time period with the intent of demonstrating a change in the targeted behaviors. The comprehensive treatment models are a set of practices performed over an extended period of time and are intense in their application, and usually have multiple components [ 116 ].

Since it was approved by the FDA in 1997, DBS has been used to send electrical impulses to specific parts of the brain [ 117 , 118 ]. In recent years, the spectrum for which therapeutic benefit is provided by DBS has widely been expanded from movement disorders such as Parkinson's disease, essential tremor, and dystonia to psychiatric disorders. Some authors have demonstrated the efficacy of DBS for psychiatric disorders including refractory obsessive-compulsive disorder, depression, Tourette syndrome, and others for the past few years [ 119 , 120 , 121 ].

To the best of our knowledge, there have been 2 published articles of 3 patients who underwent DBS for ASD accompanied by life-threatening self-injurious behaviors not alleviated by antipsychotic medication [ 122 , 123 ]. The targets were anterior limb of the internal capsule and globus pallidus internus, only globus pallidus, and BL nucleus of the amygdala, respectively. All patients obtained some benefit from DBS. Although the first patient showed gradual re-deterioration after temporary improvement, the patient who underwent DBS of the BL nucleus experienced substantial improvement in self-injurious behavior and social communication. These experiences suggested the possibility of DBS for the treatment of ASD. For patients who did not obtain benefit from other treatments, DBS may be a viable therapeutic option. Understanding the structures which contribute to the occurrence of ASD might open a new horizon for management of ASD, particularly DBS. Accompanying development of neuroimaging technique enables more accurate targeting and heightens the efficacy of DBS. However, the optimal DBS target and stimulation parameters are still unknown, and prospective controlled trials of DBS for various possible targets are required to determine optimal target and stimulation parameters for the safety and efficacy of DBS.

ASD should be considered as a complex disorder. It has many etiologies involving genetic and environmental factors, and further evidence for the role of amygdala and NA in the pathophysiology of ASD has been obtained from numerous studies. However, the key architecture of ASD development which could be a target for treatment is still an uncharted territory. Further work is needed to broaden the horizons on the understanding of ASD.

Acknowledgements

This study was partly supported by the Korea Institute of Planning & Evaluation for Technology in Food, Agriculture, Forestry, and Fisheries, Republic of Korea (311011-05-3-SB020), by the Korea Healthcare Technology R&D Project (HI11C21100200) funded by Ministry of Health & Welfare, Republic of Korea, by the Technology Innovation Program (10050154, Business Model Development for Personalized Medicine Based on Integrated Genome and Clinical Information) funded by the Ministry of Trade, Industry & Energy (MI, Korea), and by the Bio & Medical Technology Development Program of the NRF funded by the Korean government, MSIP (2015M3C7A1028926).

• Download PDF
• CME & MOC
• Share X Facebook Email LinkedIn
• Permissions

Autism Spectrum Disorder : A Review

• 1 Department of Psychiatry and Behavioral Sciences, UCSF Weill Institute for Neurosciences, University of California, San Francisco
• Special Communication Screening for Autism Spectrum Disorder in Young Children Albert L. Siu, MD, MSPH; and the US Preventive Services Task Force (USPSTF); Kirsten Bibbins-Domingo, PhD, MD, MAS; David C. Grossman, MD, MPH; Linda Ciofu Baumann, PhD, RN, APRN; Karina W. Davidson, PhD, MASc; Mark Ebell, MD, MS; Francisco A. R. García, MD, MPH; Matthew Gillman, MD, SM; Jessica Herzstein, MD, MPH; Alex R. Kemper, MD, MPH, MS; Alex H. Krist, MD, MPH; Ann E. Kurth, PhD, RN, MSN, MPH; Douglas K. Owens, MD, MS; William R. Phillips, MD, MPH; Maureen G. Phipps, MD, MPH; Michael P. Pignone, MD, MPH JAMA
• JAMA Patient Page Screening for Autism Spectrum Disorder Jill Jin, MD, MPH JAMA
• JAMA Patient Page Patient Information: Autism Spectrum Disorder Rebecca Voelker, MSJ JAMA
• Review The Emerging Clinical Neuroscience of Autism Spectrum Disorder Rebecca A. Muhle, MD, PhD; Hannah E. Reed, MD; Katharine A. Stratigos, MD; Jeremy Veenstra-VanderWeele, MD JAMA Psychiatry
• Original Investigation Association of Allergies With Autism Spectrum Disorder Guifeng Xu, MD; Linda G. Snetselaar, PhD; Jin Jing, MD, PhD; Buyun Liu, MD, PhD; Lane Strathearn, MBBS, FRACP, PhD; Wei Bao, MD, PhD JAMA Network Open
• Research Letter Racial and Ethnic Differences in Rates and Age of Diagnosis of Autism Spectrum Disorder Hoangmai H. Pham, MD, MPH; Neil Sandberg, MS; Jeff Trinkl, MD; Johnston Thayer, MBA, RN JAMA Network Open
• Original Investigation Concordance of Diagnosis of ASD Made by Pediatricians vs a Multidisciplinary Specialist Team Melanie Penner, MSc, MD; Lili Senman, MA; Lana Andoni, MSc; Annie Dupuis, PhD; Evdokia Anagnostou, MD; Shawn Kao, MD; Abbie Solish, PhD; Michelle Shouldice, MEd, MD; Genevieve Ferguson, MEd; Jessica Brian, PhD JAMA Network Open
• Original Investigation Association Between Autism Spectrum Disorders and Cardiometabolic Diseases Chathurika S. Dhanasekara, MD, MS, PhD; Dominic Ancona, M-PAS; Leticia Cortes, M-PAS; Amy Hu, M-PAS; Afrina H. Rimu, MD, MS; Christina Robohm-Leavitt, M-PAS, DMSc; Drew Payne, DO; Sarah M. Wakefield, MD; Ann M. Mastergeorge, PhD; Chanaka N. Kahathuduwa, MD, MPhil, PhD JAMA Pediatrics

Importance   Autism spectrum disorder (ASD), characterized by deficits in social communication and the presence of restricted, repetitive behaviors or interests, is a neurodevelopmental disorder affecting approximately 2.3% children aged 8 years in the US and approximately 2.2% of adults. This review summarizes evidence on the diagnosis and treatment of ASD.

Observations   The estimated prevalence of ASD has been increasing in the US, from 1.1% in 2008 to 2.3% in 2018, which is likely associated with changes in diagnostic criteria, improved performance of screening and diagnostic tools, and increased public awareness. No biomarkers specific to the diagnosis of ASD have been identified. Common early signs and symptoms of ASD in a child’s first 2 years of life include no response to name when called, no or limited use of gestures in communication, and lack of imaginative play. The criterion standard for the diagnosis of ASD is a comprehensive evaluation with a multidisciplinary team of clinicians and is based on semistructured direct observation of the child’s behavior and semistructured caregiver interview focused on the individual’s development and behaviors using standardized measures, such as the Autism Diagnostic Observation Schedule-Second Edition and the Autism Diagnostic Interview. These diagnostic measures have sensitivity of 91% and 80% and specificity of 76% and 72%, respectively. Compared with people without ASD, individuals with ASD have higher rates of depression (20% vs 7%), anxiety (11% vs 5%), sleep difficulties (13% vs 5%), and epilepsy (21% with co-occurring intellectual disability vs 0.8%). Intensive behavioral interventions, such as the Early Start Denver Model, are beneficial in children 5 years or younger for improvement in language, play, and social communication (small to medium effect size based on standardized mean difference). Pharmacotherapy is indicated for co-occurring psychiatric conditions, such as emotion dysregulation or attention-deficit/hyperactivity disorder. Risperidone and aripiprazole can improve irritability and aggression (standardized mean difference of 1.1, consistent with a large effect size) compared with placebo. Psychostimulants are effective for attention-deficit/hyperactivity disorder (standardized mean difference of 0.6, consistent with a moderate effect size) compared with placebo. These medications are associated with adverse effects including, most commonly, changes in appetite, weight, and sleep.

Conclusions and Relevance   ASD affects approximately 2.3% of children aged 8 years and approximately 2.2% of adults in the US. First-line therapy consists of behavioral interventions, while co-occurring psychiatric conditions, such as anxiety or aggression, may be treated with specific behavioral therapy or medication.

Read More About

Hirota T , King BH. Autism Spectrum Disorder : A Review . JAMA. 2023;329(2):157–168. doi:10.1001/jama.2022.23661

Manage citations:

© 2024

Artificial Intelligence Resource Center

Cardiology in JAMA : Read the Latest

Browse and subscribe to JAMA Network podcasts!

Others Also Liked

Select your interests.

Customize your JAMA Network experience by selecting one or more topics from the list below.

• Academic Medicine
• Acid Base, Electrolytes, Fluids
• Allergy and Clinical Immunology
• American Indian or Alaska Natives
• Anesthesiology
• Anticoagulation
• Art and Images in Psychiatry
• Artificial Intelligence
• Assisted Reproduction
• Bleeding and Transfusion
• Caring for the Critically Ill Patient
• Challenges in Clinical Electrocardiography
• Climate and Health
• Climate Change
• Clinical Challenge
• Clinical Decision Support
• Clinical Implications of Basic Neuroscience
• Clinical Pharmacy and Pharmacology
• Complementary and Alternative Medicine
• Consensus Statements
• Coronavirus (COVID-19)
• Critical Care Medicine
• Cultural Competency
• Dental Medicine
• Dermatology
• Diabetes and Endocrinology
• Diagnostic Test Interpretation
• Drug Development
• Electronic Health Records
• Emergency Medicine
• End of Life, Hospice, Palliative Care
• Environmental Health
• Equity, Diversity, and Inclusion
• Facial Plastic Surgery
• Gastroenterology and Hepatology
• Genetics and Genomics
• Genomics and Precision Health
• Global Health
• Guide to Statistics and Methods
• Hair Disorders
• Health Care Delivery Models
• Health Care Economics, Insurance, Payment
• Health Care Quality
• Health Care Reform
• Health Care Safety
• Health Care Workforce
• Health Disparities
• Health Inequities
• Health Policy
• Health Systems Science
• History of Medicine
• Hypertension
• Images in Neurology
• Implementation Science
• Infectious Diseases
• Innovations in Health Care Delivery
• JAMA Infographic
• Law and Medicine
• Leading Change
• Less is More
• LGBTQIA Medicine
• Lifestyle Behaviors
• Medical Coding
• Medical Devices and Equipment
• Medical Education
• Medical Education and Training
• Medical Journals and Publishing
• Mobile Health and Telemedicine
• Narrative Medicine
• Neuroscience and Psychiatry
• Notable Notes
• Nutrition, Obesity, Exercise
• Obstetrics and Gynecology
• Occupational Health
• Ophthalmology
• Orthopedics
• Otolaryngology
• Pain Medicine
• Palliative Care
• Pathology and Laboratory Medicine
• Patient Care
• Patient Information
• Performance Improvement
• Performance Measures
• Perioperative Care and Consultation
• Pharmacoeconomics
• Pharmacoepidemiology
• Pharmacogenetics
• Pharmacy and Clinical Pharmacology
• Physical Medicine and Rehabilitation
• Physical Therapy
• Physician Leadership
• Population Health
• Primary Care
• Professional Well-being
• Professionalism
• Psychiatry and Behavioral Health
• Public Health
• Pulmonary Medicine
• Regulatory Agencies
• Reproductive Health
• Research, Methods, Statistics
• Resuscitation
• Rheumatology
• Risk Management
• Scientific Discovery and the Future of Medicine
• Shared Decision Making and Communication
• Sleep Medicine
• Sports Medicine
• Stem Cell Transplantation
• Substance Use and Addiction Medicine
• Surgical Innovation
• Surgical Pearls
• Teachable Moment
• Technology and Finance
• The Art of JAMA
• The Arts and Medicine
• The Rational Clinical Examination
• Tobacco and e-Cigarettes
• Translational Medicine
• Trauma and Injury
• Treatment Adherence
• Ultrasonography
• Users' Guide to the Medical Literature
• Vaccination
• Venous Thromboembolism
• Veterans Health
• Women's Health
• Workflow and Process
• Wound Care, Infection, Healing
• Register for email alerts with links to free full-text articles
• Access PDFs of free articles
• Manage your interests
• Save searches and receive search alerts

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

• View all journals
• Explore content
• About the journal
• Publish with us
• Sign up for alerts
• Published: 16 January 2020

Autism spectrum disorder

• Catherine Lord 1 ,
• Traolach S. Brugha 2 ,
• Tony Charman 3 ,
• James Cusack 4 ,
• Guillaume Dumas 5 ,
• Thomas Frazier 6 ,
• Emily J. H. Jones 7 ,
• Rebecca M. Jones 8 , 9 ,
• Andrew Pickles 3 ,
• Matthew W. State 10 ,
• Julie Lounds Taylor 11 &
• Jeremy Veenstra-VanderWeele 12  

Nature Reviews Disease Primers volume  6 , Article number:  5 ( 2020 ) Cite this article

45k Accesses

681 Citations

428 Altmetric

Metrics details

• Autism spectrum disorders
• Cognitive neuroscience
• Paediatrics

Autism spectrum disorder is a construct used to describe individuals with a specific combination of impairments in social communication and repetitive behaviours, highly restricted interests and/or sensory behaviours beginning early in life. The worldwide prevalence of autism is just under 1%, but estimates are higher in high-income countries. Although gross brain pathology is not characteristic of autism, subtle anatomical and functional differences have been observed in post-mortem, neuroimaging and electrophysiological studies. Initially, it was hoped that accurate measurement of behavioural phenotypes would lead to specific genetic subtypes, but genetic findings have mainly applied to heterogeneous groups that are not specific to autism. Psychosocial interventions in children can improve specific behaviours, such as joint attention, language and social engagement, that may affect further development and could reduce symptom severity. However, further research is necessary to identify the long-term needs of people with autism, and treatments and the mechanisms behind them that could result in improved independence and quality of life over time. Families are often the major source of support for people with autism throughout much of life and need to be considered, along with the perspectives of autistic individuals, in both research and practice.

This is a preview of subscription content, access via your institution

Access options

Access Nature and 54 other Nature Portfolio journals

Get Nature+, our best-value online-access subscription

24,99 € / 30 days

cancel any time

Subscribe to this journal

Receive 1 digital issues and online access to articles

92,52 € per year

only 92,52 € per issue

Buy this article

• Purchase on Springer Link
• Instant access to full article PDF

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

Neurogenetic disorders across the lifespan: from aberrant development to degeneration

Neuroimaging genetics approaches to identify new biomarkers for the early diagnosis of autism spectrum disorder

Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism

Lord, C. et al. Autism from 2 to 9 years of age. Arch. Gen. Psychiatry 63 , 694–701 (2006). This paper establishes that autism is a stable diagnosis (as a spectrum) beginning at least by 2 years of age. The paper also establishes parent interview and clinician observation as predictive of autism at 9 years of age. Finally, it is the first paper that shows that the specific DSM-IV-TR diagnoses is unstable across childhood but that the instability is almost all shifting across categories not outside the spectrum.

Article   PubMed   Google Scholar  

Risi, S. et al. Combining information from multiple sources in the diagnosis of autism spectrum disorders. J. Am. Acad. Child Adolesc. Psychiatry 45 , 1094–1103 (2006).

Loomes, R., Hull, L. & Mandy, W. P. L. What is the male-to-female ratio in autism spectrum disorder? A systematic review and meta-analysis. J. Am. Acad. Child Adolesc. Psychiatry 56 , 466–474 (2017).

Brugha, T. S. et al. Epidemiology of autism in adults across age groups and ability levels. Br. J. Psychiatry 209 , 498–503 (2016). This paper uses active case-finding to provide representative estimates of the prevalence of autism and demonstrated that rates of autism in men and women are equivalent in adults with moderate-to-profound intellectual disability.

Brugha, T., Bankart, J., McManus, S. & Gullon-Scott, F. CDC autism rate: misplaced reliance on passive sampling? Lancet 392 , 732–733 (2018).

Baxter, A. J. et al. The epidemiology and global burden of autism spectrum disorders. Psychol. Med. 45 , 601–613 (2015).

Article   CAS   PubMed   Google Scholar  

Elsabbagh, M. et al. Global prevalence of autism and other pervasive developmental disorders. Autism Res. 5 , 160–179 (2012).

Article   PubMed   PubMed Central   Google Scholar  

Magnusson, C. et al. Migration and autism spectrum disorder: population-based study. Br. J. Psychiatry 201 , 109–115 (2012).

Goodman, R. & Richards, H. Child and adolescent psychiatric presentations of second-generation Afro-Caribbeans in Britain. Br. J. Psychiatry 167 , 362–369 (1995).

Dyches, T. T., Wilder, L. K., Sudweeks, R. R., Obiakor, F. E. & Algozzine, B. Multicultural issues in autism. J. Autism Dev. Disord. 34 , 211–222 (2004).

Keen, D. V., Reid, F. D. & Arnone, D. Autism, ethnicity and maternal immigration. Br. J. Psychiatry 196 , 274–281 (2010).

McManus, S., Bebbington, P., Jenkins, R. & Brugha, T. Adult Psychiatric Morbidity Survey: mental health and wellbeing in England, 2014. NHS https://digital.nhs.uk/data-and-information/publications/statistical/adult-psychiatric-morbidity-survey/adult-psychiatric-morbidity-survey-survey-of-mental-health-and-wellbeing-england-2014 (2016).

GBD 2017 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392 , 1789–1858 (2018).

Article   Google Scholar  

Marcheselli, F. et al. Mental health of children and young people in England, 2017. NHS https://digital.nhs.uk/data-and-information/publications/statistical/mental-health-of-children-and-young-people-in-england/2017/2017 (2018).

Brugha, T. C. et al. Autism Spectrum Disorder, Adult Psychiatric Morbidity Survey 2014. (2014).

Lundstrom, S., Reichenberg, A., Anckarsater, H., Lichtenstein, P. & Gillberg, C. Autism phenotype versus registered diagnosis in Swedish children: prevalence trends over 10 years in general population samples. BMJ 350 , h1961 (2015).

Tromans, S., Chester, V., Kiani, R., Alexander, R. & Brugha, T. The prevalence of autism spectrum disorders in adult psychiatric inpatients: a systematic review. Clin. Pract. Epidemiol. Ment. Health 14 , 177–187 (2018).

Modabbernia, A., Velthorst, E. & Reichenberg, A. Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses. Mol. Autism 8 , 13 (2017).

Article   PubMed   PubMed Central   CAS   Google Scholar  

Wu, S. et al. Advanced parental age and autism risk in children: a systematic review and meta-analysis. Acta Psychiatr. Scand. 135 , 29–41 (2017).

Taylor, L. E., Swerdfeger, A. L. & Eslick, G. D. Vaccines are not associated with autism: an evidence-based meta-analysis of case-control and cohort studies. Vaccine 32 , 3623–3629 (2014).

Lai, M.-C., Lombardo, M. V. & Baron-Cohen, S. Autism. Lancet 383 , 896–910 (2014).

Velikonja, T., Fett, A.-K. & Velthorst, E. Patterns of nonsocial and social cognitive functioning in adults with autism spectrum disorder: a systematic review and meta-analysis. JAMA Psychiatry 76 , 135–151 (2019).

McNally Keehn, R. H., Lincoln, A. J., Brown, M. Z. & Chavira, D. A. The coping cat program for children with anxiety and autism spectrum disorder: a pilot randomized controlled trial. J. Autism Dev. Disord. 43 , 57–67 (2013).

Jones, E. J. H., Gliga, T., Bedford, R., Charman, T. & Johnson, M. H. Developmental pathways to autism: a review of prospective studies of infants at risk. Neurosci. Biobehav. Rev. 39 , 1–33 (2014).

Ozonoff, S. et al. Recurrence risk for autism spectrum disorders: a baby siblings research consortium study. Pediatrics 128 , e488–e495 (2011).

PubMed   PubMed Central   Google Scholar  

Jones, R. M. & Lord, C. Diagnosing autism in neurobiological research studies. Behav. Brain Res. 251 , 113–124 (2013).

Johnson, M. H. Autism: demise of the innate social orienting hypothesis. Curr. Biol. 24 , R30–R31 (2014).

Johnson, M. H., Jones, E. J. H. & Gliga, T. Brain adaptation and alternative developmental trajectories. Dev. Psychopathol. 27 , 425–442 (2015).

The Lancet Psychiatry. Of mice and mental health. Lancet Psychiatry 6 , 877 (2019).

Nelson, C. A. et al. An integrative, multidisciplinary approach to the study of brain-behavior relations in the context of typical and atypical development. Dev. Psychopathol. 14 , 499–520 (2002).

Cross-Disorder Group of the Psychiatric Genomics Consortium et al. Genetic relationship between five psychiatric disorders estimated from genome-wide SNPs. Nat. Genet. 45 , 984–994 (2013).

Article   CAS   Google Scholar  

Gaugler, T. et al. Most genetic risk for autism resides with common variation. Nat. Genet. 46 , 881–885 (2014).

Article   CAS   PubMed   PubMed Central   Google Scholar  

Wang, K., Gaitsch, H., Poon, H., Cox, N. J. & Rzhetsky, A. Classification of common human diseases derived from shared genetic and environmental determinants. Nat. Genet. 49 , 1319–1325 (2017).

Sanders, S. J. et al. Insights into autism spectrum disorder genomic architecture and biology from 71 risk loci. Neuron 87 , 1215–1233 (2015).

Satterstrom, F. K. et al. Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Preprint at https://doi.org/10.1101/484113 (2019).

Sanders, S. J. et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 485 , 237–241 (2012).

Neale, B. M. et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 485 , 242–245 (2012).

O’Roak, B. J. et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 485 , 246–250 (2012).

Sanders, S. J. et al. Multiple recurrent de novo CNVs, including duplications of the 7q11.23 Williams syndrome region, are strongly associated with autism. Neuron 70 , 863–885 (2011).

Levy, D. et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 70 , 886–897 (2011).

Sebat, J. et al. Strong association of de novo copy number mutations with autism. Science 316 , 445–449 (2007). This paper is the first to focus explicitly on simplex autism and show the importance of de novo CNVs in simplex cases, versus familial cases, versus controls.

Grove, J. et al. Identification of common genetic risk variants for autism spectrum disorder. Nat. Genet. 51 , 431–444 (2019).

Willsey, J. et al. De novo coding variants are strongly associated with Tourette syndrome. Eur. Neuropsychopharmacol. 29 , S737 (2019).

Epi4K Consortium. Epi4K: gene discovery in 4,000 genomes. Epilepsia 53 , 1457–1467 (2012).

Jamain, S. et al. Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nat. Genet. 34 , 27–29 (2003). This is the first paper to show a de novo loss-of-function mutation in a synaptic gene associated with non-syndromic autism and was a harbinger for many of the findings that came after.

Iossifov, I. et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 515 , 216–221 (2014).

De Rubeis, S. et al. Synaptic, transcriptional and chromatin genes disrupted in autism. Nature 515 , 209–215 (2014).

Sestan, N. & State, M. W. Lost in translation: traversing the complex path from genomics to therapeutics in autism spectrum disorder. Neuron 100 , 406–423 (2018).

State, M. W. & Sestan, N. The emerging biology of autism spectrum disorders. Science 337 , 1301–1303 (2012).

Schizophrenia Working Group of the Psychiatric Genomics Consortium. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511 , 421–427 (2014).

Article   PubMed Central   CAS   Google Scholar  

Devlin, B. & Scherer, S. W. Genetic architecture in autism spectrum disorder. Curr. Opin. Genet. Dev. 22 , 229–237 (2012).

de la Torre-Ubieta, L., Won, H., Stein, J. L. & Geschwind, D. H. Advancing the understanding of autism disease mechanisms through genetics. Nat. Med. 22 , 345–361 (2016).

SFARI Gene Website. https://gene.sfari.org/ (2019).

Parikshak, N. N. et al. Integrative functional genomic analyses implicate specific molecular pathways and circuits in autism. Cell 155 , 1008–1021 (2013).

Ben-David, E. & Shifman, S. Combined analysis of exome sequencing points toward a major role for transcription regulation during brain development in autism. Mol. Psychiatry 18 , 1054–1056 (2013).

Willsey, A. J. et al. Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism. Cell 155 , 997–1007 (2013).

Pinto, D. et al. Functional impact of global rare copy number variation in autism spectrum disorders. Nature 466 , 368–372 (2010).

Gilman, S. R. et al. Rare de novo variants associated with autism implicate a large functional network of genes involved in formation and function of synapses. Neuron 70 , 898–907 (2011).

Fuccillo, M. V. Striatal circuits as a common node for autism pathophysiology. Front. Neurosci. 10 , 27 (2016).

Velmeshev, D. et al. Single-cell genomics identifies cell type-specific molecular changes in autism. Science 364 , 685–689 (2019).

Mendell, J. R. et al. Single-dose gene-replacement therapy for spinal muscular atrophy. N. Engl. J. Med. 377 , 1713–1722 (2017).

Mercuri, E. et al. Nusinersen versus sham control in later-onset spinal muscular atrophy. N. Engl. J. Med. 378 , 625–635 (2018).

Matharu, N. et al. CRISPR-mediated activation of a promoter or enhancer rescues obesity caused by haploinsufficiency. Science 363 , eaau0629 (2019).

Abudayyeh, O. O. et al. RNA targeting with CRISPR–cas13. Nature 550 , 280–284 (2017).

Power, J. D. et al. Customized head molds reduce motion during resting state fMRI scans. NeuroImage 189 , 141–149 (2019).

Solso, S. et al. Diffusion tensor imaging provides evidence of possible axonal overconnectivity in frontal lobes in autism spectrum disorder toddlers. Biol. Psychiatry 79 , 676–684 (2016).

Clements, C. C. et al. Evaluation of the social motivation hypothesis of autism: a systematic review and meta-analysis. JAMA Psychiatry 75 , 797–808 (2018).

Ecker, C. Brain anatomy and its relationship to behavior in adults with autism spectrum disorder: a multicenter magnetic resonance imaging study. Arch. Gen. Psychiatry 69 , 195–209 (2012).

Langen, M. et al. Changes in the development of striatum are involved in repetitive behavior in autism. Biol. Psychiatry 76 , 405–411 (2014).

Elsabbagh, M. & Johnson, M. H. Autism and the social brain: the first-year puzzle. Biol. Psychiatry 80 , 94–99 (2016).

Courchesne, E. et al. Unusual brain growth patterns in early life in patients with autistic disorder: an MRI study. Neurology 57 , 245–254 (2001).

Hazlett, H. C. et al. Magnetic resonance imaging and head circumference study of brain size in autism: birth through age 2 years. Arch. Gen. Psychiatry 62 , 1366–1376 (2005).

Wolff, J. J. et al. Differences in white matter fiber tract development present from 6 to 24 months in infants with autism. Am. J. Psychiatry 169 , 589–600 (2012).

Hazlett, H. C. et al. Early brain development in infants at high risk for autism spectrum disorder. Nature 542 , 348–351 (2017). This seminal paper, through careful recruitment and methodology, was the first to show significant early differences that may contribute to our understanding of developmental features in neural structure and circuits .

Wolff, J. J. et al. Neural circuitry at age 6 months associated with later repetitive behavior and sensory responsiveness in autism. Mol. Autism 8 , 8 (2017).

Emerson, R. W. et al. Functional neuroimaging of high-risk 6-month-old infants predicts a diagnosis of autism at 24 months of age. Sci. Transl. Med. 9 , eaag2882 (2017).

Smith, E. et al. Cortical thickness change in autism during early childhood: CT in early childhood ASD. Hum. Brain Mapp. 37 , 2616–2629 (2016).

Uddin, L. Q., Dajani, D. R., Voorhies, W., Bednarz, H. & Kana, R. K. Progress and roadblocks in the search for brain-based biomarkers of autism and attention-deficit/hyperactivity disorder. Transl. Psychiatry 7 , e1218 (2017).

Herringshaw, A. J., Ammons, C. J., DeRamus, T. P. & Kana, R. K. Hemispheric differences in language processing in autism spectrum disorders: a meta-analysis of neuroimaging studies. Autism Res. 9 , 1046–1057 (2016).

He, Y., Byrge, L. & Kennedy, D. P. Non-replication of functional connectivity differences in autism spectrum disorder across multiple sites and denoising strategies. Preprint at https://doi.org/10.1101/640797 (2019).

Lawrence, K. E., Hernandez, L. M., Bookheimer, S. Y. & Dapretto, M. Atypical longitudinal development of functional connectivity in adolescents with autism spectrum disorder. Autism Res. 12 , 53–65 (2019).

Plitt, M., Barnes, K. A., Wallace, G. L., Kenworthy, L. & Martin, A. Resting-state functional connectivity predicts longitudinal change in autistic traits and adaptive functioning in autism. Proc. Natl Acad. Sci. USA 112 , E6699–E6706 (2015).

Di Martino, A. et al. The autism brain imaging data exchange: towards a large-scale evaluation of the intrinsic brain architecture in autism. Mol. Psychiatry 19 , 659–667 (2014).

Doyle-Thomas, K. A. R. et al. Atypical functional brain connectivity during rest in autism spectrum disorders. Ann. Neurol. 77 , 866–876 (2015).

Supekar, K. et al. Brain hyperconnectivity in children with autism and its links to social deficits. Cell Rep. 5 , 738–747 (2013).

Dajani, D. R. & Uddin, L. Q. Local brain connectivity across development in autism spectrum disorder: a cross-sectional investigation. Autism Res. 9 , 43–54 (2016).

Hull, J. V. et al. Resting-state functional connectivity in autism spectrum disorders: a review. Front. Psychiatry 7 , 205 (2017).

Lombardo, M. V. et al. Different functional neural substrates for good and poor language outcome in autism. Neuron 86 , 567–577 (2015).

Carlisi, C. O. et al. Disorder-specific and shared brain abnormalities during vigilance in autism and obsessive-compulsive disorder. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 2 , 644–654 (2017).

Alaerts, K., Swinnen, S. P. & Wenderoth, N. Sex differences in autism: a resting-state fMRI investigation of functional brain connectivity in males and females. Soc. Cogn. Affect. Neurosci. 11 , 1002–1016 (2016).

Kirkovski, M., Enticott, P. G., Hughes, M. E., Rossell, S. L. & Fitzgerald, P. B. Atypical neural activity in males but not females with autism spectrum disorder. J. Autism Dev. Disord. 46 , 954–963 (2016).

Venkataraman, A. et al. Pivotal response treatment prompts a functional rewiring of the brain among individuals with autism spectrum disorder. NeuroReport 27 , 1081–1085 (2016).

Levisohn, P. M. The autism-epilepsy connection. Epilepsia 48 , 33–35 (2007).

Cantor, D. S., Thatcher, R. W., Hrybyk, M. & Kaye, H. Computerized EEG analyses of autistic children. J. Autism Dev. Disord. 16 , 169–187 (1986).

Lefebvre, A. et al. Alpha waves as a neuromarker of autism spectrum disorder: the challenge of reproducibility and heterogeneity. Front. Neurosci. 12 , 662 (2018).

Tierney, A. L., Gabard-Durnam, L., Vogel-Farley, V., Tager-Flusberg, H. & Nelson, C. A. Developmental trajectories of resting EEG power: an endophenotype of autism spectrum disorder. PLOS ONE 7 , e39127 (2012).

Oberman, L. M. et al. EEG evidence for mirror neuron dysfunction in autism spectrum disorders. Cogn. Brain Res. 24 , 190–198 (2005).

Fan, Y.-T., Decety, J., Yang, C.-Y., Liu, J.-L. & Cheng, Y. Unbroken mirror neurons in autism spectrum disorders. J. Child Psychol. Psychiatry 51 , 981–988 (2010).

Southgate, V. & Hamilton, A. F. Unbroken mirrors: challenging a theory of autism. Trends Cogn. Sci. 12 , 225–229 (2008).

Bernier, R., Aaronson, B. & McPartland, J. The role of imitation in the observed heterogeneity in EEG mu rhythm in autism and typical development. Brain Cogn. 82 , 69–75 (2013).

Raymaekers, R., Wiersema, J. R. & Roeyers, H. EEG study of the mirror neuron system in children with high functioning autism. Brain Res. 1304 , 113–121 (2009).

Dumas, G., Soussignan, R., Hugueville, L., Martinerie, J. & Nadel, J. Revisiting mu suppression in autism spectrum disorder. Brain Res. 1585 , 108–119 (2014). This paper replicates the mu suppression deficits in autism during action observation but questions, through high-density spectral analyses and source reconstruction, its previously drawn relation to the mirror neuron system.

Marco, E. J., Hinkley, L. B. N., Hill, S. S. & Nagarajan, S. S. Sensory processing in autism: a review of neurophysiologic findings. Pediatr. Res. 69 , 48R–54R (2011).

Schwartz, S., Shinn-Cunningham, B. & Tager-Flusberg, H. Meta-analysis and systematic review of the literature characterizing auditory mismatch negativity in individuals with autism. Neurosci. Biobehav. Rev. 87 , 106–117 (2018).

Kang, E. et al. Atypicality of the N170 event-related potential in autism spectrum disorder: a meta-analysis. Biol. Psychiatry Cogn. Neurosci. Neuroimaging 3 , 657–666 (2018).

Bonnet-Brilhault, F. et al. GABA/glutamate synaptic pathways targeted by integrative genomic and electrophysiological explorations distinguish autism from intellectual disability. Mol. Psychiatry 21 , 411–418 (2016).

Schilbach, L. Towards a second-person neuropsychiatry. Phil. Trans. R. Soc. B 371 , 20150081 (2016). This review supports that psychiatric disorders are more commonly characterized by impairments of social interaction rather than social observation, and advocates for an interactive turn in neuropsychiatry .

Barraza, P. et al. Implementing EEG hyperscanning setups. MethodsX 6 , 428–436 (2019).

Dumas, G., de Guzman, G. C., Tognoli, E. & Kelso, J. A. The human dynamic clamp as a paradigm for social interaction. Proc. Natl Acad. Sci. USA 111 , E3726–E3734 (2014).

Jones, E. J. H. et al. Reduced engagement with social stimuli in 6-month-old infants with later autism spectrum disorder: a longitudinal prospective study of infants at high familial risk. J. Neurodev. Disord. 8 , 7 (2016).

Ciarrusta, J. et al. Social brain functional maturation in newborn infants with and without a family history of autism spectrum disorder. JAMA Netw. Open 2 , e191868 (2019).

Levin, A. R., Varcin, K. J., O’Leary, H. M., Tager-Flusberg, H. & Nelson, C. A. EEG power at 3 months in infants at high familial risk for autism. J. Neurodev. Disord. 9 , 34 (2017).

Kolesnik, A. et al. Increased cortical reactivity to repeated tones at 8 months in infants with later ASD. Transl. Psychiatry 9 , 46 (2019).

Rippon, G., Brock, J., Brown, C. & Boucher, J. Disordered connectivity in the autistic brain: challenges for the ‘new psychophysiology’. Int. J. Psychophysiol. 63 , 164–172 (2007).

Rosenberg, A., Patterson, J. S. & Angelaki, D. E. A computational perspective on autism. Proc. Natl Acad. Sci. USA 112 , 9158–9165 (2015).

Masuda, F. et al. Motor cortex excitability and inhibitory imbalance in autism spectrum disorder assessed with transcranial magnetic stimulation: a systematic review. Transl. Psychiatry 9 , 110 (2019).

O’Reilly, C., Lewis, J. D. & Elsabbagh, M. Is functional brain connectivity atypical in autism? A systematic review of EEG and MEG studies. PLOS ONE 12 , e0175870 (2017).

Khan, S. et al. Somatosensory cortex functional connectivity abnormalities in autism show opposite trends, depending on direction and spatial scale. Brain 138 , 1394–1409 (2015).

Chen, H., Nomi, J. S., Uddin, L. Q., Duan, X. & Chen, H. Intrinsic functional connectivity variance and state-specific under-connectivity in autism. Hum. Brain Mapp. 38 , 5740–5755 (2017).

Catarino, A., Churches, O., Baron-Cohen, S., Andrade, A. & Ring, H. Atypical EEG complexity in autism spectrum conditions: a multiscale entropy analysis. Clin. Neurophysiol. 122 , 2375–2383 (2011).

Engemann, D. A. et al. Robust EEG-based cross-site and cross-protocol classification of states of consciousness. Brain 141 , 3179–3192 (2018).

Open Science Collaboration. Psychology. Estimating the reproducibility of psychological science. Science 349 , aac4716 (2015).

Lord, C. et al. Autism diagnostic observation schedule: ADOS-2 (Western Psychological Services, 2012).

Regier, D. A. et al. DSM-5 field trials in the United States and Canada, part II: test-retest reliability of selected categorical diagnoses. Am. J. Psychiatry 170 , 59–70 (2013).

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders , 5th Edn (American Psychiatric Association, 2013).

World Health Organization. International classification of diseases for mortality and morbidity statistics (11th Revision). https://icd.who.int/browse11/l-m/en (WHO, 2018).

Constantino, J. N. & Charman, T. Diagnosis of autism spectrum disorder: reconciling the syndrome, its diverse origins, and variation in expression. Lancet Neurol. 15 , 279–291 (2016).

Lord, C. A multisite study of the clinical diagnosis of different autism spectrum disorders. Arch. Gen. Psychiatry 69 , 306–313 (2012).

Miller, J. N. & Ozonoff, S. The external validity of Asperger disorder: lack of evidence from the domain of neuropsychology. J. Abnorm. Psychol. 109 , 227–238 (2000).

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders , Fourth Edn (American Psychiatric Association, 1994).

Green, D., Chandler, S., Charman, T., Simonoff, E. & Baird, G. Brief report: DSM-5 sensory behaviours in children with and without an autism spectrum disorder. J. Autism Dev. Disord. 46 , 3597–3606 (2016).

Ozonoff, S. et al. Diagnosis of autism spectrum disorder after age 5 in children evaluated longitudinally since infancy. J. Am. Acad. Child Adolesc. Psychiatry 57 , 849–857.e2 (2018).

Russell, G., Steer, C. & Golding, J. Social and demographic factors that influence the diagnosis of autistic spectrum disorders. Soc. Psychiatry Psychiatr. Epidemiol. 46 , 1283–1293 (2011).

Charman, T. & Gotham, K. Measurement issues: screening and diagnostic instruments for autism spectrum disorders—lessons from research and practice. Child Adolesc. Ment. Health 18 , 52–63 (2013).

Ashwood, K. L., Buitelaar, J., Murphy, D., Spooren, W. & Charman, T. European clinical network: autism spectrum disorder assessments and patient characterisation. Eur. Child Adolesc. Psychiatry 24 , 985–995 (2015).

Rutter, M., LeCouteur, A. & Lord, C. Autism Diagnostic Interview-Revised (ADI-R). (Western Psychological Services, 2003).

Durkin, M. S. et al. Autism screening and diagnosis in low resource settings: challenges and opportunities to enhance research and services worldwide. Autism Res. 8 , 473–476 (2015). This position paper highlights the challenges to translating knowledge on better awareness, understanding, identification and diagnosis (and then treatments) from the past two decades of clinical research in high-income countries into low-income and middle-income countries.

Baird, G. et al. Prevalence of disorders of the autism spectrum in a population cohort of children in South Thames: the Special Needs and Autism Project (SNAP). Lancet 368 , 210–215 (2006).

Luyster, R. et al. The autism diagnostic observation schedule — toddler module: a new module of a standardized diagnostic measure for autism spectrum disorders. J. Autism Dev. Disord. 39 , 1305–1320 (2009).

de Vries, P. J. Thinking globally to meet local needs: autism spectrum disorders in Africa and other low-resource environments. Curr. Opin. Neurol. 29 , 130–136 (2016).

Article   PubMed   CAS   Google Scholar  

Georgiades, S., Bishop, S. L. & Frazier, T. Editorial perspective: longitudinal research in autism—introducing the concept of ‘chronogeneity’. J. Child Psychol. Psychiatry 58 , 634–636 (2017).

Fountain, C., Winter, A. S. & Bearman, P. S. Six developmental trajectories characterize children with autism. Pediatrics 129 , e1112–e1120 (2012).

Kim, S. H. et al. Variability in autism symptom trajectories using repeated observations from 14 to 36 months of age. J. Am. Acad. Child Adolesc. Psychiatry 57 , 837–848.e2 (2018).

Bussu, G. et al. Latent trajectories of adaptive behaviour in infants at high and low familial risk for autism spectrum disorder. Mol. Autism 10 , 13 (2019).

Zerbi, V. et al. Dysfunctional autism risk genes cause circuit-specific connectivity deficits with distinct developmental trajectories. Cereb. Cortex 28 , 2495–2506 (2018).

Fein, D. et al. Optimal outcome in individuals with a history of autism. J. Child Psychol. Psychiatry 54 , 195–205 (2013).

Anderson, D. K., Liang, J. W. & Lord, C. Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. J. Child Psychol. Psychiatry 55 , 485–494 (2014).

Chlebowski, C., Robins, D. L., Barton, M. L. & Fein, D. Large-scale use of the modified checklist for autism in low-risk toddlers. Pediatrics 131 , e1121–e1127 (2013).

Stenberg, N. et al. Identifying children with autism spectrum disorder at 18 months in a general population sample. Paediatr. Perinat. Epidemiol. 28 , 255–262 (2014).

Pierce, K., Courchesne, E. & Bacon, E. To screen or not to screen universally for autism is not the question: why the task force got it wrong. J. Pediatr. 176 , 182–194 (2016).

Siu, A. L. et al. Screening for autism spectrum disorder in young children: US Preventive Services Task Force recommendation statement. JAMA 315 , 691–696 (2016).

Øien, R. A. et al. Clinical features of children with autism who passed 18-month screening. Pediatrics 141 , e20173596 (2018).

Sánchez-García, A. B., Galindo-Villardón, P., Nieto-Librero, A. B., Martín-Rodero, H. & Robins, D. L. Toddler screening for autism spectrum disorder: a meta-analysis of diagnostic accuracy. J. Autism Dev. Disord. 49 , 1837–1852 (2019).

Marlow, M., Servili, C. & Tomlinson, M. A review of screening tools for the identification of autism spectrum disorders and developmental delay in infants and young children: recommendations for use in low- and middle-income countries. Autism Res. 12 , 176–199 (2019).

Raza, S. et al. Brief report: evaluation of the short quantitative checklist for autism in toddlers (Q-CHAT-10) as a brief screen for autism spectrum disorder in a high-risk sibling cohort. J. Autism Dev. Disord. 49 , 2210–2218 (2019).

Charman, T. et al. Testing two screening instruments for autism spectrum disorder in UK community child health services. Dev. Med. Child Neurol. 58 , 369–375 (2016).

Brett, D., Warnell, F., McConachie, H. & Parr, J. R. Factors affecting age at ASD diagnosis in UK: no evidence that diagnosis age has decreased between 2004 and 2014. J. Autism Dev. Disord. 46 , 1974–1984 (2016).

Zuckerman, K. E., Lindly, O. J. & Sinche, B. K. Parental concerns, provider response, and timeliness of autism spectrum disorder diagnosis. J. Pediatr. 166 , 1431–1439.e1 (2015).

Boterberg, S., Charman, T., Marschik, P. B., Bölte, S. & Roeyers, H. Regression in autism spectrum disorder: a critical overview of retrospective findings and recommendations for future research. Neurosci. Biobehav. Rev. 102 , 24–55 (2019).

Pearson, N., Charman, T., Happé, F., Bolton, P. F. & McEwen, F. S. Regression in autism spectrum disorder: reconciling findings from retrospective and prospective research. Autism Res. 11 , 1602–1620 (2018).

Ozonoff, S. & Iosif, A.-M. Changing conceptualizations of regression: what prospective studies reveal about the onset of autism spectrum disorder. Neurosci. Biobehav. Rev. 100 , 296–304 (2019). Despite its potential importance as a biological marker and/or subgroup of ASD, developmental regression has remained very poorly understood. This paper outlines recent data and reconceptualization about patterns of onset (and loss) that chime with a more contemporaneous understanding of ASD as a heterogeneous condition in terms of its manifestation both within and across individuals .

Brugha, T. S. et al. Validating two survey methods for identifying cases of autism spectrum disorder among adults in the community. Psychol. Med. 42 , 647–656 (2012).

Brugha, T. S. The Psychiatry of Adult Autism and Asperger Syndrome: a Practical Guide (Oxford Univ. Press, 2018).

Epstein, J., Johnson, D. E. & Conners, C. K. Conners Adult ADHD Diagnostic Interview for DSM-IV (CAADID) (MHS, 2001).

Lai, M.-C. et al. Prevalence of co-occurring mental health diagnoses in the autism population: a systematic review and meta-analysis. Lancet Psychiatry 6 , 819–829 (2019).

Havdahl, A. & Bishop, S. Heterogeneity in prevalence of co-occurring psychiatric conditions in autism. Lancet Psychiatry 6 , 794–795 (2019).

Croen, L. A. et al. The health status of adults on the autism spectrum. Autism 19 , 814–823 (2015).

Mannion, A., Leader, G. & Healy, O. An investigation of comorbid psychological disorders, sleep problems, gastrointestinal symptoms and epilepsy in children and adolescents with autism spectrum disorder. Res. Autism Spectr. Disord. 7 , 35–42 (2013).

Soke, G. N., Maenner, M. J., Christensen, D., Kurzius-Spencer, M. & Schieve, L. A. Prevalence of co-occurring medical and behavioral conditions/symptoms among 4- and 8-year-old children with autism spectrum disorder in selected areas of the United States in 2010. J. Autism Dev. Disord. 48 , 2663–2676 (2018).

Chandler, S. et al. Emotional and behavioural problems in young children with autism spectrum disorder. Dev. Med. Child Neurol. 58 , 202–208 (2016).

Pezzimenti, F., Han, G. T., Vasa, R. A. & Gotham, K. Depression in youth with autism spectrum disorder. Child Adolesc. Psychiatr. Clin. N. Am. 28 , 397–409 (2019).

Hwang, Y. I. J., Srasuebkul, P., Foley, K. R., Arnold, S. & Trollor, J. N. Mortality and cause of death of Australians on the autism spectrum. Autism Res. 12 , 806–815 (2019).

Hirvikoski, T. et al. Premature mortality in autism spectrum disorder. Br. J. Psychiatry 208 , 232–238 (2016).

Havdahl, K. A. et al. Multidimensional influences on autism symptom measures: implications for use in etiological research. J. Am. Acad. Child Adolesc. Psychiatry 55 , 1054–1063.e3 (2016).

Nicolaidis, C. et al. Comparison of healthcare experiences in autistic and non-autistic adults: a cross-sectional online survey facilitated by an academic-community partnership. J. Gen. Intern. Med. 28 , 761–769 (2013).

Schreibman, L. et al. Naturalistic developmental behavioral interventions: empirically validated treatments for autism spectrum disorder. J. Autism Dev. Disord. 45 , 2411–2428 (2015).

Tomlinson, M. et al. Setting global research priorities for developmental disabilities, including intellectual disabilities and autism: setting research priorities for developmental disabilities. J. Intellect. Disabil. Res. 58 , 1121–1130 (2014).

Rahman, A. et al. Effectiveness of the parent-mediated intervention for children with autism spectrum disorder in South Asia in India and Pakistan (PASS): a randomised controlled trial. Lancet Psychiatry 3 , 128–136 (2016).

Lovaas, O. I. Behavioral treatment and normal educational and intellectual functioning in young autistic children. J. Consult. Clin. Psychol. 55 , 3–9 (1987).

Nevill, R. E., Lecavalier, L. & Stratis, E. A. Meta-analysis of parent-mediated interventions for young children with autism spectrum disorder. Autism 22 , 84–98 (2018).

Kasari, C. et al. Randomized controlled trial of parental responsiveness intervention for toddlers at high risk for autism. Infant Behav. Dev. 37 , 711–721 (2014).

Shire, S. Y. et al. Hybrid implementation model of community-partnered early intervention for toddlers with autism: a randomized trial. J. Child Psychol. Psychiatry 58 , 612–622 (2017).

Siller, M., Hutman, T. & Sigman, M. A parent-mediated intervention to increase responsive parental behaviors and child communication in children with ASD: a randomized clinical trial. J. Autism Dev. Disord. 43 , 540–555 (2013).

Rogers, S. J. et al. Effects of a brief early start denver model (ESDM)-based parent intervention on toddlers at risk for autism spectrum disorders: a randomized controlled trial. J. Am. Acad. Child Adolesc. Psychiatry 51 , 1052–1065 (2012).

Green, J. et al. Parent-mediated communication-focused treatment in children with autism (PACT): a randomised controlled trial. Lancet 375 , 2152–2160 (2010).

Pickles, A. et al. Parent-mediated social communication therapy for young children with autism (PACT): long-term follow-up of a randomised controlled trial. Lancet 388 , 2501–2509 (2016).

Dawson, G. et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics 125 , e17–e23 (2010).

Charman, T. Editorial: trials and tribulations in early autism intervention research. J. Am. Acad. Child Adolesc. Psychiatry 58 , 846–848 (2019).

Rogers, S. J. et al. A multisite randomized controlled two-phase trial of the early start denver model compared to treatment as usual. J. Am. Acad. Child Adolesc. Psychiatry 58 , 853–865 (2019).

Dawson, G. et al. Early behavioral intervention is associated with normalized brain activity in young children with autism. J. Am. Acad. Child Adolesc. Psychiatry 51 , 1150–1159 (2012).

Myers, S. M., Johnson, C. P. & The Council on Children With Disabilities. Management of children with autism spectrum disorders. Pediatrics 120 , 1162–1182 (2007).

Laugeson, E. A., Frankel, F., Gantman, A., Dillon, A. R. & Mogil, C. Evidence-based social skills training for adolescents with autism spectrum disorders: the UCLA PEERS program. J. Autism Dev. Disord. 42 , 1025–1036 (2012).

Reichow, B., Servili, C., Yasamy, M. T., Barbui, C. & Saxena, S. Non-specialist psychosocial interventions for children and adolescents with intellectual disability or lower-functioning autism spectrum disorders: a systematic review. PLOS Med. 10 , e1001572 (2013).

Brignell, A. et al. Communication interventions for autism spectrum disorder in minimally verbal children. Cochrane Database Syst. Rev. 11 , CD012324 (2018).

PubMed   Google Scholar  

Tarver, J. et al. Child and parent outcomes following parent interventions for child emotional and behavioral problems in autism spectrum disorders: a systematic review and meta-analysis. Autism 23 , 1630–1644 (2019).

Keefer, A. et al. Exploring relationships between negative cognitions and anxiety symptoms in youth with autism spectrum disorder. Behav. Ther. 49 , 730–740 (2018).

Bearss, K. et al. Effect of parent training vs parent education on behavioral problems in children with autism spectrum disorder: a randomized clinical trial. JAMA 313 , 1524–1533 (2015).

Da Paz, N. S. & Wallander, J. L. Interventions that target improvements in mental health for parents of children with autism spectrum disorders: a narrative review. Clin. Psychol. Rev. 51 , 1–14 (2017).

Kasari, C. et al. Children with autism spectrum disorder and social skills groups at school: a randomized trial comparing intervention approach and peer composition. J. Child Psychol. Psychiatry 57 , 171–179 (2016).

Marshall, D. et al. Social stories in mainstream schools for children with autism spectrum disorder: a feasibility randomised controlled trial. BMJ Open 6 , e011748 (2016).

Taylor, J. L. et al. A systematic review of vocational interventions for young adults with autism spectrum disorders. Pediatrics 130 , 531–538 (2012).

Pallathra, A. A., Cordero, L., Wong, K. & Brodkin, E. S. Psychosocial interventions targeting social functioning in adults on the autism spectrum: a literature review. Curr. Psychiatry Rep. 21 , 5 (2019).

White, S. W. et al. Psychosocial treatments targeting anxiety and depression in adolescents and adults on the autism spectrum: review of the latest research and recommended future directions. Curr. Psychiatry Rep. 20 , 82 (2018).

Shattuck, P. T., Wagner, M., Narendorf, S., Sterzing, P. & Hensley, M. Post-high school service use among young adults with an autism spectrum disorder. Arch. Pediatr. Adolesc. Med. 165 , 141–146 (2011).

Wehman, P. et al. Effects of an employer-based intervention on employment outcomes for youth with significant support needs due to autism. Autism 21 , 276–290 (2017).

McCracken, J. T. et al. Risperidone in children with autism and serious behavioral problems. N. Engl. J. Med. 347 , 314–321 (2002).

Owen, R. et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 124 , 1533–1540 (2009).

McPheeters, M. L. et al. A systematic review of medical treatments for children with autism spectrum disorders. Pediatrics 127 , e1312–e1321 (2011).

Anagnostou, E. et al. Metformin for treatment of overweight induced by atypical antipsychotic medication in young people with autism spectrum disorder: a randomized clinical trial. JAMA Psychiatry 73 , 928–937 (2016).

Research Units on Pediatric Psychopharmacology Autism Network. Randomized, controlled, crossover trial of methylphenidate in pervasive developmental disorders with hyperactivity. Arch. Gen. Psychiatry 62 , 1266–1274 (2005).

Handen, B. L. et al. Atomoxetine, parent training, and their combination in children with autism spectrum disorder and attention-deficit/hyperactivity disorder. J. Am. Acad. Child Adolesc. Psychiatry 54 , 905–915 (2015).

Scahill, L. et al. Extended-release guanfacine for hyperactivity in children with autism spectrum disorder. Am. J. Psychiatry 172 , 1197–1206 (2015).

Hollander, E. et al. A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. Am. J. Psychiatry 169 , 292–299 (2012).

King, B. H. et al. Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism. Arch. Gen. Psychiatry 66 , 583–590 (2009).

Anagnostou, E. et al. Intranasal oxytocin in the treatment of autism spectrum disorders: a review of literature and early safety and efficacy data in youth. Brain Res. 1580 , 188–198 (2014).

Guastella, A. J. et al. The effects of a course of intranasal oxytocin on social behaviors in youth diagnosed with autism spectrum disorders: a randomized controlled trial. J. Child Psychol. Psychiatry 56 , 444–452 (2015).

Parker, K. J. et al. A randomized placebo-controlled pilot trial shows that intranasal vasopressin improves social deficits in children with autism. Sci. Transl. Med. 11 , eaau7356 (2019).

Bolognani, F. et al. A phase 2 clinical trial of a vasopressin V1a receptor antagonist shows improved adaptive behaviors in men with autism spectrum disorder. Sci. Transl. Med. 11 , eaat7838 (2019).

Rubenstein, J. L. R. & Merzenich, M. M. Model of autism: increased ratio of excitation/inhibition in key neural systems. Genes Brain Behav. 2 , 255–267 (2003).

Veenstra-VanderWeele, J. et al. Arbaclofen in children and adolescents with autism spectrum disorder: a randomized, controlled, phase 2 trial. Neuropsychopharmacology 42 , 1390–1398 (2017).

Berry-Kravis, E. et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci. Transl. Med. 8 , 321ra5 (2016).

Krueger, D. A. et al. Everolimus for treatment of tuberous sclerosis complex-associated neuropsychiatric disorders. Ann. Clin. Transl. Neurol. 4 , 877–887 (2017).

Georgiades, S. & Kasari, C. Reframing optimal outcomes in autism. JAMA Pediatr. 172 , 716–717 (2018).

Bishop-Fitzpatrick, L. et al. Characterizing objective quality of life and normative outcomes in adults with autism spectrum disorder: an exploratory latent class analysis. J. Autism Dev. Disord. 46 , 2707–2719 (2016).

The WHOQOL Group. Development of the World Health Organization WHOQOL-BREF quality of life assessment. Psychol. Med. 28 , 551–558 (1998).

Gotham, K. et al. Characterizing the daily life, needs, and priorities of adults with autism spectrum disorder from interactive autism network data. Autism 19 , 794–804 (2015).

Taylor, J. L. & Seltzer, M. M. Employment and post-secondary educational activities for young adults with autism spectrum disorders during the transition to adulthood. J. Autism Dev. Disord. 41 , 566–574 (2011).

Orsmond, G. I., Shattuck, P. T., Cooper, B. P., Sterzing, P. R. & Anderson, K. A. Social participation among young adults with an autism spectrum disorder. J. Autism Dev. Disord. 43 , 2710–2719 (2013).

Henninger, N. A. & Taylor, J. L. Outcomes in adults with autism spectrum disorders: a historical perspective. Autism 17 , 103–116 (2013).

Howlin, P. & Moss, P. Adults with autism spectrum disorders. Can. J. Psychiatry 57 , 275–283 (2012).

Farley, M. A. et al. Twenty-year outcome for individuals with autism and average or near-average cognitive abilities. Autism Res. 2 , 109–118 (2009).

Taylor, J. L., Henninger, N. A. & Mailick, M. R. Longitudinal patterns of employment and postsecondary education for adults with autism and average-range IQ. Autism 19 , 785–793 (2015).

Lai, M.-C. et al. Quantifying and exploring camouflaging in men and women with autism. Autism 21 , 690–702 (2016).

van Heijst, B. F. & Geurts, H. M. Quality of life in autism across the lifespan: a meta-analysis. Autism 19 , 158–167 (2015).

Moss, P., Mandy, W. & Howlin, P. Child and adult factors related to quality of life in adults with autism. J. Autism Dev. Disord. 47 , 1830–1837 (2017).

Bishop-Fitzpatrick, L., Mazefsky, C. A. & Eack, S. M. The combined impact of social support and perceived stress on quality of life in adults with autism spectrum disorder and without intellectual disability. Autism 22 , 703–711 (2017).

Kamio, Y., Inada, N. & Koyama, T. A nationwide survey on quality of life and associated factors of adults with high-functioning autism spectrum disorders. Autism 17 , 15–26 (2013).

Mason, D. et al. Predictors of quality of life for autistic adults. Autism Res. 11 , 1138–1147 (2018).

Autistica. Your questions shaping future autism research. https://www.autistica.org.uk/downloads/files/Autism-Top-10-Your-Priorities-for-Autism-Research.pdf (2016).

Ontario Brain Institute. Community priorities for research on neurodevelopmental disorders. http://braininstitute.ca/img/JLA-NDD-Final-Report.pdf (2018).

den Houting, J. Neurodiversity: an insider’s perspective. Autism 23 , 271–273 (2018).

Szatmari, P. Risk and resilience in autism spectrum disorder: a missed translational opportunity? Dev. Med. Child Neurol. 60 , 225–229 (2018).

Markowitz, L. A. et al. Development and psychometric evaluation of a psychosocial quality-of-life questionnaire for individuals with autism and related developmental disorders. Autism 20 , 832–844 (2016).

Ryan, S. & Cole, K. R. From advocate to activist? Mapping the experiences of mothers of children on the autism spectrum. J. Appl. Res. Intellect. Disabil. 22 , 43–53 (2009).

McCann, D., Bull, R. & Winzenberg, T. The daily patterns of time use for parents of children with complex needs: a systematic review. J. Child Health Care 16 , 26–52 (2012).

Karst, J. S. & Van Hecke, A. V. Parent and family impact of autism spectrum disorders: a review and proposed model for intervention evaluation. Clin. Child Fam. Psychol. Rev. 15 , 247–277 (2012).

Lounds, J., Seltzer, M. M., Greenberg, J. S. & Shattuck, P. T. Transition and change in adolescents and young adults with autism: longitudinal effects on maternal well-being. Am. J. Ment. Retard. 112 , 401–417 (2007).

Burke, M. & Heller, T. Individual, parent and social-environmental correlates of caregiving experiences among parents of adults with autism spectrum disorder. J. Intellect. Disabil. Res. 60 , 401–411 (2016).

Kim, S. H., Bal, V. H. & Lord, C. Longitudinal follow-up of academic achievement in children with autism from age 2 to 18. J. Child Psychol. Psychiatry 59 , 258–267 (2017).

Lord, C., Bishop, S. & Anderson, D. Developmental trajectories as autism phenotypes. Am. J. Med. Genet. C Semin. Med. Genet. 169 , 198–208 (2015).

Global Research on Developmental Disabilities Collaborators. Developmental disabilities among children younger than 5 years in 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancel Glob. Health 6 , e1100–e1121 (2018).

Kahn, R. S. et al. Schizophrenia. Nat. Rev. Dis. Primers 1 , 15067 (2015).

Patel, V. et al. Addressing the burden of mental, neurological, and substance use disorders: key messages from Disease Control Priorities, 3rd edition. Lancet 387 , 1672–1685 (2016).

Franz, L., Chambers, N., von Isenburg, M. & de Vries, P. J. Autism spectrum disorder in sub-Saharan Africa: a comprehensive scoping review. Autism Res. 10 , 723–749 (2017).

World Health Organization. Training parents to transform children’s lives. https://www.who.int/mental_health/maternal-child/PST/en/ (WHO, 2019).

Naslund, J. A. et al. Digital innovations for global mental health: opportunities for data science, task sharing, and early intervention. Curr. Treat. Options Psychiatry https://doi.org/10.1007/s40501-019-00186-8 (2019).

Sadowsky, J., Donvan, J. & Zucker, C. In a different key: the story of autism. J. Hist. Behav. Sci. 54 , 66–67 (2018). This paper presents a different, broad overview of the changes in perspective about autism and ASD over the years .

Rutter, M., Greenfeld, D. & Lockyer, L. A five to fifteen year follow-up study of infantile psychosis. II. Social and behavioural outcome. Br. J. Psychiatry 113 , 1183–1199 (1967).

Hermelin, B. & O’Connor, N. Psychological Experiments with Autistic Children (Pergamon Press, 1970).

Rimland, B. Infantile Autism: the Syndrome and its Implications for a Neural Theory of Behaviour (Meredith Publishing Company, 1964).

Frith, U. Studies in pattern detection in normal and autistic children: I. Immediate recall of auditory sequences. J. Abnorm. Psychol. 76 , 413–420 (1970).

Folstein, S. & Rutter, M. in Autism (eds. Rutter M. & Schopler E.) 219–241 (Springer, 1978).

Mundy, P., Sigman, M. & Kasari, C. A longitudinal study of joint attention and language development in autistic children. J. Autism Dev. Disord. 20 , 115–128 (1990).

Schopler, E. & Reichler, R. J. Parents as cotherapists in the treatment of psychotic children. J. Autism Child. Schizophr. 1 , 87–102 (1971).

Sinclair, J. Don’t mourn for us. Autism Network International http://www.autreat.com/dont_mourn.html (1993).

Wing, L. & Gould, J. Severe impairments of social interaction and associated abnormalities in children: epidemiology and classification. J. Autism Dev. Disord. 9 , 11–29 (1979).

Chawner, S. et al. A genetic first approach to dissecting the heterogeneity of autism: phenotypic comparison of autism risk copy number variants. Eur. Neuropsychopharmacol. 29 (Suppl. 3), S783–S784 (2019).

Modabbernia, A., Mollon, J., Boffetta, P. & Reichenberg, A. Impaired gas exchange at birth and risk of intellectual disability and autism: a meta-analysis. J. Autism Dev. Disord. 46 , 1847–1859 (2016).

Christensen, J. et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA 309 , 1696–1703 (2013).

Xie, F., Peltier, M. & Getahun, D. Is the risk of autism in younger siblings of affected children moderated by sex, race/ethnicity, or gestational age? J. Dev. Behav. Pediatr. 37 , 603–609 (2016).

Guy, A. et al. Infants born late/moderately preterm are at increased risk for a positive autism screen at 2 years of age. J. Pediatr. 166 , 269–275.e3 (2015).

Schendel, D. & Bhasin, T. K. Birth weight and gestational age characteristics of children with autism, including a comparison with other developmental disabilities. Pediatrics 121 , 1155–1164 (2008).

Windham, G. C. et al. Maternal pre-pregnancy body mass index and gestational weight gain in relation to autism spectrum disorder and other developmental disorders in offspring. Autism Res. 12 , 316–327 (2019).

Schmidt, R. J. et al. Maternal periconceptional folic acid intake and risk of autism spectrum disorders and developmental delay in the CHARGE (CHildhood Autism Risks from Genetics and Environment) case-control study. Am. J. Clin. Nutr. 96 , 80–89 (2012).

Conde-Agudelo, A., Rosas-Bermudez, A. & Norton, M. H. Birth spacing and risk of autism and other neurodevelopmental disabilities: a systematic review. Pediatrics 137 , e20153482 (2016).

Lyall, K. et al. The changing epidemiology of autism spectrum disorders. Annu. Rev. Public Health 38 , 81–102 (2017).

Cheslack-Postava, K., Liu, K. & Bearman, P. S. Closely spaced pregnancies are associated with increased odds of autism in California sibling births. Pediatrics 127 , 246–253 (2011).

Conti, E., Mazzotti, S., Calderoni, S., Saviozzi, I. & Guzzetta, A. Are children born after assisted reproductive technology at increased risk of autism spectrum disorders? A systematic review. Hum. Reprod. 28 , 3316–3327 (2013).

Lehti, V. et al. Autism spectrum disorders in IVF children: a national case-control study in Finland. Hum. Reprod. 28 , 812–818 (2013).

Rossignol, D. A., Genuis, S. J. & Frye, R. E. Environmental toxicants and autism spectrum disorders: a systematic review. Transl. Psychiatry 4 , e360 (2014).

Curran, E. A. et al. Research review: birth by caesarean section and development of autism spectrum disorder and attention-deficit/hyperactivity disorder: a systematic review and meta-analysis. J. Child Psychol. Psychiatry 56 , 500–508 (2015).

Chandler, S., Howlin, P., Simonoff, E., Kennedy, J. & Baird, G. Comparison of parental estimate of developmental age with measured IQ in children with neurodevelopmental disorders. Child Care Health Dev. 42 , 486–493 (2016).

Charman, T. et al. IQ in children with autism spectrum disorders: data from the Special Needs and Autism Project (SNAP). Psychol. Med. 41 , 619–627 (2011).

Sparrow, S. S., Cicchetti, D. & Balla, D. A. Vineland Adaptive Behavior Scales, 2nd Edn. https://doi.org/10.1037/t15164-000 (AGS, 2005).

Jones, R. M., Pickles, A. & Lord, C. Evaluating the quality of peer interactions in children and adolescents with autism with the Penn Interactive Peer Play Scale (PIPPS). Mol. Autism 8 , 28 (2017).

Lord, C., Elsabbagh, M., Baird, G. & Veenstra-Vanderweele, J. Autism spectrum disorder. Lancet 392 , 508–520 (2018).

Duncan, A. W. & Bishop, S. L. Understanding the gap between cognitive abilities and daily living skills in adolescents with autism spectrum disorders with average intelligence. Autism 19 , 64–72 (2015).

Download references

Acknowledgements

The authors thank J. McCauley, S. Gaspar, K. Byrne and A. Holbrook from UCLA for help with manuscript preparation. S. Tromans is thanked for his updated review of the epidemiology literature. We recognize the many investigators who contributed research that we cannot cite due to space limitations. C.L. is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHHD; R01 HD081199), the National Institute of Mental Health (NIMH; R01MH081873-01A1) and the Simons Foundation. T.S.B. is supported by grants from the Health and Social Care Information Centre, Leeds, and the National Institute for Health Research (NIHR HTA; grant ref. NIHR127337). T.C. is supported by grants from Innovative Medicines Initiative 2 (no. 777394), the Medical Research Council (MRC; grants MR/K021389/1) and the NIHR (grant 13/119/18). J.C. is funded by Autistica. G.D. is supported by the Institut Pasteur. T.F. is supported by the Autism Speaks Foundation. E.J.H.J. is supported by grants from the Economic and Social Research Council (ESRC; ES/R009368/1), the Innovative Medicines Initiative 2 (no. 777394), the MRC (MR/K021389/1) and the Simons Foundation (609081). R.M.J. acknowledges the Mortimer D. Sackler Family and the NIMH (R01MH114999). J.L.T. is supported by grants from the FAR fund and the NIMH (R34 MH104428, R03 MH 112783 and R01 MH116058). A.P. is partially supported by the Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London and the NIHR (NF-SI-0617-10120). M.W.S. is supported by the National Institutes of Health (NIH; MH106934, MH109901, MH110928, MH116487 MH102342, MH111662, MH105575 and MH115747), the Overlook International Foundation and the Simons Foundation. J.V.-V. is supported by the NIH (MH016434 and MH094604), the Simons Foundation and the New York State Psychiatric Institute. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health and Social Care.

Author information

Authors and affiliations.

Departments of Psychiatry and School of Education, University of California, Los Angeles, Los Angeles, CA, USA

Catherine Lord

Department of Health Sciences, University of Leicester, Leicester, UK

Traolach S. Brugha

Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

Tony Charman & Andrew Pickles

Autistica, London, UK

James Cusack

Institut Pasteur, UMR3571 CNRS, Université de Paris, Paris, France

Guillaume Dumas

Autism Speaks, New York, NY, USA

Thomas Frazier

Centre for Brain & Cognitive Development, University of London, London, UK

Emily J. H. Jones

The Sackler Institute for Developmental Psychobiology, New York, NY, USA

Rebecca M. Jones

The Center for Autism and the Developing Brain, White Plains, NY, USA

Department of Psychiatry, Langley Porter Psychiatric Institute and Weill Institute for Neurosciences, University of California, San Francisco, CA, USA

Matthew W. State

Department of Pediatrics and Vanderbilt Kennedy Center, Vanderbilt University Medical Center, Nashville, TN, USA

Julie Lounds Taylor

Department of Psychiatry, Columbia University, New York, NY, USA

Jeremy Veenstra-VanderWeele

You can also search for this author in PubMed   Google Scholar

Contributions

All authors read and edited the full document. Introduction (C.L.), Epidemiology (T.S.B.), Mechanisms/pathophysiology (M.W.S., G.D., R.M.J., T.C. and E.J.H.J.), Diagnosis, screening and prevention (T.C., E.J.H.J. and T.S.B.), Management (T.S.B., T.C., E.J.H.J., J.L.T. and J.V.-V.), Quality of life (J.L.T., J.C. and T.F.), Outlook (C.L. and A.P.), Overview of Primer (C.L.).

Corresponding author

Correspondence to Catherine Lord .

Ethics declarations

Competing interests.

C.L. acknowledges the receipt of royalties from Western Psychological Services for the sale of the Autism Diagnostic Interview-Revised (ADIR), the Autism Diagnostic Observation Schedule (ADOS) and the Social Communication Questionnaire (SCQ). T.S.B. has received royalties from Cambridge University Press and Oxford University Press. T.C. has served as a consultant to F. Hoffmann-La Roche. and has received royalties from Guilford Publications and Sage Publications. T.F. has received federal funding research support from, acted as a consultant to, received travel support from, and/or received a speaker’s honorarium from the Brain and Behaviour Research Foundation, Bristol-Myers Squibb, the Cole Family Research Fund, EcoEos, Forest Laboratories, Ingalls Foundation, IntegraGen, Kugona LLC, the National Institutes of Health, Roche Pharma, Shire Development and the Simons Foundation. J.L.T. receives compensation from Sage Publishers for editorial work. A.P. receives royalties from Imperial College Press, Oxford University Press and Western Psychological Services. M.W.S. serves on the scientific advisory boards and has stock or stock options for Arett Pharmaceuticals and BlackThorn Therapeutics. J.V.-V. has consulted or served on an advisory board for Novartis, Roche Pharmaceuticals and SynapDx, has received research funding from Forest, Novartis, Roche Pharmaceuticals, Seaside Therapeutics, SynapDx, and has received an editorial stipend from Springer and Wiley. All other authors declare no competing interests.

Additional information

Peer review information.

Nature Reviews Disease Primers thanks S. Spence, P. Szatmari and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Cite this article.

Lord, C., Brugha, T.S., Charman, T. et al. Autism spectrum disorder. Nat Rev Dis Primers 6 , 5 (2020). https://doi.org/10.1038/s41572-019-0138-4

Download citation

Accepted : 26 November 2019

Published : 16 January 2020

DOI : https://doi.org/10.1038/s41572-019-0138-4

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

This article is cited by

Pharmacological and non-pharmacological interventions for irritability in autism spectrum disorder: a systematic review and meta-analysis with the grade assessment.

• Hangnyoung Choi
• Jae Han Kim
• Marco Solmi

Molecular Autism (2024)

The gut metabolite indole-3-propionic acid activates ERK1 to restore social function and hippocampal inhibitory synaptic transmission in a 16p11.2 microdeletion mouse model

• Dilong Wang
• Ningning Li

Microbiome (2024)

Effects of mini-basketball training program on social communication impairments and regional homogeneity of brain functions in preschool children with autism spectrum disorder

• Dandan Chen

BMC Sports Science, Medicine and Rehabilitation (2024)

Dietary intake and gastrointestinal symptoms are altered in children with Autism Spectrum Disorder: the relative contribution of autism-linked traits

• Saijun Huang

Nutrition Journal (2024)

Sex, hormones and cerebrovascular function: from development to disorder

• Adeline Collignon
• Laurence Dion-Albert
• Vanessa Coelho-Santos

Fluids and Barriers of the CNS (2024)

Quick links

• Explore articles by subject
• Guide to authors
• Editorial policies

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Introduction

Reading in autism spectrum disorders: a literature review.

• Split-Screen
• Article contents
• Figures & tables
• Supplementary Data
• Peer Review
• Open the PDF for in another window
• Get Permissions
• Cite Icon Cite
• Search Site

Fernanda Dreux Miranda Fernandes , Cibelle Albuquerque de La Higuera Amato , Carla Cardoso , Ana Luiza Gomes Pinto Navas , Daniela Regina Molini-Avejonas; Reading in Autism Spectrum Disorders: A Literature Review. Folia Phoniatr Logop 1 March 2016; 67 (4): 169–177. https://doi.org/10.1159/000442086

Download citation file:

• Ris (Zotero)
• Reference Manager

Objective: To review what the literature says about reading abilities of children on the autism spectrum (autism spectrum disorders, ASD) as well as to assess the results of intervention proposals. The broad ASD diagnosis used in the last decades and the resulting changes in the prevalence of these disorders have led to a relevant increase in the number of children diagnosed with ASD in the school system. The purpose of this review is to identify the different profiles of reading abilities shown by children with ASD described in the recent literature and the results of reported intervention methods. Methods: A review of the literature was conducted in the Web of Sciences and PubMed databases with the keywords ‘autism' AND ‘read*' and the filter 2010-2015. All articles published in the last 5 years focusing on description of and intervention for reading abilities in individuals with ASD were included. Review articles were excluded. Results: The selected 58 articles were divided into those that described reading abilities in individuals with ASD (n = 27) and those that reported intervention procedures for reading development (n = 31). Conclusions: Direct comparisons and associations were prevented due to different inclusion criteria and lack of detailed information about intervention processes. We propose tentative conclusions that should be confirmed by further studies.

The increasing number of children with a diagnosis of autism spectrum disorders (ASD) in the school system demands consistent information about the characterization of their reading abilities and the results of different intervention alternatives.

ASD have been the focus of many studies based on several different perspectives. These may vary from genetic and neurologic correlates [ 1,2,3,4 ] to social and emotional impact [ 5,6,7 ], or educational issues [ 8,9 ], family perspectives [ 10,11 ] and different intervention proposals [ 12,13 ].

The definitions and diagnostic criteria for ASD vary significantly in different studies [ 14,15 ], and therefore the conclusions can hardly be compared or accumulated, providing consistent data. The changes in the definition of what should be included within the autism spectrum are just one of the many variations that must be considered [ 16,17 ].

The changes implemented in the DSM-5 classification criteria will probably lead to different groups of individuals receiving the diagnosis of ASD [ 18,19 ]. Therefore, comparing the results of studies conducted before and after these changes may become even more complicated. It can be assumed that the vast majority of the subjects in studies published until 2015 were diagnosed according to the DSM-IV criteria. However, it is virtually impossible to determine a time frame from which all papers refer to subjects diagnosed according to the DSM-5 criteria.

On the other hand, the broad ASD diagnosis used in the last three decades and the resulting changes in the prevalence of these disorders [ 20,21 ] have led to a relevant increase in the number of children diagnosed with ASD in the school system [ 22 ].

Regarding reading abilities, studies should describe whether they refer to decoding, such as performance in tasks of word recognition performance, or in a broader sense to word reading comprehension [ 23 ]. Children with ASD are often characterized as showing precocious word reading abilities [ 24 ], but even though these children may have good decoding skills, comprehension is impaired in most cases.

Considering these aspects, it is relevant to know, at this point, what the recent literature describes about reading abilities in children with ASD and the intervention approaches proposed to improve such skills. Therefore, a literature review was performed with the purpose to address the questions: ‘do children with autism have specific reading impairments?' and ‘do interventions with focus on reading abilities of children with autism have positive results?'.

The purpose of this review was to identify the different profiles of reading abilities of children with ASD and the results of different intervention methods reported in the literature.

Search Strategy

A review of the literature was conducted to answer the questions stated above. The Web of Sciences (WoS) and PubMed (PM) databases were searched with the keywords ‘autism' AND ‘read*' with the filter 2010-2015.

Inclusion criteria were: articles published in the last 5 years in peer-reviewed journals indexed in WoS and PM databases with the focus on a description of reading abilities and intervention with individuals with ASD. Review articles were excluded.

In order to obtain an overview of the available information about the characterization of reading abilities and intervention proposals no further criteria were applied in the selection of the reviewed papers.

The first search resulted in 782 articles; 604 in WoS and 178 in PM. The initial analysis aimed to determine which of them focused specifically on both autism and reading. This process resulted in 58 papers in WoS and 32 in PM, a total of 90 articles. They were further analyzed to eliminate duplicates (i.e. articles that were included both in WoS and PM) and publications that did not have enough data; this search resulted in 72 articles that were analyzed according to their content. Among these, 14 articles were reports on literature reviews and were, therefore, excluded. The remaining 58 were divided into two categories: (a) those that described the reading abilities of individuals with ASD (n = 27) and (b) those that reported intervention procedures towards reading development (n = 31) (fig. 1 ). Further inspection of the articles helped specifying the details of each study, number of participants, measures of literacy skills used, and main conclusions. The results are presented in tables 1 and 2 .

Articles about reading characteristics of persons with ASD

Articles describing intervention proposals regarding reading abilities of persons with ASD

Search and selection process.

It can be observed that the number of participants in each study varied significantly. There are several papers describing studies with a relatively large numbers (59% of them report studies with more than 20 participants), some single-case studies (7%), and 4 studies that did not report the number of subjects (14%). Only 11% of 27 articles described studies with adults.

Regarding the type of measures used to evaluate literacy skills, most studies (44%) focused on single-word reading and text comprehension measures, some (29%) assessed cognitive abilities that are related to reading such as memory and oral language skills, whereas only 2 studies investigated spelling skills in this specific population.

Although the inclusion criteria for the participants in each study are not equivalent across the different papers, thus preventing a true meta-analysis, some tentative conclusions can be drawn.

- Performance in single-word reading tasks is better than reading comprehension.

- The oral language level is associated with reading comprehension.

- Persons with ASD have difficulties with reading comprehension despite eventually good or intact decoding skills.

- There is no confirmation of the weak central coherence hypothesis; it seems that the lack of association between meaning and word recognition is based on other factors.

- Nonverbal social and cognitive abilities are associated with reading comprehension and reading performance.

- Phonological processing seems to be less associated with reading comprehension performance than semantics and syntactic knowledge.

Contrary to what could be observed in articles describing reading abilities of persons with ASD, most of the papers describing intervention procedures had a small number of subjects [22 papers (70%) had 6 participants or less]. In total, these papers reported on 62 children and 5 adults. Six articles reported interventions with more than 18 participants, leading to a total of 143 children in these larger-number studies.

The intervention procedures described can be divided in two groups: those aiming to improve single-word reading and those directed to reading comprehension. Behavioral techniques are the basis for the strategies used in studies that focused on improving single-word reading. The conclusions of these articles imply that not all progress was generalized or maintained after the end of the training programs. The papers reporting programs for enhancing reading comprehension describe different approaches such as computer-assisted instruction, direct instruction, talking about a book, graphic organizers, story maps and prompting. Generalization to other abilities and stability of improvement were reported by these studies.

Three other articles refer to suggestions of intervention strategies such as scaffolding and the use of software designed to improve reading comprehension. These approaches are described as flexible, allowing one-to-one adaptations.

Characteristics of the reading process of persons with ASD were described in 27 articles that included 1,490 individuals. Direct comparisons and associations are prevented by the different inclusion criteria used in the different studies. However, it is possible to propose some preliminary conclusions that should be confirmed by further studies. Reading comprehension seems to be more associated with semantic and syntactic abilities in oral language than with phonological development. Decoding skills, apparently, are not directly associated with reading comprehension, thus leading to better performance in single-word reading tests than in reading comprehension. Nonverbal social and cognitive abilities seem to be associated with reading comprehension and reading performance, especially in what refers to the association of meaning to a word.

Intervention proposals regarding reading abilities of persons with ASD are reported in 31 articles that refer to a total of 210 subjects, including just 5 adults. Not all studies provide the detailed descriptions of the intervention procedures that would be necessary to make comparisons and associations between them. Very few studies include information about the duration of the intervention and the prior training of the therapists. Therefore, any conclusion about the reasons for the reported results would be premature. Better and more stable results are described by the articles that report interventions focused towards the improvement of reading comprehension, as opposed to the studies regarding the use of behavioral techniques to increase single-word reading abilities. However, there is not enough data about the duration of the intervention processes, specific characteristics of the participants before the intervention, training of the therapists in the area, specific material or resources used to allow hypotheses about better or more successful intervention methods.

Literacy acquisition in children and adults with ASD demand further assessment. The large individual variations of the autism spectrum may be reflected in the reading performance of persons with ASD, therefore resulting either in hyperlexia or in different forms of reading deficits. The identification of different reading strategies and specific profiles of abilities and impairments depends on efficient assessment tools that are essential to the design of more efficient intervention procedures.

Email alerts

Citing articles via, suggested reading.

• Online ISSN 1421-9972
• Print ISSN 1021-7762

INFORMATION

• Contact & Support
• Information & Downloads
• Rights & Permissions
• Terms & Conditions
• Catalogue & Pricing
• Policies & Information
• People & Organization
• Stay Up-to-Date
• Regional Offices
• Community Voice

SERVICES FOR

• Researchers
• Healthcare Professionals
• Patients & Supporters
• Health Sciences Industry
• Medical Societies
• Agents & Booksellers

Karger International

• S. Karger AG
• P.O Box, CH-4009 Basel (Switzerland)
• Allschwilerstrasse 10, CH-4055 Basel
• Tel: +41 61 306 11 11
• Fax: +41 61 306 12 34
• Contact: Front Office
• Experience Blog
• Privacy Policy
• Terms of Use

This Feature Is Available To Subscribers Only

Sign In or Create an Account

Application of the Acceptance and Commitment Therapy in Autism Spectrum Disorder and Their Caregivers: A Scoping Review

• Review Paper
• Published: 06 May 2024

Cite this article

• Dazhi Yao 1 ,
• Jiayi Chen 1 ,
• Jianqin Cao 1 ,
• Shuanglan Lin 2 ,
• Shuai Yuan 3 ,
• Mian Wang 2 &
• Quanzhi Zhang 1  

76 Accesses

1 Altmetric

Explore all metrics

The global prevalence of autism spectrum disorder (ASD) is increasing, leading to long-term challenges for both individuals with ASD and their parents. To address these issues, Acceptance and Commitment Therapy (ACT) has emerged as a promising approach. This scoping review aimed to examine the existing literature on the application of ACT in the field of ASD. A systematic search of databases including PubMed, PsycINFO, and Scopus yielded 18 articles that met the inclusion criteria. In conclusion, ACT holds promise as a therapeutic intervention for individuals with ASD and their parents. Nonetheless, further research is necessary to explore its effectiveness and determine the most suitable strategies for adapting the intervention to meet the unique needs of this population.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price includes VAT (Russian Federation)

Instant access to the full article PDF.

Rent this article via DeepDyve

Institutional subscriptions

Similar content being viewed by others

A Systematic Review: Acceptance and Commitment Therapy for the Parents of Children and Adolescents with Autism Spectrum Disorder

Measuring Outcomes for Adults with Autism Spectrum Disorders: Historical Perspectives and Hope for the Future

Evaluation of Acceptance and Commitment Therapy (ACT) for Mothers of Children and Youth with Autism SpectrumDisorder

Alonso-Fernández, M., López-López, A., Losada, A., González, J. L., & Wetherell, J. L. (2016). Acceptance and commitment therapy and selective optimization with compensation for institutionalized older people with chronic pain. Pain Medicine, 17 (2), 264–277. https://doi.org/10.1111/pme.12885

Article   PubMed   Google Scholar  

Anderson, D. K., Liang, J. W., & Lord, C. (2014). Predicting young adult outcome among more and less cognitively able individuals with autism spectrum disorders. Journal of Child Psychology and Psychiatry, 55 (5), 485–494. https://doi.org/10.1111/jcpp.12178

Andrews, D. S., Aksman, L., Kerns, C. M., Lee, J. K., Winder-Patel, B. M., Harvey, D. J., Waizbard-Bartov, E., Heath, B., Solomon, M., Rogers, S. J., Altmann, A., Nordahl, C. W., & Amaral, D. G. (2022a). Association of amygdala development with different forms of anxiety in autism spectrum disorder. Biological Psychiatry, 91 (11), 977–987. https://doi.org/10.1016/j.biopsych.2022.01.016

Article   PubMed   PubMed Central   Google Scholar  

Andrews, M. L., Garcia, Y. A., Catagnus, R. M., & Gould, E. R. (2022b). Effects of acceptance and commitment training plus behavior parent training on parental implementation of autism treatment. Psychological Record, 72 (4), 601–617. https://doi.org/10.1007/s40732-021-00496-5

Article   Google Scholar  

Billstedt, E., Gillberg, C., & Gillberg, C. (2005). Autism after adolescence: Population-based 13- to 22-year follow-up study of 120 individuals with autism diagnosed in childhood. Journal of Autism and Developmental Disorders, 35 (3), 351–360. https://doi.org/10.1007/s10803-005-3302-5

Byrne, G., Ghráda Á, N., O’Mahony, T., & Brennan, E. (2021). A systematic review of the use of acceptance and commitment therapy in supporting parents. Psychology and Psychotherapy, 94 (Suppl 2), 378–407. https://doi.org/10.1111/papt.12282

Carlson, J. M., & Miller, P. A. (2017). Family burden, child disability, and the adjustment of mothers caring for children with epilepsy: Role of social support and coping. Epilepsy & Behavior, 68 , 168–173. https://doi.org/10.1016/j.yebeh.2017.01.013

Çiçek Gümüş, E., & Öncel, S. (2022). Effects of Acceptance and Commitment Therapy-based interventions on the mental states of parents with special needs children: Randomized controlled trial. Current Psychology, 42 (23), 19429–19442. https://doi.org/10.1007/s12144-022-03760-1

Corti, C., Pergolizzi, F., Vanzin, L., Cargasacchi, G., Villa, L., Pozzi, M., & Molteni, M. (2018). Acceptance and Commitment Therapy-Oriented Parent-Training for Parents of Children with Autism. Journal of Child and Family Studies, 27 (9), 2887–2900. https://doi.org/10.1007/s10826-018-1123-3

Dindo, L., Van Liew, J. R., & Arch, J. J. (2017). Acceptance and commitment therapy: A transdiagnostic behavioral intervention for mental health and medical conditions. Neurotherapeutics, 14 (3), 546–553. https://doi.org/10.1007/s13311-017-0521-3

Fung, K., Lake, J., Steel, L., Bryce, K., & Lunsky, Y. (2018). ACT processes in group intervention for mothers of children with autism spectrum disorder. Journal of Autism and Developmental Disorders, 48 (8), 2740–2747. https://doi.org/10.1007/s10803-018-3525-x

Garcia, Y., Keller-Collins, A., Andrews, M., Kurumiya, Y., Imlay, K., Umphrey, B., & Foster, E. (2022). Systematic review of acceptance and commitment therapy in individuals with neurodevelopmental disorders, caregivers, and staff. Behavior Modification, 46 (5), 1236–1274. https://doi.org/10.1177/01454455211027301

Gould, E. R., Tarbox, J., & Coyne, L. (2018). Evaluating the effects of acceptance and commitment training on the overt behavior of parents of children with autism. Journal of Contextual Behavioral Science, 7 , 81–88. https://doi.org/10.1016/j.jcbs.2017.06.003

Gould, R. L., Wetherell, J. L., Kimona, K., Serfaty, M. A., Jones, R., Graham, C. D., Lawrence, V., Livingston, G., Wilkinson, P., Walters, K., Le Novere, M., Leroi, I., Barber, R., Lee, E., Cook, J., Wuthrich, V. M., & Howard, R. J. (2021). Acceptance and commitment therapy for late-life treatment-resistant generalised anxiety disorder: A feasibility study. Age and Ageing, 50 (5), 1751–1761. https://doi.org/10.1093/ageing/afab059

Hahs, A. D., Dixon, M. R., & Paliliunas, D. (2019). Randomized controlled trial of a brief acceptance and commitment training for parents of individuals diagnosed with autism spectrum disorders. Journal of Contextual Behavioral Science, 12 , 154–159. https://doi.org/10.1016/j.jcbs.2018.03.002

Han, A., Yuen, H. K., & Jenkins, J. (2021a). Acceptance and commitment therapy for family caregivers: A systematic review and meta-analysis. Journal of Health Psychology, 26 (1), 82–102. https://doi.org/10.1177/1359105320941217

Han, E., Scior, K., Avramides, K., & Crane, L. (2021b). A systematic review on autistic peopleʼs experiences of stigma and coping strategies. Autism Research, 15 (1), 12–26. https://doi.org/10.1002/aur.2652

Hayes, S. C. (2016). Acceptance and commitment therapy, relational frame theory, and the third wave of behavioral and cognitive therapies - Republished Article. Behavior Therapy, 47 (6), 869–885. https://doi.org/10.1016/j.beth.2016.11.006

Hayes, S. C. (2019). Acceptance and commitment therapy: Towards a unified model of behavior change. World Psychiatry, 18 (2), 226–227. https://doi.org/10.1002/wps.20626

Hayes, S. A., & Watson, S. L. (2013). The impact of parenting stress: A meta-analysis of studies comparing the experience of parenting stress in parents of children with and without autism spectrum disorder. Journal of Autism and Developmental Disorders, 43 (3), 629–642. https://doi.org/10.1007/s10803-012-1604-y

Hirota, T., & King, B. H. (2023). Autism SPECTRUM DISORDer: A Review. Jama, 329 (2), 157–168. https://doi.org/10.1001/jama.2022.23661

Holmberg Bergman, T., Renhorn, E., Berg, B., Lappalainen, P., Ghaderi, A., & Hirvikoski, T. (2023). Acceptance and Commitment therapy group intervention for parents of children with disabilities (Navigator ACT): An open feasibility trial. Journal of Autism and Developmental Disorders, 53 (5), 1834–1849. https://doi.org/10.1007/s10803-022-05490-6

Howlin, P., Moss, P., Savage, S., & Rutter, M. (2013). Social Outcomes in Mid- to Later Adulthood Among Individuals Diagnosed With Autism and Average Nonverbal IQ as Children. Journal of the American Academy of Child & Adolescent Psychiatry, 52 (6), 572–581. https://doi.org/10.1016/j.jaac.2013.02.017

Hutchinson, V. D., Rehfeldt, R. A., Hertel, I., & Root, W. B. (2019). Exploring the Efficacy of Acceptance and Commitment Therapy and Behavioral Skills Training to Teach Interview Skills to Adults with Autism Spectrum Disorders. Advances in Neurodevelopmental Disorders, 3 (4), 450–456. https://doi.org/10.1007/s41252-019-00136-8

JGL, A. T., Morina, N., Topper, M., & Emmelkamp, P. M. G. (2021). One year follow-up and mediation in cognitive behavioral therapy and acceptance and commitment therapy for adult depression. BMC Psychiatry, 21 (1), 41. https://doi.org/10.1186/s12888-020-03020-1

Keenan, B. M., Newman, L. K., Gray, K. M., & Rinehart, N. J. (2016). Parents of children with ASD experience more psychological distress, parenting stress, and attachment-related anxiety. Journal of Autism and Developmental Disorders, 46 (9), 2979–2991. https://doi.org/10.1007/s10803-016-2836-z

Lawson, L. P., Richdale, A. L., Denney, K., & Morris, E. M. J. (2023). ACT-i, an insomnia intervention for autistic adults: A pilot study. Behavioural and Cognitive Psychotherapy, 51 (2), 146–163. https://doi.org/10.1017/s1352465822000571

Leadbitter, K., Smallman, R., James, K., Shields, G., Ellis, C., Langhorne, S., Harrison, L., Hackett, L., Dunkerley, A., Kroll, L., Davies, L., Emsley, R., Bee, P., & Green, J. (2022). REACH-ASD: A UK randomised controlled trial of a new post-diagnostic psycho-education and acceptance and commitment therapy programme against treatment-as-usual for improving the mental health and adjustment of caregivers of children recently diagnosed with autism spectrum disorder. Trials, 23 (1), 585. https://doi.org/10.1186/s13063-022-06524-1

Lord, C., Charman, T., Havdahl, A., Carbone, P., Anagnostou, E., Boyd, B., Carr, T., de Vries, P. J., Dissanayake, C., Divan, G., Freitag, C. M., Gotelli, M. M., Kasari, C., Knapp, M., Mundy, P., Plank, A., Scahill, L., Servili, C., Shattuck, P., … McCauley, J. B. (2022). The Lancet Commission on the future of care and clinical research in autism. The Lancet, 399 (10321), 271–334. https://doi.org/10.1016/s0140-6736(21)01541-5

Lunsky, Y., Fung, K., Lake, J., Steel, L., & Bryce, K. (2018). Evaluation of acceptance and commitment therapy (ACT) for mothers of children and youth with autism spectrum disorder. Mindfulness, 9 (4), 1110–1116. https://doi.org/10.1007/s12671-017-0846-3

Marino, F., Failla, C., Chilà, P., Minutoli, R., Puglisi, A., Arnao, A. A., Pignolo, L., Presti, G., Pergolizzi, F., Moderato, P., Tartarisco, G., Ruta, L., Vagni, D., Cerasa, A., & Pioggia, G. (2021). The effect of acceptance and commitment therapy for improving psychological well-being in parents of individuals with autism spectrum disorders: A randomized controlled trial. Brain Sci , 11 (7). https://doi.org/10.3390/brainsci11070880

Mathur, S. K., Renz, E., & Tarbox, J. (2024). Affirming Neurodiversity within applied behavior analysis. Behavior Analysis in Practice. 1–15. https://doi.org/10.1007/s40617-024-00907-3

McCracken, L. M., & Vowles, K. E. (2014). Acceptance and commitment therapy and mindfulness for chronic pain: Model, process, and progress. American Psychologist, 69 (2), 178–187. https://doi.org/10.1037/a0035623

McStay, R. L., Dissanayake, C., Scheeren, A., Koot, H. M., & Begeer, S. (2013). Parenting stress and autism: The role of age, autism severity, quality of life and problem behaviour of children and adolescents with autism. Autism, 18 (5), 502–510. https://doi.org/10.1177/1362361313485163

McStay, R. L., Trembath, D., & Dissanayake, C. (2014). Stress and family quality of life in parents of children with autism spectrum disorder: Parent gender and the double ABCX model. Journal of Autism and Developmental Disorders, 44 (12), 3101–3118. https://doi.org/10.1007/s10803-014-2178-7

Moens, M., Jansen, J., De Smedt, A., Roulaud, M., Billot, M., Laton, J., Rigoard, P., & Goudman, L. (2022). Acceptance and commitment therapy to increase resilience in chronic pain patients: A clinical guideline. Medicina (Kaunas), 58 (4), 499. https://doi.org/10.3390/medicina58040499

Pahnke, J., Jansson-Fröjmark, M., Andersson, G., Bjureberg, J., Jokinen, J., Bohman, B., & Lundgren, T. (2022). Acceptance and commitment therapy for autistic adults: A randomized controlled pilot study in a psychiatric outpatient setting. Autism , 13623613221140749. https://doi.org/10.1177/13623613221140749

Pahnke, J., Lundgren, T., Hursti, T., & Hirvikoski, T. (2014). Outcomes of an acceptance and commitment therapy-based skills training group for students with high-functioning autism spectrum disorder: A quasi-experimental pilot study. Autism, 18 (8), 953–964. https://doi.org/10.1177/1362361313501091

Suarez, V. D., Moon, E. I., & Najdowski, A. C. (2021). Systematic review of acceptance and commitment training components in the behavioral intervention of individuals with autism and developmental disorders. Behavior Analysis in Practice, 15 (1), 126–140. https://doi.org/10.1007/s40617-021-00567-7

Szabo, T. G. (2019). Acceptance and Commitment Training for reducing inflexible behaviors in children with autism. Journal of Contextual Behavioral Science, 12 , 178–188. https://doi.org/10.1016/j.jcbs.2019.03.001

Szabo, T. G., Willis, P. B., & Palinski, C. J. (2019). Watch Me Try: ACT for Improving Athletic Performance of Young Adults with ASD. Advances in Neurodevelopmental Disorders, 3 (4), 434–449. https://doi.org/10.1007/s41252-019-00129-7

Veneziano, J., & Shea, S. (2023). They have a Voice; are we Listening? Behavior Analysis in Practice, 16 , 127–144. https://doi.org/10.1007/s40617-022-00690-z

Watanabe, T. (2021). Treatment of major depressive disorder with autism spectrum disorder by acceptance and commitment therapy matrix. Case Rep Psychiatry, 2021 , 5511232. https://doi.org/10.1155/2021/5511232

Whittingham, K., McGlade, A., Kulasinghe, K., Mitchell, A. E., Heussler, H., & Boyd, R. N. (2020). ENACT (ENvironmental enrichment for infants; parenting with Acceptance and Commitment Therapy): a randomised controlled trial of an innovative intervention for infants at risk of autism spectrum disorder. BMJ Open, 10 (8), e034315. https://doi.org/10.1136/bmjopen-2019-034315

Wittkopf, S., Stroth, S., Langmann, A., Wolff, N., Roessner, V., Roepke, S., Poustka, L., & Kamp-Becker, I. (2022). Differentiation of autism spectrum disorder and mood or anxiety disorder. Autism, 26 (5), 1056–1069. https://doi.org/10.1177/13623613211039673

Download references

This study was funded by Natural Science Foundation of Heilongjiang Province, China (LH2021H023).

Author information

Authors and affiliations.

School of Nursing, Harbin Medical University, Harbin, China

Dazhi Yao, Jiayi Chen, Jianqin Cao & Quanzhi Zhang

School of Nursing, The Hong Kong Polytechnic University, Hong Kong, China

Shuanglan Lin & Mian Wang

Psychiatric Department, Daqing Third Hospital, Daqing, China

You can also search for this author in PubMed   Google Scholar

Corresponding author

Correspondence to Quanzhi Zhang .

Ethics declarations

Conflict of interest.

The authors declare no competing interests.

Additional information

Publisher's note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Dazhi Yao and Jiayi Chen are co-first authors.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Yao, D., Chen, J., Cao, J. et al. Application of the Acceptance and Commitment Therapy in Autism Spectrum Disorder and Their Caregivers: A Scoping Review. Rev J Autism Dev Disord (2024). https://doi.org/10.1007/s40489-024-00460-3

Download citation

Received : 28 June 2023

Accepted : 10 April 2024

Published : 06 May 2024

DOI : https://doi.org/10.1007/s40489-024-00460-3

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Autism spectrum disorder,
• Acceptance and Commitment Therapy,
• Parents of children with ASD,
• Find a journal
• Publish with us
• Track your research

A .gov website belongs to an official government organization in the United States.

A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

• Signs and Symptoms
• Living with Autism Spectrum Disorder
• Frequently Asked Questions (FAQs)
• Data and Statistics on Autism Spectrum Disorder
• Autism Materials and Resources
• Diagnosis ASD
• Information on ASD for Healthcare Providers
• Acceptance Month Partner Toolkit
• 2023 Community Report on Autism
• Autism Data Visualization Tool

Autism Spectrum Disorder in Teenagers and Adults

• People with autism spectrum disorder (ASD) face challenges during the transition from childhood to adolescence and adulthood.
• Research suggests fewer young people with ASD have the same opportunities as their peers without ASD.
• People with ASD may experience changes in their ASD symptoms, behaviors, and related health conditions during adolescence and young adulthood.

A greater number of children identified with ASD has led to a growing interest in the transition to adolescence and adulthood. For most young people, including those with ASD, adolescence and young adulthood are filled with new challenges, responsibilities, and opportunities. However, research suggests fewer young people with ASD have the same opportunities as their peers without ASD:

• High rates of unemployment or under-employment 1 2 3 4 5 6 7
• Low participation in education beyond high school 4 7 8
• Majority continue to live with family members or relatives 1 9
• Limited opportunity for community or social activities—nearly 40% spend little or no time with friends 6 10 11 12

In addition, individuals with ASD may experience changes in their ASD symptoms, behaviors, and co-occurring health conditions during adolescence and young adulthood. These changes can affect their ability to function and participate in the community.

CDC's work for adults with ASD

Planning for service needs.

Beginning in 2018, CDC's Autism and Developmental Disabilities Monitoring (ADDM) Network began to track 16-year-olds who had been identified with ASD by 8 years of age across five ADDM Network sites. These efforts will provide valuable information on identifying health care needs for youth with ASD and transition planning in special education services and potential service needs after high school.

Promoting better outcomes

CDC's Study to Explore Early Development (SEED) began identifying children with ASD in the mid-2000s and these children are now beginning the transition from adolescence to adulthood. Through SEED Teen , CDC began tracking the changes that occur during this transition period to learn about factors that may promote more successful transitions and better outcomes in young adults with ASD.

In the current phase of SEED, known as SEED Follow-Up , CDC's goal is to learn how best to improve the health and functioning of children with ASD as they mature, better understand the service use and needs of children, adolescents, and young adults with ASD, and better understand how to support families.

Key Findings on Adults with ASD

Key Findings‎

• Levy A, Perry A. Outcomes in adolescents and adults with autism: A review of the literature. Research in Autism Spectrum Disorders. 2011;5(4):1271-82.
• Taylor JL, Seltzer MM. Employment and post-secondary educational activities for young adults with autism spectrum disorders during the transition to adulthood. J Autism Dev Disord . 2011;41(5):566-574.
• Shattuck PT, Lau L, Anderson KA, Kuo AA. A National Research Agenda for the Transition of Youth With Autism. Pediatrics . 2018;141(Suppl 4):S355-S361.
• Shattuck PT, Narendorf SC, Cooper B, Sterzing PR, Wagner M, Taylor JL. Postsecondary education and employment among youth with an autism spectrum disorder. Pediatrics . 2012;129(6):1042-1049.
• Roux, Anne M. National autism indicators report: Transition into young adulthood . AJ Drexel Autism Institute, 2015.
• Kirby AV. Parent Expectations Mediate Outcomes for Young Adults with Autism Spectrum Disorder. J Autism Dev Disord . 2016;46(5):1643-1655.
• Roux AM, Shattuck PT, Cooper BP, Anderson KA, Wagner M, Narendorf SC. Postsecondary employment experiences among young adults with an autism spectrum disorder. J Am Acad Child Adolesc Psychiatry . 2013;52(9):931-939.
• Hendricks DR, Wehman P. Transition from school to adulthood for youth with autism spectrum disorders: Review and recommendations. Focus on autism and other developmental disabilities. 2009 Jun;24(2):77-88.
• Dudley KM, Klinger MR, Meyer A, Powell P, Klinger LG. Understanding Service Usage and Needs for Adults with ASD: The Importance of Living Situation. J Autism Dev Disord . 2019;49(2):556-568.
• Liptak GS, Kennedy JA, Dosa NP. Social participation in a nationally representative sample of older youth and young adults with autism. J Dev Behav Pediatr . 2011;32(4):277-283.
• DaWalt LS, Usher LV, Greenberg JS, Mailick MR. Friendships and social participation as markers of quality of life of adolescents and adults with fragile X syndrome and autism. Autism . 2019;23(2):383-393.
• Orsmond GI, Shattuck PT, Cooper BP, Sterzing PR, Anderson KA. Social participation among young adults with an autism spectrum disorder. J Autism Dev Disord . 2013;43(11):2710-2719.

Autism Spectrum Disorder (ASD)

Autism spectrum disorder (ASD) is a developmental disability that can cause significant social, communication and behavioral challenges. CDC is committed to continuing to provide essential data on ASD and develop resources that help identify children with ASD as early as possible.

For Everyone

Health care providers, public health.

• Open access
• Published: 13 May 2024

Synergistic effect of mesenchymal stem cell-derived extracellular vesicle and miR-137 alleviates autism-like behaviors by modulating the NF-κB pathway

• Qian Qin 1   na1 ,
• Zhiyan Shan 2   na1 ,
• Lei Xing 1 ,
• Yutong Jiang 1 ,
• Mengyue Li 1 ,
• Linlin Fan 1 ,
• Xin Zeng 1 ,
• Xinrui Ma 1 ,
• Danyang Zheng 1 ,
• Han Wang 1 ,
• Hui Wang 1 ,
• Hao Liu 1 ,
• Shengjun Liang 1 ,
• Lijie Wu 1 &
• Shuang Liang   ORCID: orcid.org/0000-0002-1542-9702 1  

Journal of Translational Medicine volume  22 , Article number:  446 ( 2024 ) Cite this article

297 Accesses

2 Altmetric

Metrics details

Autism spectrum disorder (ASD) is a multifaceted neurodevelopmental disorder predominant in childhood. Despite existing treatments, the benefits are still limited. This study explored the effectiveness of mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) loaded with miR-137 in enhancing autism-like behaviors and mitigating neuroinflammation. Utilizing BTBR mice as an autism model, the study demonstrated that intranasal administration of MSC-miR137-EVs ameliorates autism-like behaviors and inhibits pro-inflammatory factors via the TLR4/NF-κB pathway. In vitro evaluation of LPS-activated BV2 cells revealed that MSC-miR137-EVs target the TLR4/NF-κB pathway through miR-137 inhibits proinflammatory M1 microglia. Moreover, bioinformatics analysis identified that MSC-EVs are rich in miR-146a-5p, which targets the TRAF6/NF-κB signaling pathway. In summary, the findings suggest that the integration of MSC-EVs with miR-137 may be a promising therapeutic strategy for ASD, which is worthy of clinical adoption.

Introduction

Autism spectrum disorder (ASD) encompasses a series of complex neurodevelopmental disorders, mainly manifested before the age of three. These disorders are characterized by diverse levels of impairment in social interaction and communication as well as restricted or repetitive behaviors and interests [ 1 ]. Epidemiological surveys show that the incidence of ASD is increasing globally, annually, and exponentially. 2023 data from the United States Centers for Disease Control and Prevention showed that 2.76% of 8-year-old children had been diagnosed with ASD [ 2 ]. ASD requires specialized educational, healthcare, and familial support services, which bring enormous economic and emotional pressure to societiy and family [ 3 ]. Therefore, ASD has escalated into a major public health issue, seriously affecting the quality of life and overall population health, making the exploration of its etiology and treatment essential crucial in contemporary medical research.

Extracellular vesicles (EVs) encapsulate distinctive bioactive molecules reflecting the composition and physiological statuses of eukaryotic cells. These vesicles promote various modes of cellular target engagement, and facilitate intercellular information transmission [ 4 , 5 , 6 ]. Studies have shown that exosomes can play pivotal roles in the therapeutic intervention of nervous system disorders [ 7 ]. In addition, the lipid bilayer structure of EVs protects their contents from degradation, enhancing their important role in intercellular communication [ 8 ].

Mesenchymal stem cells (MSCs) are pluripotent stem cells with various differentiation potential, immune regulation ability, tissue repair ability, and neuroprotective ability, among other functionalities. In recent years, they have become increasingly prominent and widely used in the treatment and research of multisystem disorders such as neurological and cardiovascular diseases [ 9 ]. MSCs are known to alleviate neuroinflammation, protect neurons, promote neuronal axon growth, and enhance neuroregeneration. Compared to MSCs, MSC-derived extracellular vesicles (MSC-EVs) present a more stable option, with stronger preservation ability and a reduced risk of immune rejection, thus providing innovative pathways for cell therapy of various diseases. Research has confirmed that MSC-EVs can reduce pro-inflammatory agents such as interferon-γ (IFN-γ) and tumor necrosis factor (TNF-α), thereby attenuating the inflammatory response [ 10 ].

MicroRNAs (miRNAs) are small regulatory RNAs prevalent in various organisms and are instrumental in modulating post-transcriptional gene expression by directing mRNA toward degradation or inhibiting translation [ 11 ]. As a specific example, miR-137 modulates neuronal synaptic length and influences neuronal maturation and dendritic morphogenesis, which are pivotal in determining neuronal structure and functionality [ 12 , 13 ]. Early studies have discerned associations between miR-137 dysfunction and various neuronal aspects such as differentiation, inflammation, and overall neurodevelopment, as well as the emergence of neurological disorders such as schizophrenia [ 14 , 15 , 16 ]. Notably, the Institute of Animal Science, Chinese Academy of Sciences has reported that mice with a nervous system-specific knockout of miR-137 exhibit phenotypic irregularities, such as stereotypical repetitive behaviors and deficits in social competency and learning memory [ 17 ]. These findings underscore the potential significance of miR-137 in the genesis and progression of ASD, necessitating further in-depth investigation and elucidation.

This study aims to explore the potential mechanisms of MSC-EVs and MSC-miR137-EVs in alleviating autism-like behaviors. These findings can offer novel perspective on targeted intervention for ASD.

Preparation and characterization of MSC-EVs and MSC-miR137-EVs

To construct MSC-miR137-EVs, lentiviruses overexpressing miR137 were transduced into MSC cells. MSC-EVs and MSC-miR137-EVs were then isolated from MSCs and MSCs expressing miR-137 (MSCs-miR137), respectively, using gradient centrifugation and ultracentrifugation method (Fig.  1 A). The isolated EVs exhibited physical homogeneity when observed under transmission electron microscopy (TEM) (Fig.  1 B, C). Meanwhile, nanoparticle analysis revealed an average size of 180 nm in diameter, as illustrated in Fig.  1 D, E. Additionally, the presence of characteristic EVs membrane proteins such as CD9, CD63, and tumor susceptibility gene 101 (TSG101), along with the intracellular protein calnexin, was verified through Western blot analysis, further substantiating the identification of the isolated particles as EVs (Fig.  1 F). In this study, the gene expression profile within the GSE89596 dataset, which is focusing specifically on miRNA levels of peripheral blood in ASD patients with control of the public Gene Expression Omnibus (GEO) database was download and analyzed. Our analysis confirmed that miR-137 expression was significantly lower in ASD patients than that in control (Fig.  1 G). Subsequently, quantitative real-time polymerase chain reaction (qRT-PCR) was employed to assess the levels of miR-137 in MSCs transfected with the lentiviral expression vector. As shown in Fig.  1 H, the expression of miR-137 was elevated in MSCs-miR137 compared to that in MSCs. Furthermore, the expression of miR-137 in MSC-miR137-EVs was higher than that in MSC-EVs (Fig.  1 I). These results collectively indicated the successful construction of MSC-EVs and MSC-miR137-EVs, confirming their suitability for subsequent studies.

Preparation and characterization of MSC-EVs and MSC-miR137-EVs. (A) Schematic illustrating the production and harvest process of MSC-miR137-EVs for targeted miR-137 delivery. (B–C) TEM images of EVs isolated from the culture medium of MSCs. (D–E) Size distribution of MSC-EVs and MSC-miR137-EVs measured using a nanoparticle size meter. (F) Western blot analysis demonstrating the expression of CD9, CD63, TSG101, and calnexin in MSC-EVs and MSC-miR137-EVs. (G) The miR-137 expression level of peripheral blood between ASD patients and controls. (H) Relative qRT-PCR analysis of miR-137 in MSCs-miR137 transduced with miR-137 lentivirus. *** P  < 0.001 versus the MSC group using Student’s t test. (I) Relative qRT-PCR analysis of miR-137 in MSC-miR137-EVs. ** P  < 0.01 versus MSC-EVs using Student’s t test. All data are presented as the mean ± SEM of three independent experiments

Engineered MSC-EVs efficiently delivered exosomal miR-137 into the brain

The BTBR T + Itpr3tf/J (BTBR) mouse model emulates numerous core clinical manifestations typically observed in patients with ASD, such as comparable behavioral attributes, brain structures, and functional abnormalities [ 18 ]. This resemblance makes the BTBR mouse model exceptionally suited for ASD research. Consequently, BTBR mice were selected for investigating the in vivo role of MSC-miR137-EVs.

To investigate the regions of decreased miR-137 expression in the BTBR mouse brain, relative qRT-PCR analysis was performed. As shown in Fig.  2 A–C, the expression of miR-137 in the cerebellar tissue of BTBR mice was lower compared to that in control mice, while no significant difference was observed in the hippocampus and prefrontal cortex. To validate the delivery efficacy of EVs to the brain, 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindotricarbocyanine iodide (DiR)-labeled EVs were monitored using an in vivo imaging system (IVIS) 6 h post-intranasal administration at a dosage of 200 µg (Fig.  2 D). The in vivo delivery efficacy of miR-137 by MSC-EVs was then evaluated using relative qRT-PCR analysis (Fig.  2 E).

miR-137 was efficiently delivered by MSC-EVs into the brain. (A–C) Relative qRT-PCR analysis was performed to assess the reduced expression of miR-137 in the brain tissue of BTBR mice. ns P  ≥ 0.05, ** P  < 0.01 versus the C57BL/6J group using Student’s t test. (D) In vivo imaging illustrating the distribution of DiR-labeled MSC-EVs and MSC-miR137-EVs in mice. (E) Relative qRT-PCR analysis of miR-137 levels in the mouse cerebellum after injection of MSC-EVs or MSC-miR137-EVs. ns P  ≥ 0.05, ** P  < 0.01, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

MSC-EVs-mediated delivery of miR-137 alleviated autism-like behaviors in BTBR mice

The BTBR mice were intranasally administered MSC-EVs or MSC-miR137-EVs for 7 days. Next, the three-chamber test, open field test (OFT), and Morris water maze (MWM) test were conducted to evaluate the social ability, anxiety level, and learning and memory abilities of the spatial position and directional senses, respectively (Fig.  3 A). As shown in Fig.  3 B–I, BTBR mice administered MSC-EVs and MSC-miR137-EVs exhibited evidence of ameliorated autism-like behaviors.

In this study, the three-chamber test was employed to evaluate the social behaviors of mice. During the initial stage of the social ability test ( Fig.  3 B, C ) , B6 mice showed a preference for interacting with Stranger 1 (S1), whereas BTBR mice showed no preference between interacting with S1 or the empty cage (E), indicating an impairment in the social abilities of the BTBR mice. However, BTBR mice in the MSC-EVs and MSC-miR137-EVs intervention groups exhibited enhanced social abilities post-intervention. In the social preference test stage ( Fig.  3 B, D ) , B6 mice favored interaction with Stranger 2 (S2). Conversely, BTBR mice showed no preferential interaction with either S1 or S2, highlighting a compromised social preference. Yet, post-intervention with MSC-EVs and MSC-miR137-EVs, an improvement in the social preference of BTBR mice was observed.

In the OFT, compared to B6 mice, BTBR mice exhibited longer movement distances and durations of activity in the open field. However, BTBR mice in the MSC-miR137-EVs intervention group exhibited reduced movement distances and durations of activity relative to the BTBR mice. These results suggested an improvement in anxiety levels within the MSC-miR137-EVs group (Fig.  3 E, F).

A five-day MWM experiment was conducted for each group of mice. During the learning phase, the BTBR mice demonstrated lower latency in finding the platform compared to B6 mice. In the test stage, the BTBR mice crossed the platform fewer times than B6 mice, indicating impairments in learning and memory. In comparison to the BTBR group, the mice in the MSC-EVs and MSC-miR137-EVs intervention groups exhibited quicker decreases in latency during the learning phase. Additionally, the test phase revealed an increase in the number of intervention group mice entering the platform area compared to the BTBR group ( Fig.  3 G–I ) . These findings suggested that MSC-miR137-EVs has the potential to improve cognitive impairments related to spatial and directional learning and memory in BTBR mice.

Effects of miR-137 and MSC-EVs on autism-like behaviors in BTBR mice. (A) Schematic representation illustrating the experimental procedure involving EVs and the subsequent behavioral studies conducted. (B–I) MSC-EVs and MSC-miR137-EVs relieved autism-like behaviors in BTBR mice, as measured by the three-chamber test (B–D) , OFT (E–F) and MWM (G–I) . ns P  ≥ 0.05, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 using one/two-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

MSC-EVs-mediated delivery of miR-137 regulated TLR4/NF-κB to attenuate neuroinflammation

Immunofluorescence detection revealed that the expression of microglia marker ionized calcium-binding adaptor molecule 1 (Iba-1) in the cerebellums of BTBR mice was elevated compared to that in the control mice, indicative of neuroinflammation in the cerebellums of BTBR mice (Figure S1 ). To assess the ability of MSC-EVs and miR-137 to attenuate neuroinflammation, we evaluated the levels of pro-inflammatory factors in the cerebellum after 7-day EVs administration. First, the mRNA expression levels of interleukin-1β (IL-1β), IL-6, TNF-α, and interferon (INF)-γ and the protein expression levels of Iba-1, IL-1β, and TNF-α were increased in BTBR cerebellums compared to that in control mice cerebellums, indicating significant neuroinflammation and microglia activation in the BTBR cerebellum (Fig.  4 A–D). After a 7-day injection, notable decreases were observed in the expression levels of Iba-1, IL-1β, and TNF-α in the BTBR cerebellums of both the MSC-EVs and the MSC-miR137-EVs groups compared to the control group. Remarkably, the reduction was more pronounced in the MSC-miR137-EVs group than in the MSC-EVs group. These observations suggested that MSC-EVs and miR-137 could ameliorate neuroinflammation in BTBR mice (Fig.  4 E–H).

MSC-EVs-mediated delivery of miR-137 to attenuate neuroinflammation. (A–D) Expression levels of IL-1β (A) , TNF-α (B) , IL-6 (C) , and INF-γ (D) were assessed by relative qRT-PCR analysis in the cerebellum following administration of MSC-EVs and MSC-miR137-EVs in BTBR mice. ns P  ≥ 0.05, ** P  < 0.01, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test. (E–H) Western blot analysis was conducted to assess the levels of IL-1β, TNF-α, and Iba-1 following the administration of MSC-EVs and MSC-miR137-EVs in BTBR mice. ns P  ≥ 0.05, * P  < 0.05, ** P  < 0.01 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

To elucidate the mechanism through which miR-137 attenuates inflammation in BTBR mice, we initially predicted the target genes of miR-137 utilizing the publicly available Starbase database ( https://starbase.sysu.edu.cn/starbase2 ). Then, we analyzed the gene expression profiles within the GSE62594 dataset of the GEO database, which references cerebellum expression in B6 and BTBR mice, and screened the differential genes that were upregulated in the cerebellums of BTBR mice. Further, the genes related to ASD and neuroinflammation within the list of upregulated differentially expressed genes were screened through literature review. Ultimately, the specific candidate gene, TLR4, of miR-137 in the BTBR cerebellar tissue was identified by integrating the list of miR-137 target genes with genes ascertained from the GEO database. Subsequent experimental verification was conducted to verify these findings (Fig.  5 A, B, Table S1 ).

To evaluate the binding of miR-137-3p with TLR4, the wild-type 3′-untranslated region (UTR) sequence and the mutated sequence were cloned into the pmirGLO vector. The reporter constructs were co-transfected into HEK293T cells with miR-137-3p mimic or a mimic negative control (NC). A dual-luciferase assay revealed that miR-137-3p decreased pmirGLO-TLR4-WT activity by binding to the target sequence. Furthermore, the inhibition of luciferase was abolished after mutation of the binding site (Fig.  5 C).

The TLR4 levels in the cerebellum were assessed using qRT-PCR analysis post-intranasal administration of EVs. As shown in Fig.  5 D, compared with the control group, the level of TLR4 mRNA in the cerebellums of mice injected with MSC-miR137-EVs was reduced compared with that in the control group, though the expression of TLR4 in the cerebellums of mice in the MSC-EVs group did not change significantly. These findings suggested that MSC-EVs facilitated the delivery of miR-137 into the mouse brain via intranasal administration.

miR-137 bound to and downregulated the expression of TLR4. (A–B) The miRNA–mRNA interaction was predicted using the Starbase public databases, and the GSE62594 dataset was analyzed to examine differences in TLR4 expression in the cerebellum between C57BL/6J and BTBR mice. (C) Dual-luciferase assay was performed to determine that miR-137 targets TLR4. ns P  ≥ 0.05, ** P  < 0.01 versus the control group using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test. (D) qRT-PCR analysis of TLR4 expression in the cerebellums of BTBR mice after EVs were introduced. ns P  ≥ 0.05, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

The TLR4 expression level was higher in BTBR mice than in B6 mice, and the protein expression levels of phosphorylated NF-κB (p-NF-κB), NF-κB, phosphorylated inhibitor of NF-κB (p-IκB), and IκB were also higher in BTBR mice than in B6 mice, indicating that the TLR4/NF-κB pathway was over-activated in the cerebellums of BTBR mice. One week after the administration of EVs, compared with the control group, the TLR4 protein expression in the cerebellums of BTBR mice in the MSC-miR137-EVs group was reduced, indicating that the activation of the TLR4/NF-κB pathway had also decreased. In the MSC-EVs group, the TLR4 expression level had not decreased, but the activation of the NF-κB pathway was reduced (Fig.  6 A–F).

MSC-EVs-mediated delivery of miR-137 regulated the TLR4/NF-κB pathway. (A) Western blot analysis of the expression of members of the TLR4/NF-κB signaling pathway in the cerebellums of BTBR mice after the introduction of EVs. (B–F) Statistical results of the expression of members of the TLR4/NF-κB signaling pathway in the cerebellums of BTBR mice after the introduction of EVs. ns P  ≥ 0.05, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test. All datas are presented as the mean ± SEM of three independent experiments

MSC-miR137-EVs inhibited mouse microglial activation and neurotoxicity in vitro

To verify the inhibition of inflammation by MSC-EVs and miR-137 in vitro, MSC-EVs or MSC-miR137-EVs were co-incubated with lipopolysaccharide (LPS)-activated BV2 microglial (LPS-BV2) cells (Fig.  7 A). MSC-EVs and MSC-miR137-EVs labeled with 2-[3-(1,3-dihydro-3,3-dimethyl-1-octadecyl-2 H-indol-2-ylidene)-1-propen-1-yl]-3,3-dimethyl-1-octadecyl-3 H-indolium, monoperchlorate (DiI) were internalized by BV2 cells at 3 h (Fig.  7 B). To investigate the effect of EVs on the LPS-induced activation of BV2 cells, after treatment with EVs (50 µg) for 48 h, we first evaluated their morphological changes. As shown in Fig.  7 C, resting microglia were spindle-shaped, with small cell bodies with long processes. After LPS treatment, microglia showed a pro-inflammatory M1 morphology, characterized by big cell bodies with short processes. However, the LPS-induced morphological changes in BV2 cells were attenuated after treatment with MSC-EVs and MSC-miR137-EVs. Then, we performed qRT-PCR and Western blot to detect the production of pro-inflammatory factors in BV2 cells. The results revealed that MSC-EVs and miR-137 could reduce the LPS-induced increases in IL-1β and TNF-α in microglia (Fig.  7 D–H). These results suggested that both MSC-EVs and miR-137 can reverse LPS-induced microglia morphological changes and inflammatory factor production.

MSC-miR137-EVs inhibited mouse microglial activation in vitro. (A) Schematic illustration of the incorporation and uptake of engineered EVs into mouse microglial BV2 cells. (B) Fluorescence images depicting BV2 cells following their incubation with DiI-labeled EVs. Scale bar: 100 μm. (C) Morphological alterations in BV2 cells were visually examined under an optical microscope following incubation with either MSC-EVs or MSC-miR137-EVs. (D–H) The expression levels of IL-1β (D) and TNF-α (E) were quantified by relative qRT-PCR and Western blot analysis (F–H) in mouse microglia co-incubated with MSC-EVs or MSC-miR137-EVs with or without LPS treatment. ns P  ≥ 0.05, ** P  < 0.01, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

Compared with the control group, the miR-137 level in LPS-induced BV2 cells decreased, and the administration of MSC-miR137-EVs increased the level of miR-137 in microglia after co-incubation with LPS-BV2 cells (Fig.  8 A). Meanwhile, we evaluated the TLR4 mRNA expression levels in LPS-induced BV2 cells after co-culture with EVs by qRT-PCR analysis, which revealed that TLR4 mRNA levels were decreased in BV2 cells co-cultured with MSC-miR137-EVs compared with the control group (Fig.  8 B).

After 48 h of co-culture of BV2 cells with EVs, we measured the TLR4 expression and the activation of the TLR4/NF-κB pathway in BV2 cells (Fig.  8 C–H). In LPS-induced BV2 cells, the TLR4 expression level was higher than that in control cells, and the protein levels of p-NF-κB, NF-κB, p-IκB, and IκB were also higher than in uninduced BV2 cells, indicating that the TLR4/NF-κB pathway was over-activated in the LPS-induced BV2 cells. However, in the MSC-miR137-EVs group, the activation level of the TLR4/NF-κB pathway was decreased. Surprisingly, in the MSC-EVs group, the TLR4 expression level was not different, but the activation of the NF-κB pathway was reduced. In conclusion, miR-137 could alleviate the activation of the TLR4/NF-κB pathway in LPS-induced BV2 cells, and MSC-EVs could also decrease the activation level of the NF-κB pathway.

To further elucidate whether microglial polarization could affect neuronal apoptosis, BV2 microglia and N2a cells were co-cultured using a Transwell system, as shown in Fig.  8 I. Briefly, BV2 cells in the upper chamber were divided into the following groups: control, LPS, LPS with MSC-EVs, and LPS with MSC-miR137-EVs. N2a cells were seeded in the lower chamber. The Western blot analysis revealed that the level of the apoptosis-associated protein cleaved caspase-3 was increased in the N2a cells in the LPS group, but the levels were observably decreased in the MSC-EVs and MSC-miR137-EVs groups (Fig.  8 J, K). In brief, these results indicated that MSC-miR137-EVs could efficiently convert microglia from the proinflammatory M1 phenotype and restrain neuronal apoptosis, which may be related to the microglia phenotype conversion.

MSC-miR137-EVs inhibited mouse microglial activation and neurotoxicity by the TLR4/NF-κB pathway in vitro. (A–B) Relative qRT-PCR analysis was conducted to assess the levels of miR-137 and TLR4 in BV2 cells following co-incubation with MSC-EVs or MSC-miR137-EVs. ns P  ≥ 0.05, * P  < 0.05, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparisons test. (C–H) Western blot analysis of the expression of members of the TLR4/NF-κB signaling pathway in LPS-induced BV2 cells after co-culture with EVs. ns P  ≥ 0.05, * P  < 0.05, ** P  < 0.01, *** P  < 0.001 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test. (I) Schematic illustration of N2a cells co-incubated with BV2 cells co-cultured with MSC-EVs or MSC-miR137-EVs with or without LPS treatment. (J–K) Western blot analysis of cleaved caspase-3 levels in N2a cells after co-incubation with LPS-BV2 cells co-cultured with MSC-EVs or MSC-miR137-EVs with or without LPS treatment. ns P  ≥ 0.05, ** P  < 0.01 using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

MSC-EVs alleviate neuroinflammation via the miR-146a-5p/TRAF6 pathway

Previous research has demonstrated that the predominant functional RNA components in exosomes are miRNAs, which can be effectively transmitted to other cells to perform various function through exosomal integration [ 19 ]. miRNAs, one of the most important cargos in exosomes, are transferred to other cells and play important roles in regulating inflammatory diseases, such as osteoarthritis [ 20 ] and inflammatory pain [ 21 ]. Therefore, to investigate the possible mechanism by which MSC-EVs influence neuroinflammation of ASD, we analyzed the top 20 highly enriched miRNAs in the GSE69909 and GSE159814 public datasets and an additional file from a report by Weijiang Liu (Fig.  9 A). The five overlapping miRNAs in MSC-EVs from the above three datasets, hsa-miR-21-5p, hsa-miR-100-5p, hsa-let-7f-5p, hsa-let-7a-5p, and hsa-miR-146a-5p, were screened (Fig.  9 B). Compared with that in the PBS group, the relative expression levels of miR-146a-5p in the cerebellum tissue of BTBR mice and LPS-BV2 cells pretreated with MSC-EVs were both significantly increased, as shown by qRT-PCR (Fig.  9 C, D). Then, the miRWalk, miRBD, and TargetScan databases were used to predict the target genes of miR-146a-5p. There were 56 overlapping genes in the three public databases (Fig.  9 E). Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment bioinformatics analysis revealed that the target genes of miR-146a-5p were highly involved in the activation of NF-κB-inducing kinase activity, negative regulation of transcription from the RNA polymerase II promoter, nervous system development, and positive regulation of viral genome replication by the host (Fig.  9 F). Intriguingly, the targeted genes of miR-146a-5p were involved in the NF-κB signaling pathway, which is well-known to activate neuroinflammation [ 22 ]. Meanwhile, TRAF6 was one of the most relevant target genes of miR-146a-5p in the NF-κB signaling pathway. Western blot analysis revealed that TRAF6 protein expression was significantly decreased in the cerebellum tissue of BTBR mice and LPS-BV2 cells treated with MSC-EVs compared with those in BTBR mice treated with PBS and LPS-BV2 cells (Fig.  9 G, H). Generally, these data suggested that MSC-EVs alleviated neuroinflammation in LPS-treated BV2 cells and BTBR mice via the miR-146a-5p/TRAF6 pathway.

MSC-EVs alleviated neuroinflammation via the miR-146a-5p/TRAF6 pathway. (A) Analysis of miRNA abundance in MSC-EVs conducted utilizing datasets GSE69909 and GSE159814 from the GEO database, complemented by sequencing data from a publication by Weijiang Liu. (B) Venn diagram of the intersection of the 20 most abundant miRNAs identified from three different datasets and the overlapping miRNAs. (C) Relative miRNA expression in the cerebellum tissue of BTBR mice pretreated with MSC-EVs, relative to the PBS group. (D) Relative miRNA expression in LPS-BV2 cells pretreated with MSC-EVs, relative to the PBS group. (E) Venn diagram of the intersection of the mRNA targets identified from three miRNA databases and the overlapping genes. (F) GO and KEGG analysis of the predicted mRNA targets for miR-146a-5p in the three datasets. (G) Western blot analysis of the relative expression levels of TRAF6 in the cerebellum tissue of mice. ** P  < 0.01. Data are the mean ± SEM and were analyzed using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test. (H) Western blot analysis of the relative expression levels of TRAF6 in BV2 cells. * P  < 0.05, ** P  < 0.01. Data are the mean ± SEM and were analyzed using one-way ANOVA followed by the Holm–Sidak post hoc multiple comparison test

Cells culture

The primary human umbilical cord tissue derived mesenchymal stem cells (hUC-MSC) isolated from human umbilical cord were purchased from the Nanjing Drum Tower Hospital. The human embryonic kidney 293T cells (HEK-293T cells) were obtained from Department of Histology and Embryology, Harbin Medical University. BV2 murine microglial cells were obtained from Department of Children’s and Adolescent Health, Harbin Medical University. The mouse neuroblastoma cell line, Neuro 2a (N2a) cells were obtained from Department of Neurobiology, Harbin Medical University. In addition, FBS for EVs production was depleted of bovine EVs by ultracentrifugation at 160,000×g for 16 h at 4 °C using an CP100NX ultracentrifuge (Hitachi, Japan). All cells were cultured in Dulbecco’s modified Eagle’s medium (DMEM, GIBCO, USA) supplemented with 10% fetal bovine serum (FBS, GIBCO, USA), 1% penicillin-streptomycin (Beyotime, China), and kept in a humidified incubator (5% CO 2 , 37 °C).

Transfection and preparation of EVs

The miR-137 overexpressed lentivirus was constructed by GeneChem Company, China. Briefly, the miR-137 coding sequence was cloned into the hU6-MCS-Ubiquitin-EGFP-IRES-puromycin lentivirus vector by using Age I and Eco RI restriction endonuclease (Figure S2 ). When MSC cells reached the third-sixth generation, the cells were seeded in six-well plate. Then, when the cells reached approximately 30% confluence, MSC cells were transfected with the miR-137 overexpressed lentivirus according to the manufacturer’s instructions. Next, MSC-EVs or MSC-miR137-EVs were prepared from the supernatant fluids of MSC cells or MSC-miR137 cells respectively by differential centrifugation. When MSC cells or MSC-miR137 cells reached the sixth-thirteenth generation, and were grown to 80–90% confluence, they were rinsed three times with phosphate-buffered saline (PBS) and switched to serum-free DMEM. The supernatants were harvested after 48 h to isolate EVs. Firstly, the supernatants were centrifuged at 300×g for 10 min and 2000×g for 10 min to eliminate cells and dead cells. Then, the supernatants were centrifuged at 10,000×g for 30 min to remove cellular debris. Next, the supernatant was centrifuged at 100,000×g for 60 min at 4 °C using an CP100NX ultracentrifuge (Hatichi, Japan). Subsequently, the pellet was resuspended in PBS and then ultracentrifuged again at 100,000×g for 60 min. All steps were performed at 4 °C. Finally, the resulting pellet was resuspended in PBS for further study.

Characterization of EVs

Protein content of EVs was measured with BCA Protein Assay Kit (P0011, Beyotime, China) following the manufacturer’s protocol. The markers of purified EVs were verified by Western blotting (WB) analysis. During WB test, the following antibodies were used: CD9 (1:1000, #13174, Cell Signaling Technology, USA), CD63 (1:1000, ab134045, Abcam, UK), TSG101 (1:1000, ab125011, Abcam, UK), Calnexin (1:1000, #2679, Cell Signaling Technology, USA). The transmission electron microscopy (TEM) (H-7650, HITACHI, Japan) was used to observe the morphology of EVs. The nanoparticles were visualized and quantitated by Zetasizer Nano ZS90 Nanometer particle size meter (Malvern, UK) in suspension. The EVs were stored at -80 °C for following applications.

The RNA was extracted from the cerebellum tissue of mice or BV2 cells using RNAiso Plus (Takara, Japan). Reverse transcription was then performed using the reaction tube mentioned above mixed with 2 µl of 2 × qRT Enzyme (Takara, Japan) and nuclease free water up to 10 µl of the final reaction volume. This reaction mixture was incubated at 37 °C for 15 min and then for 2 min at 85 °C. Next, the RT products (cDNA) obtained in the previous step were used as the template for qRT-PCR. The qRT-PCR reactions were carried out using SYBR Green qRT-PCR Master Mix (Q712-02, Vazyme, China) containing 1 µl of cDNA in a 10 µl final volume reaction with the following steps: 5 min at 95 °C followed by 45 cycles of 15 s at 95 °C, 30 s at 60 °C and 30 s at 72 °C, then followed 5 s at 95 °C, 1 min at 60 °C, 10 s at 95 °C and 30 s at 50 °C. The 2 −ΔΔ Ct method was used to calculate the relative expression levels of mRNA. Primers were synthesized by Sangon Biotech (Shanghai, China). The primers used in this article are listed in table S2 .

EVs staining

The EVs samples were stained and purified based on the steps described in previous studies as follows [ 23 ]. The resuspended EVs protein concentration was 100 µg/ml and then stained with Dil (C1036, Beyotime, China) or DiR (D131031, Aladdin, USA) dyes at 37 °C for 15 min. Excess dye was bound with 10% EVs removal rate of fetal bovine serum. EVs were diluted with PBS and ultracentrifuged at 100,000×g for 1 h at 4 °C. The pellet was gently resuspended in 200 µl PBS.

EVs uptake by BV2

A dose of 50 µg of MSC-EVs or MSC-miR137-EVs was resuspended in serum-free medium and added to BV2 cells. After incubation, cells were washed three times with PBS to remove excess EVs and to prepare for subsequent experiments. BV2 cells (2 × 10 4 cells) were seeded in 35 mm discs. 24 h later, Dil-labeled control MSC-EVs or MSC-miR137-EVs were added to the cultured cells. Then, 3 h later (37 °C, 5% CO 2 ), cells were stained with DAPI (Beyotime, China) and photographed with a Fluro microscope (ZEISS, Germany).

In vivo imaging system (IVIS)

DiR-labeled MSC-EVs or MSC-miR137-EVs was used to investigate biodistribution in mice at the dose of 200 µg in this study. Then after 6 h, the intensity and distribution of fluorescence were recorded in vivo using an IVIS Spectrum Imaging System (Vilber Lourmat, France).

Immunofluorescence staining

The mice were perfused with 100 ml PBS and then 25 ml 4% PFA and the brain tissues were isolated and cut into 10 μm thickness and were treated by 0.3% Triton X-100 (Beyotime, China) for 15 min and blocked with 10% normal goat serum (ZLI-9056, ZSGB-BIO, China) in 0.3% Triton X-100 for 1 h at room temperature. The sections were incubated with anti-Iba-1 (1:250, 019–19741, Wako Pure Chemicals) antibodies over night at 4 °C. After washing three times using PBS, the sections were incubated with Alexa 488-conjugated goat anti-rabbit IgG (1:1000, SA00013-2, Proteintech group, USA) for 1 h. The samples were washed three times with PBS and stained with an anti-quench agent containing DAPI. Images were taken with a laser confocal microscope (Nikon, Japan).

C57BL/6J (B6) mice were purchased from the Beijing Vital River Laboratory Animal Technology Co., Ltd. BTBR T + Itpr3tf/J (BTBR) mice were bred at the Jackson Laboratory as a model for ASD. Mice were randomly assigned to different groups and maintained in a 12-h light/dark cycle with a temperature of 21 ± 1 °C; humidity of 55 ± 5%, and food and water were freely available. All mice procedures were approved by the ethnic committee of Harbin Medical University (Approval number: HMUIRB20210002).

Intranasal delivery of EVs in animals

PBS, MSC-EVs or MSC-miR137-EVs were injected intranasally into BTBR mice. In brief, each mouse was injected with 50 µg of EVs every other day, four times in total. To determine the tissue distribution of miR-137 overexpression in vivo, the cerebellar tissue was collected and monitored the delivery efficiency through qRT-PCR. BTBR mice and control (B6 mice) were grouped to evaluate the improvement of miR-137 on autism behaviors. To explore the effect of miR-137 mediated by MSC-EVs on autism-like behaviors in BTBR mice, the mice were divided into four groups: C57BL/6J + PBS group, BTBR + PBS group, BTBR + MSC-EVs group and BTBR + MSC-miR137-EVs group.

Behavioral tests

All behavioral tests were performed in a quiet and low-intensity environment and scored by the same researcher. Mice were moved to the test room at least 3 h prior to the behavioral test.

Three-chamber test

The three-chamber device is a box with three chambers, each with an area of 20 cm × 40 cm. The three-chamber test was performed to detect social ability and social preference of mice. In the first adaptation phase, the test mouse was placed in the middle-chamber for 10 min. In the second phase of the sociability test, this was considered evidence of social behaviors when the test mice were within 2 cm of the cage or caged mice. Stranger mouse 1 (S1) was placed in a mouse cage in the left chamber. The empty cage was placed in the right chamber, while the test mice were placed in the central chamber. In addition, the movement and activity time in each box was recorded by a video camera for 10 min. This phase tested the preference of the test mice for contact with unfamiliar mice compared to the empty cage. The social preference test then began with the cage containing stranger mouse 1 (S1) being switched to the right chamber, while the cage containing mouse 2 (S2) was placed in the left chamber. The movements and activity times of the test mice were recorded by a video camera for 10 min similarly. This phase tested the preference of the test mice for contact with new, unfamiliar mice compared to familiar mice.

Open field test (OFT)

The OFT was performed in a quiet field which was a 45 cm × 45 cm × 40 cm open box made of black polycarbonate and used to test the locomotor and anxiety-like exploratory behaviors in mice. The test mouse was placed in the center area for simultaneous imaging and timing. After a 5 min adaptation phase, each mouse was allowed to explore the chamber for 10 min and the movement time, distance and trajectory of the mice were recorded using the SMART 3.0 experiment system.

It is a commonly used experiment to evaluate the anxiety of mice by detecting their spontaneous activity behaviors and exploratory behaviors. The movement distance and movement time of mice are regarded as the main data reflecting their anxiety behaviors. Within a certain period of time, the longer the movement distance and movement time of mice reflect the more serious their anxiety behaviors.

Morris water maze test (MWM)

The MWM test was used to assess the cognitive function of mice with respect to position and orientation. The experimental equipment used for this test was the WMT-100 Morris Water Maze Automated Analysis System with a 160 cm diameter flume carrying a far-infrared camera. The sink was divided into four quadrants, and an 8 cm × 8 cm platform was placed on the third quadrant. The liquid was made opaque with non-toxic white paint. The water surface was 1–2 cm above the platform. The experiment consisted of day 1–4 of training, which was performed twice a day. A training trial was accomplished when the mice found a platform within 60 s and stayed on the platform for 30 s after the trial when the mice climbed on the platform. On the fifth day, the spatial exploration ability was tested. The platform was displaced, the mice were placed in the first quadrant, and the number of times they traversed the original platform position within 60 s was recorded. Mice with cognitive deficits should traverse the platform less often in the exploration experiment.

Western blotting

Lysates were harvested from cerebellum tissue of mice, BV2 cells or N2a cells in buffer containing RIPA (Applygen, China), protease inhibitor (MedChemexpress, USA), and phosphatase inhibitor (Applygen, China). Protein concentrations were determined using the BCA kit (Applygen, China), after which a total of 30 µg of protein were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and then transferred onto polyvinylidene fluoride membranes (PVDF, Millipore, USA). The PVDF membranes were blocked with 5% non-fat milk at room temperature for 1 h, Next, the membranes were incubated with primary antibody solution at 4 °C overnight. The primary antibodies includes Anti-CD9 (1:1000, #13174, Cell Signaling Technology, USA), Anti-CD63 (1:1000, ab134045, Abcam, UK), Anti-TSG101 (1:1000, ab125011, Abcam, UK), Anti-Calnexin(1:1000, #2679, Cell Signaling Technology, USA), Anti-TLR4 (1:1000, 19811-1-AP, Proteintech group, USA), Anti-p-IKBα (1:500, sc-8404, Santa Cruz Biotechnology, USA), Anti-IKBα (1:500, sc-1643, Santa Cruz Biotechnology, USA), Anti-p-NF-κB (1:500, sc-135769, Santa Cruz Biotechnology, USA), Anti-NF-κB (1:500, sc-8008, Santa Cruz Biotechnology, USA), Anti-IL-1β (1:1000, D220820, Sangon Biotech, China), Anti-TNF-α (1:1000, sc-52746, Santa Cruz Biotechnology, USA), Anti-Iba1 (1:1000, 17168-1-AP, Proteintech group), Anti-Cleaved Caspase-3 (1:2000, 20260-1-AP, Proteintech group), Anti-TRAF6 (1:1000, BS3684, bioworlde, China), Anti-β-actin (1:10000, 81115-1-RR, Proteintech group, USA), or Anti-GADPH (1:10000, 60004-1-AP, Proteintech group) overnight at 4 °C. After washing three times with TBST, the membranes were incubated with secondary antibody (1:10000, Boster, China) for 2 h. Proteins on the membranes were detected using the ECL Plus kit (MA0186-1, meilunbio, China) and bands were detected and quantified using Image-Pro Plus software by chemiluminescence (BIO-RAD, USA). The protein band intensity was quantified by ImageJ software and exhibited as relative density to GAPDH.

Dual-luciferase reporter assay

PmirGLO/TLR4-3′-UTR WT and pmirGLO/TLR4-3′-UTR MT reporter plasmids were constructed in advanced according to the binding sites, and the binding sites of miR-137 and TLR4 were predicted through the Starbase database. HEK-293T cells were seeded into six-well plates, and according to the manufacturer’s instruction, when the confluence of HEK-293T cells reached to 70-80%, the cells were transiently co-transfected with miR-137 mimic or control mimic together with PmirGLO/TLR4-3′-UTR WT and pmirGLO/TLR4-3′-UTR MT reporter plasmids using Golden-Tran-DR (DR149260005-S, Golden Transfer Science and Technology, China). After 48 h, Dual-luciferase Reporter Assay System (E1910, Promega, USA) was used to detect firefly and Renilla luciferase activities and recorded using GloMax 96 Microplate Luminometer (Promega, USA).

BV2 and N2a coculture system

BV2 cells were exposed to LPS (M1 phenotype inducer, 1 µg/mL, Sigma-Aldrich, USA) for the imitation of BV2 cells M1 phenotype. To elucidate the influence of microglia polarization on the neurotoxicity, we co-cultured BV2 cells with N2a cells in a 0.4 μm pore size Transwell co-culture system (Corning, USA). BV2 cells were seeded in the upper chamber (1 × 10 5 /chamber), which were then treated with PBS, EVs (50 µg/mL) or LPS respectively. After LPS exposure, the inserts were gently rinsed three times and placed above the N2a cells (5 × 10 5 /well) in 24-well plates. N2a cells were collected after co-culture for 48 h for cell apoptosis analysis.

Public data availability and bioinformatic analysis

The miRNA expression profile datasets of MSC-EVs were obtained from the Gene Expression Omnibus (GEO, https://www.ncbi.nlm.nih.gov/geo/ ) public database as GSE69909 [ 24 ] and GSE159814 [ 25 ], and additional file from Weijiang Liu’s article (https://stemcellres.biomedcentral.com/articles/ https://doi.org/10.1186/s13287-021-02159-2 ) [ 26 ]. Nextly, the top 20 miRNAs in above three datasets about MSC-EVs were selected. TargetScan [ 27 ], miRDB [ 28 ] and miRwalk [ 29 ] were used to predict the target genes of miRNAs enriched in MSC-EVs. The expression profiling datas of the cerebellum in B6 and BTBR mice were obtained from GSE62594 dataset of the GEO database [ 30 ]. The miR-137 expression datas of peripheral blood from ASD patients and controls were also obtained from the GEO public database as GSE89596 [ 31 ]. All predicted targets were subjected to GO and KEGG analysis by DAVID online [ 32 ].

Statistical analysis

Statistical analysis was performed by GraphPad Prism software. All datas were presented as mean ± SEM. Significance was assessed with a two-tailed Student’s t test for comparisons of two groups. One/two-way ANOVA followed by the Holm-Sidak test were used for multi-group (three or more) comparisons. The results were considered to be statistically significant if P  < 0.05.

In this study, we successfully performed that MSC-EVs and MSC-miR137-EVs could ameliorate autism-like behaviors in BTBR mice. Mechanism studies revealed that miR-137 could target to TLR4 and alleviate the microglial activation, neuroinflammation and neurotoxicity through downregulating the TLR4/NF-κB signaling pathway. It was also relieved the inflammatory response of BV2 cells induced by LPS, and further reduced the apoptosis of N2a cells. Additionally, we demonstrated that MSC-EVs could also alleviate neuroinflammation and autism-like behaviors in BTBR mice via the miR-146a-5p/TRAF6 pathway.

In the initial segment of this study, we demonstrated that MSC-EVs could effectively deliver miR-137 to the mouse cerebellum. The therapeutic administration of MSC-miR137-EVs ameliorated the autism-like behaviors exhibited by BTBR mice. Moreover, miR-137 delivered by MSC-EVs reduced central nervous system (CNS) inflammation through the inhibition of microglial BV2 cell activation, in addition to the remission of microglial activation, neuroinflammation, and neurotoxicity. Consistent with previous reports, an augmented activation and quantity of microglial cells have been observed in the prefrontal cortices of individuals with ASD [ 33 ]. This abnormal neuroinflammatory activation potentially contributes to emotional disorders, behavioral abnormalities, and cognitive impairments [ 34 , 35 ].

Current research on ASD has traditionally focused on the prefrontal cortex and hippocampus. However, our study highlights the importance of the cerebellum as a candidate brain region for ASD. Perets et al. revealed that MSC-EVs could be accumulated significantly in the cerebellum of BTBR mice as well, by utilizing gold nanoparticles [ 36 , 37 ]. Additionally, we also found that MSC-EVs and MSC-miR137-EVs could reduce neuroinflammation in the cerebellum and alleviate autism-like behaviors in BTBR mice, underscoring the crucial role of the cerebellum in the pathological processes of ASD.

Our findings reveal that the reintroduction of miR-137 mitigates autism-like behaviors by targeting TLR4, subsequently regulating microglial activation via the NF-κB signaling pathway. TLR4, an innate immune receptor predominantly located on the surfaces of microglia and other cells, plays a pivotal role in identifying external and internal stimuli, thereby initiating inflammatory responses [ 38 ]. According to previous research, systemic and neurological inflammation in patients with ASD is brought on by elevated TLR4 expression in their B cells, over-activation of the NF-κB signaling pathway, and an increase in oxidative stress [ 39 ]. A recent study revealed unusual elevations in TLR4 and NF-κB in the intestinal tracts of BTBR mice, suggesting the TLR4 signaling pathway as a viable target for treating autism-related gastrointestinal dysfunctions [ 40 ]. Aligning with these discoveries, our study established that miR-137 diminished NF-κB levels in microglial cells exposed to LPS.

MSCs are a type of adult stem cells, and they have become powerful tools to treat diseases such as inflammation, tissue damage, and regeneration and post-injury repair [ 41 ]. MSC-EVs have a lower risk of immune rejection and tumor formation compared to MSCs, which greatly enhances their use in clinical disease treatment [ 42 ]. Based on previous studies, MSC-EVs not only have the ability to penetrate the blood–brain barrier due to their unique nanoscale and lipid membrane encapsulation advantages but also carry the immune and neuroprotective factors that are enriched in MSCs.

MSC-EVs have been found to contain 4850 gene products and 4150 miRNAs through mass spectrometry and microarray analysis [ 43 ]. A notable finding of the present study was that the treatment of the BTBR mouse model with MSC-EVs alleviated neuroinflammation and autism-like behaviors. Previous studies have shown that intranasal administration of MSC-EVs can improve autism-like behaviors in ASD mice model [ 44 , 45 ], but the mechanism remains unclear. Our study identified the miR-146 within MSC-EVs could target to TRAF6 to alleviate phenotypes in BTBR mice. Likewise, miRNA-146 administered from MSC-EVs has been found to inhibit microglial neuroinflammation by inhibiting TRAF6 and IL-1 receptor-related kinase 1 in microglia in patients with Alzheimer’s disease [ 46 ]. Therefore, the results of the current study add to the evidence that miRNA-146a-5p in MSC-EVs is involved in the regulation of the neuroinflammation associated with ASD in addition to other types of disease.

In this study, EVs were administered intranasally to mouse brains. Intranasal administration has been viewed as a possible alternative technique to improve drug delivery to the CNS due to increased research on the development of drug delivery systems. Anatomically, the nasal cavity has a direct path to the brain, and after nasal administration, the drug can enter the cerebrospinal fluid without causing harm and exert its therapeutic effects there, avoiding the BBB by passing through the olfactory mucosa and entering the CNS, cerebrospinal fluid, or brain tissue. Nasal drug delivery is a current research hotspot for CNS drug delivery. Nasal drug delivery for CNS diseases also has significant advantages over traditional drug delivery methods such as oral administration and injection, including high drug bioavailability, noninvasiveness, high blood flow, large surface area available for drug absorption, ease of application, rapid onset of action, and avoidance of drug damage to the liver and gastrointestinal tract and first-pass effect in the liver [ 47 , 48 ]. Currently, permeation and absorption enhancers, enzyme inhibitors, mucoadhesive, and hydrogel systems have been incorporated into nasal formulation to improve drug absorption and permeability and to increase the residence time in the nasal mucosa.

Although significant progress has been made in EV-based drug delivery systems, it should be noted that there are many challenges in optimizing the techniques to isolate highly purified EVs. To extract EVs on a large scale for subsequent functional verification, this study used the ultracentrifugation method to prepare EVs. However, this method may lead to EVs aggregation and damage their membrane structures and may alter their targeting and therapeutic effects. In addition, it is worth noting that to achieve the targeting ability of EVs, ligands are attached to their surfaces through chemical conjugation. These active targeting molecular combinational techniques and systems need to be evaluated for safety and efficacy. The present study demonstrated that MSC-EVs enhanced the efficiency of miR-137 delivery, suggesting that EV-based miR-137 delivery is a promising therapeutic strategy for the treatment of ASD.

As a reliable carrier, MSC-EVs can encapsulate miR-137, a small molecule that can be introduced into BTBR mice by intranasal administration or co-cultured with microglia in vitro, thereby alleviating autism-like behaviors and inhibiting neuroinflammatory responses in the brain and microglia through the TLR4/NF-κB pathway in mice. Meanwhile, the MSC-EVs contained abundant miR-146a-5p, which targeted the TRAF6/NF-κB signaling pathway. Taken together, our study suggested that combining MSC-EVs with miR-137 holds promise for the therapy of ASD and may have potential for clinical application.

Data availability

The data and materials used during the current study are available from the corresponding author on reasonable request.

Hirota T, King BH. Autism spectrum disorder: a review. JAMA. 2023;329:157–68.

Article   CAS   PubMed   Google Scholar  

Maenner MJ, Warren Z, Williams AR, Amoakohene E, Bakian AV, Bilder DA, Durkin MS, Fitzgerald RT, Furnier SM, Hughes MM, et al. Prevalence and characteristics of Autism Spectrum Disorder among children aged 8 years - Autism and Developmental Disabilities Monitoring Network, 11 sites, United States, 2020. MMWR Surveill Summ. 2023;72:1–14.

Article   PubMed   PubMed Central   Google Scholar  

Juneja M, Sairam S, Jain R, Gupta A. Practical aspects of ASD Management-what pediatricians should know. Indian J Pediatr. 2023;90:369–76.

Article   PubMed   Google Scholar  

van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol Rev. 2012;64:676–705.

Costa Verdera H, Gitz-Francois JJ, Schiffelers RM, Vader P. Cellular uptake of extracellular vesicles is mediated by clathrin-independent endocytosis and macropinocytosis. J Control Release. 2017;266:100–8.

Rai AK, Johnson PJ. Trichomonas Vaginalis extracellular vesicles are internalized by host cells using proteoglycans and caveolin-dependent endocytosis. Proc Natl Acad Sci U S A. 2019;116:21354–60.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Ferguson SW, Wang J, Lee CJ, Liu M, Neelamegham S, Canty JM, Nguyen J. The microRNA regulatory landscape of MSC-derived exosomes: a systems view. Sci Rep. 2018;8:1419.

Elsharkasy OM, Nordin JZ, Hagey DW, de Jong OG, Schiffelers RM, Andaloussi SE, Vader P. Extracellular vesicles as drug delivery systems: why and how? Adv Drug Deliv Rev. 2020;159:332–43.

Gorabi AM, Kiaie N, Barreto GE, Read MI, Tafti HA, Sahebkar A. The therapeutic potential of mesenchymal stem cell-derived exosomes in treatment of neurodegenerative diseases. Mol Neurobiol. 2019;56:8157–67.

Kota DJ, Prabhakara KS, Toledano-Furman N, Bhattarai D, Chen Q, DiCarlo B, Smith P, Triolo F, Wenzel PL, Cox CS Jr., Olson SD. Prostaglandin E2 indicates therapeutic efficacy of mesenchymal stem cells in experimental traumatic brain Injury. Stem Cells. 2017;35:1416–30.

Saliminejad K, Khorram Khorshid HR, Soleymani Fard S, Ghaffari SH. An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol. 2019;234:5451–65.

Guella I, Sequeira A, Rollins B, Morgan L, Torri F, van Erp TG, Myers RM, Barchas JD, Schatzberg AF, Watson SJ, et al. Analysis of miR-137 expression and rs1625579 in dorsolateral prefrontal cortex. J Psychiatr Res. 2013;47:1215–21.

Smrt RD, Szulwach KE, Pfeiffer RL, Li X, Guo W, Pathania M, Teng ZQ, Luo Y, Peng J, Bordey A, et al. MicroRNA miR-137 regulates neuronal maturation by targeting ubiquitin ligase mind bomb-1. Stem Cells. 2010;28:1060–70.

Yin J, Lin J, Luo X, Chen Y, Li Z, Ma G, Li K. miR-137: a new player in schizophrenia. Int J Mol Sci. 2014;15:3262–71.

Mahmoudi E, Cairns MJ. MiR-137: an important player in neural development and neoplastic transformation. Mol Psychiatry. 2017;22:44–55.

Tamim S, Vo DT, Uren PJ, Qiao M, Bindewald E, Kasprzak WK, Shapiro BA, Nakaya HI, Burns SC, Araujo PR, et al. Genomic analyses reveal broad impact of miR-137 on genes associated with malignant transformation and neuronal differentiation in glioblastoma cells. PLoS ONE. 2014;9:e85591.

Cheng Y, Wang ZM, Tan W, Wang X, Li Y, Bai B, Li Y, Zhang SF, Yan HL, Chen ZL, et al. Partial loss of psychiatric risk gene Mir137 in mice causes repetitive behavior and impairs sociability and learning via increased Pde10a. Nat Neurosci. 2018;21:1689–703.

Cristiano C, Pirozzi C, Coretti L, Cavaliere G, Lama A, Russo R, Lembo F, Mollica MP, Meli R, Calignano A, Mattace Raso G. Palmitoylethanolamide counteracts autistic-like behaviours in BTBR T + tf/J mice: contribution of central and peripheral mechanisms. Brain Behav Immun. 2018;74:166–75.

Fang S, Xu C, Zhang Y, Xue C, Yang C, Bi H, Qian X, Wu M, Ji K, Zhao Y, et al. Umbilical cord-derived mesenchymal stem cell-derived exosomal MicroRNAs suppress myofibroblast differentiation by inhibiting the transforming growth Factor-β/SMAD2 pathway during Wound Healing. Stem Cells Transl Med. 2016;5:1425–39.

Li K, Yan G, Huang H, Zheng M, Ma K, Cui X, Lu D, Zheng L, Zhu B, Cheng J, Zhao J. Anti-inflammatory and immunomodulatory effects of the extracellular vesicles derived from human umbilical cord mesenchymal stem cells on osteoarthritis via M2 macrophages. J Nanobiotechnol. 2022;20:38.

Article   CAS   Google Scholar  

Hua T, Yang M, Song H, Kong E, Deng M, Li Y, Li J, Liu Z, Fu H, Wang Y, Yuan H. Huc-MSCs-derived exosomes attenuate inflammatory pain by regulating microglia pyroptosis and autophagy via the miR-146a-5p/TRAF6 axis. J Nanobiotechnol. 2022;20:324.

Ding B, Lin C, Liu Q, He Y, Ruganzu JB, Jin H, Peng X, Ji S, Ma Y, Yang W. Tanshinone IIA attenuates neuroinflammation via inhibiting RAGE/NF-κB signaling pathway in vivo and in vitro. J Neuroinflammation. 2020;17:302.

Karimi N, Cvjetkovic A, Jang SC, Crescitelli R, Hosseinpour Feizi MA, Nieuwland R, Lötvall J, Lässer C. Detailed analysis of the plasma extracellular vesicle proteome after separation from lipoproteins. Cell Mol Life Sci. 2018;75:2873–86.

Qian X, Xu C, Fang S, Zhao P, Wang Y, Liu H, Yuan W, Qi Z. Exosomal MicroRNAs derived from umbilical mesenchymal stem cells inhibit Hepatitis C virus infection. Stem Cells Transl Med. 2016;5:1190–203.

Wang Y, Lai X, Wu D, Liu B, Wang N, Rong L. Umbilical mesenchymal stem cell-derived exosomes facilitate spinal cord functional recovery through the miR-199a-3p/145-5p-mediated NGF/TrkA signaling pathway in rats. Stem Cell Res Ther. 2021;12:117.

Liu W, Zhou N, Liu Y, Zhang W, Li X, Wang Y, Zheng R, Zhang Y. Mesenchymal stem cell exosome-derived miR-223 alleviates acute graft-versus-host disease via reducing the migration of donor T cells. Stem Cell Res Ther. 2021;12:153.

Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. Elife 2015, 4.

Chen Y, Wang X. miRDB: an online database for prediction of functional microRNA targets. Nucleic Acids Res. 2020;48:D127–31.

Dweep H, Sticht C, Pandey P, Gretz N. miRWalk–database: prediction of possible miRNA binding sites by walking the genes of three genomes. J Biomed Inf. 2011;44:839–47.

Shpyleva S, Ivanovsky S, de Conti A, Melnyk S, Tryndyak V, Beland FA, James SJ, Pogribny IP. Cerebellar oxidative DNA damage and altered DNA methylation in the BTBR T + tf/J mouse model of autism and similarities with human post mortem cerebellum. PLoS ONE. 2014;9:e113712.

Nakata M, Kimura R, Funabiki Y, Awaya T, Murai T, Hagiwara M. MicroRNA profiling in adults with high-functioning autism spectrum disorder. Mol Brain. 2019;12:82.

Sherman BT, Hao M, Qiu J, Jiao X, Baseler MW, Lane HC, Imamichi T, Chang W. DAVID: a web server for functional enrichment analysis and functional annotation of gene lists (2021 update). Nucleic Acids Res. 2022;50:W216–21.

Edmonson C, Ziats MN, Rennert OM. Altered glial marker expression in autistic post-mortem prefrontal cortex and cerebellum. Mol Autism. 2014;5:3.

Gopinath A, Collins A, Khoshbouei H, Streit WJ. Microglia and other myeloid cells in Central Nervous System Health and Disease. J Pharmacol Exp Ther. 2020;375:154–60.

Jia X, Gao Z, Hu H. Microglia in depression: current perspectives. Sci China Life Sci. 2021;64:911–25.

Betzer O, Perets N, Angel A, Motiei M, Sadan T, Yadid G, Offen D, Popovtzer R. In vivo neuroimaging of Exosomes using gold nanoparticles. ACS Nano. 2017;11:10883–93.

Perets N, Betzer O, Shapira R, Brenstein S, Angel A, Sadan T, Ashery U, Popovtzer R, Offen D. Golden exosomes selectively target brain pathologies in neurodegenerative and neurodevelopmental disorders. Nano Lett. 2019;19:3422–31.

Heidari A, Yazdanpanah N, Rezaei N. The role of toll-like receptors and neuroinflammation in Parkinson’s disease. J Neuroinflammation. 2022;19:135.

Al-Harbi NO, Nadeem A, Ahmad SF, Al-Ayadhi LY, Al-Harbi MM, As Sobeai HM, Ibrahim KE, Bakheet SA. Elevated expression of toll-like receptor 4 is associated with NADPH oxidase-induced oxidative stress in B cells of children with autism. Int Immunopharmacol. 2020;84:106555.

Franco C, Gianò M, Favero G, Rezzani R. Impairment in the intestinal morphology and in the immunopositivity of toll-like Receptor-4 and other proteins in an autistic mouse model. Int J Mol Sci 2022, 23.

Siniscalco D, Giordano A, Galderisi U. Novel insights in basic and applied stem cell therapy. J Cell Physiol. 2012;227:2283–6.

Phinney DG, Pittenger MF. Concise Review: MSC-Derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8.

Harrell CR, Jovicic N, Djonov V, Arsenijevic N, Volarevic V. Mesenchymal stem cell-derived exosomes and other Extracellular vesicles as new remedies in the Therapy of Inflammatory diseases. Cells 2019, 8.

Perets N, Hertz S, London M, Offen D. Intranasal administration of exosomes derived from mesenchymal stem cells ameliorates autistic-like behaviors of BTBR mice. Mol Autism. 2018;9:57.

Perets N, Oron O, Herman S, Elliott E, Offen D. Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B. Mol Autism. 2020;11:65.

Nakano M, Kubota K, Kobayashi E, Chikenji TS, Saito Y, Konari N, Fujimiya M. Bone marrow-derived mesenchymal stem cells improve cognitive impairment in an Alzheimer’s disease model by increasing the expression of microRNA-146a in hippocampus. Sci Rep. 2020;10:10772.

Alshweiat A, Ambrus R, Csoka I. Intranasal Nanoparticulate Systems as Alternative Route of Drug Delivery. Curr Med Chem. 2019;26:6459–92.

Ali J, Ali M, Baboota S, Sahani JK, Ramassamy C, Dao L. Bhavna: potential of nanoparticulate drug delivery systems by intranasal administration. Curr Pharm Des. 2010;16:1644–53.

Download references

Acknowledgements

This study received assistance from the Province Key Laboratory of Children development and genetic research in Harbin Medical University, Heilongjiang, China. We also thank Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (Harbin Medical University), Ministry of Education.

This study was supported by grants from the National Natural Science Foundation of China (81973068, 82271888); Heilongjiang Province Postdoctoral Start-up Fund (LBH-Q19029); the Excellent Young Teachers’ Basic Research Support Program of Heilongjiang Province (NO.YQJH2023040); the Open Project Program of Key Laboratory of Preservation of Human Genetic Resources and Disease Control in China (LPHGRDC2021-004).

Author information

Qian Qin and Zhiyan Shan contributed equally to this work.

Authors and Affiliations

Department of Children’s and Adolescent Health, Public Health College, Harbin Medical University, Harbin, 150081, China

Qian Qin, Lei Xing, Yutong Jiang, Mengyue Li, Linlin Fan, Xin Zeng, Xinrui Ma, Danyang Zheng, Han Wang, Hui Wang, Hao Liu, Shengjun Liang, Lijie Wu & Shuang Liang

Department of Histology and Embryology, Harbin Medical University, Harbin, 150081, China

Zhiyan Shan

You can also search for this author in PubMed   Google Scholar

Contributions

QQ, ZYS, SL and LJW conceptualized and designed experiments for this research. QQ and ZYS performed molecular experiments; analyzed the data; and wrote and edited the original manuscript. LX and XRM performed cell culture experiments. DYZ, YTJ and HW (Han Wang) performed mice behavior experiments. MYL, LLF and XZ performed bioinformatic analysis. HW (Hui Wang), HL and JSL performed animal breeding. SL and LJW critically reviewed the manuscript.

Corresponding authors

Correspondence to Lijie Wu or Shuang Liang .

Ethics declarations

Ethics approval and consent to participate.

All animal experiments were approved by the Ethics Committee of Harbin Medical University (Approval number: HMUIRB20210002).

Consent for publication

Not applicable.

Competing interests

All the authors declare that they have no competing interests.

Additional information

Publisher’s note.

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

12967_2024_5257_MOESM1_ESM.docx

Supplementary Material 1: Figure S1: Immunofluorescence of Iba-1 expression in cerebellum of C57BL/6J and BTBR mice. Figure S2: The vector map of miR-137 overexpressed lentivirus.

12967_2024_5257_MOESM2_ESM.docx

Supplementary Material 2: Table S1. Overlap of GSE62594 upregulates differential genes and miR-137 target gene. Table S2. The primer sequences used in this study.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Cite this article.

Qin, Q., Shan, Z., Xing, L. et al. Synergistic effect of mesenchymal stem cell-derived extracellular vesicle and miR-137 alleviates autism-like behaviors by modulating the NF-κB pathway. J Transl Med 22 , 446 (2024). https://doi.org/10.1186/s12967-024-05257-w

Download citation

Received : 09 November 2023

Accepted : 29 April 2024

Published : 13 May 2024

DOI : https://doi.org/10.1186/s12967-024-05257-w

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Autism spectrum disorder
• Extracellular vesicles
• Mesenchymal stem cell
• TLR4/NF-κB pathway

Journal of Translational Medicine

ISSN: 1479-5876

• Submission enquiries: Access here and click Contact Us
• General enquiries: [email protected]

What Creative Arts Therapies Teach Us About DBT Skills Training

Bridging dbt with the arts for deeper understanding..

Posted April 15, 2024 | Reviewed by Jessica Schrader

• What Is Therapy?
• Find a therapist near me
• Research supports the effectiveness of combining DBT with creative arts to improve outcomes.
• Facilitators can teach wise-mind skills through drama therapy techniques.
• Action-based DBT utilizes storytelling and role-play to make skill learning more accessible and impactful.

In the ever-evolving realm of mental health, therapists are always exploring new and innovative methods to enhance traditional treatments. Creative arts therapists have led the way in utilizing art-based interventions to teach DBT skills.

Creative arts therapy combines visual arts, movement, drama, music, writing, and other creative processes to support clients in their healing process. Many mental health clinicians have embraced creative arts therapy interventions to improve their clients' health and wellness.

There is a growing body of research that indicates that therapists can utilize creative interventions to help clients learn and generalize DBT skills. In this post, I will provide a brief literature review of therapists who have been doing this integrative work and provide an example of how drama therapy can be utilized to teach the DBT skill of wise mind.

DBT and Art Therapy

Research indicates that integrating art therapy into established psychotherapy forms, such as cognitive-behavioral therapies, can have significant positive effects on client well-being. For example, a study by Monti et al. (2012) demonstrated the potential of mindfulness -based art therapy (MBAT) in alleviating emotional distress, highlighting the power of combining art therapy with the core feature of mindfulness in DBT. Though this study did not specifically discuss DBT, it demonstrated that implementing mindfulness, a core component of DBT, can assist individuals who are facing significant physical and emotional stressors.

Building on research that examined mindfulness and art therapy, several practitioners have contributed articles that specifically address the integration of DBT and art therapy within clinical populations. For example, researchers Huckvale and Learmonth (2009) led the charge by developing a new and innovative art therapy approach grounded in DBT for patients facing mental health challenges. Furthermore, Heckwolf, Bergland, and Mouratidis (2014) demonstrated how visual art and integrative treatments could help clients access DBT, resulting in stronger generalization and implementation of these skills outside of the session. The clinicians concluded that this integrative approach to treatment could reinforce skills, contribute to interdisciplinary team synergy, and enact bilateral integration.

Other notable examples from art therapists include Susan Clark’s (2017) DBT-informed art therapy, a strategic approach to treatment that incorporates creative visual exercises to explore, practice, and generalize DBT concepts and skills.

Expanding Beyond Visual Art Therapy

DBT has now been integrated with other expressive art therapies, including drama and music. Art therapists Karin von Daler and Lori Schwanbeck (2014) were instrumental in this expansion when they developed Creative Mindfulness, an approach to therapy integrating various expressive arts therapies with DBT. Creative Mindfulness “suggests a way of working therapeutically that is as containing and structured as DBT and as creative, embodied, and multi-sensory as expressive arts” (p. 235). These clinicians incorporated improvisation into their work, a tool that can be simultaneously playful, experiential, and grounding, ultimately producing substantial new insights for clients.

Moreover, music and drama therapists have recognized the benefits of multisensory skill teaching, expanding the creative techniques used to teach DBT skills ( Deborah Spiegel, 2020 ; Nicky Morris, 2018 , and Roohan and Trottier, 2021 ).

My Own Experience Integrating Drama Therapy and DBT

Personally, I am a big advocate of both dialectical behavior therapy (DBT) and drama therapy. In fact, I love these modalities so much that I dedicated not only my master's thesis but also my dissertation to better understanding how to reinforce DBT skills through dramatic techniques. In the process, I developed a new approach called Action-Based DBT that uses dramatic interventions like storytelling, embodiment, and role-playing to create a supportive environment for participants to learn skills in a more personalized and embodied way. An expert panel review demonstrated that this format can effectively support skill learning, especially for clients who struggle with the standard format of DBT skills training. Additionally, mental health clinicians found the program easily adaptable across populations in both individual and group settings.

Embodying the Mind States

To illustrate this approach and its effectiveness, the following is an example of how drama therapy methods can teach the DBT skill of wise mind within the context of an action-based DBT group.

The facilitator begins the group session by reviewing general guidelines and introducing the targeted DBT skill for the day: wise mind. The group then participates in improvisational warm-up activities to promote creativity , positive social interaction, and group connectivity. Following the warm-up, the facilitator distributes the DBT mind states handout (Linehan, 2015) and provides brief psychoeducation on this skill. Three chairs are placed in the front of the group room, facing the semi-circle of clients. Each chair had a piece of colored construction paper taped to the front, reading as Reasonable, Wise and Emotion . The facilitator explains that each chair represents one of the three mind states: reasonable mind, emotion mind and wise mind. To encourage exploration of the mind states, the facilitator can assign a more specific role to each state of mind. For example, the reasonable mind is The Computer, the emotion mind is The Tornado, and the wise mind is The Sage. Group members are invited to think of a scenario in which they felt they had difficulty accessing their wise mind. Clients then take turns embodying each mind state by sitting in the chair and speaking from the respective role. When a client first sits in a chair, the facilitator aids in enrolling the individual by asking questions about the role (i.e. The Computer, The Tornado, The Sage). For example, the facilitator may ask about the posture, tone of voice, or a “catchphrase” for this role. The client then embodies the role and responds to questions from the group as the specific mind state. After the embodiment, clients engage in verbal processing. The wise mind directive supports clients in developing kinaesthetic awareness of the three mind states. Embodying these mind states within the context of a supportive group and engaging in verbal processing around the experience can increase awareness of the mind states, which is helpful for clients who are trying to understand their emotional response to lived events outside of the group setting.

The creative arts therapies offer a dynamic pathway to teaching and reinforcing DBT skills. Incorporating visual art, drama, or music in the process of learning DBT skills allows clients to engage with these concepts in a multisensory and embodied way.

In my personal experience, weaving drama therapy techniques into DBT skills training has proven to be profoundly impactful. The Action-Based DBT approach, with its emphasis on storytelling and embodiment, offers an immersive and experiential learning environment that can be especially beneficial for those who find traditional methods challenging.

Looking ahead, my next post will delve into how storytelling can be harnessed to teach DBT skills in a way that is both engaging and memorable.

To find a therapist, please visit the Psychology Today Therapy Directory .

Clark, S. M. (2017). DBT-informed art therapy: Mindfulness, cognitive behavior therapy, and the creative process. Jessica Kingsley Publishers.

Heckwolf, J. I., Bergland, M. C., & Mouratidis, M. (2014). Coordinating principles of art therapy and DBT. The Arts in Psychotherapy, 41(4), 329-335.

Huckvale, K., & Learmonth, M. (2009). A case example of art therapy in relation to dialectical behaviour therapy. International Journal of Art Therapy, 14(2), 52-63.

Monti, D. A., Kash, K. M., Kunkel, E. J., Brainard, G., Wintering, N., Moss, A. S., Rao, H., Zhu, S., & Newberg, A. B. (2012). Changes in cerebral blood flow and anxiety associated with an 8-week mindfulness programme in women with breast cancer. Stress and Health, 28(5), 397-407.

Morris, N. (2018). Dramatherapy for borderline personality disorder: Empowering and nurturing people through creativity. Routledge.

Roohan Mary Kate, Trottier Dana George. (2021) Action-based DBT: Integrating drama therapy to access wise mind. Drama Therapy Review, 7 (2), 193 https://doi.org/10.1386/dtr_00073_1

Spiegel, D., Makary, S., & Bonavitacola, L. (2020). Creative DBT activities using music: Interventions for enhancing engagement and effectiveness in therapy. Jessica Kingsley Publishers.

Von Daler, K., and Schwanbeck, L. (2014). Creative mindfulness: Dialectical behavior therapy and expressive arts therapy. In L. Rappaport (Ed.), Mindfulness and the arts therapies: Theory and practice (pp. 107-116). Jessica Kingsley Publishers.

Mary Kate Roohan, Psy.D., is a licensed psychologist and drama therapist and the founder of Thrive and Feel, a therapy practice that supports clients in managing emotional sensitivity.

• Find a Therapist
• Find a Treatment Center
• Find a Psychiatrist
• Find a Support Group
• Find Online Therapy
• United States
• Brooklyn, NY
• Chicago, IL
• Houston, TX
• Los Angeles, CA
• New York, NY
• Portland, OR
• San Diego, CA
• San Francisco, CA
• Seattle, WA
• Washington, DC
• Asperger's
• Bipolar Disorder
• Chronic Pain
• Eating Disorders
• Passive Aggression
• Personality
• Goal Setting
• Positive Psychology
• Stopping Smoking
• Low Sexual Desire
• Relationships
• Child Development
• Self Tests NEW
• Therapy Center
• Diagnosis Dictionary
• Types of Therapy

At any moment, someone’s aggravating behavior or our own bad luck can set us off on an emotional spiral that threatens to derail our entire day. Here’s how we can face our triggers with less reactivity so that we can get on with our lives.

• Emotional Intelligence
• Gaslighting
• Affective Forecasting
• Neuroscience