Relationship of autistic traits between parents and children with and without autism spectrum disorder

BackgroundAlthough parents with a child with autism spectrum disorder (ASD) have usually been identified as having the “broader autism phenotype”, empirical research on the differences in autistic-like characteristics between parents with and without ASD children has yielded inconsistent results.MethodThis survey of the autistic traits of parents and children was conducted in 119 parents with ASD children and 108 parents with typically developing (TD) children. Parents’ autistic traits were quantified using the Autism-Spectrum Quotient and children’s autistic traits were quantified using the Autism Spectrum Quotient—Children’s Version.ResultsThe autistic traits of ASD children were significantly higher than those of the TD children; however, autistic traits were similar between parents in the two groups. Furthermore, the correlations of autistic traits between parents and children were only significant for the TD group and not for the ASD group.ConclusionsThe current findings indicate that the relationship of autistic traits between parents and children exists in the TD group, and that the Autism-Spectrum Quotient may be used for parents as a screening aid to identify children who should be further screened for autistic traits.     

Discrimination learning and reversal of the conditioned eyeblink reflex in a rodent model of autism

Offspring of rats exposed to valproic acid (VPA) on gestational day (GD) 12 have been advocated as a rodent model of autism because they show neuron loss in brainstem nuclei and the cerebellum resembling that seen in human autistic cases . Studies of autistic children have reported alterations in acquisition of classical eyeblink conditioning and in reversal of instrumental discrimination learning . Acquisition of discriminative eyeblink conditioning depends on known brainstem-cerebellar circuitry whereas reversal depends on interactions of this circuitry with the hippocampus and prefrontal cortex. In order to explore behavioral parallels of the VPA rodent model with human autism, the present study exposed pregnant Long-Evans rats to 600 mg/kg VPA on GD12 and tested their offspring from Postnatal Day (PND26-31) on discriminative eyeblink conditioning and reversal. VPA rats showed faster eyeblink conditioning, consistent with studies in autistic children . This suggests that previously reported parallels between human autism and the VPA rodent model with respect to injury to brainstem-cerebellar circuitry are accompanied by behavioral parallels when a conditioning task engaging this circuitry is used. VPA rats also showed impaired reversal learning, but this likely reflected "carry-over" of enhanced conditioning during acquisition rather than a reversal learning deficit like that seen in human autism. Further studies of eyeblink conditioning in human autism and in various animal models may help to identify the etiology of this developmental disorder.     

Vitamin A deficiency exacerbates autism-like behaviors and abnormalities of the enteric nervous system in a valproic acid-induced rat model of autism

The manifestations of autism spectrum disorder (ASD) are highly heterogeneous. As many individuals with ASD have gastrointestinal (GI) comorbidities, ASD with GI problems is considered to be a subtype of ASD. Vitamin A (VA) plays an important role in the development of both the central and peripheral nervous system. However, the relationship between VA deficiency (VAD) and ASD with GI comorbidities is still unclear. We established rat models with different VA levels based on the valproic acid-induced autism model. Compared to autism model rats with VA normal (VAN), autism model rats with gestational VAD showed more severe autism-like behavior, increased GI transit time, and impairment of the enteric nervous system (ENS). Besides, the expression levels of retinoic acid receptor α (RARα) and Ret in autism model rats with VAD were decreased compared with those in rats with VAN. Supplementation with VA was found to effectively ameliorate autism-like behaviors and impairments of GI motility and the ENS in autism model rats with VAD. Chromatin immunoprecipitation results suggested that RARa can bind to the promoter region of the Ret gene and regulate the Ret signaling pathway. We speculate that VAD in autism might lead to impairments of both the brain and ENS. VAD might be a factor that causes individuals to be more susceptible to ASD-related risk factors and aggravates a subtype of ASD with GI comorbidities.     

Overlapping Molecular Pathways Leading to Autism Spectrum Disorders,Fragile X Syndrome,and Targeted Treatments

Autism spectrum disorders (ASD) are subdivided into idiopathic (unknown) etiology and secondary, based on known etiology. There are hundreds of causes of ASD and most of them are genetic in origin or related to the interplay of genetic etiology and environmental toxicology. Approximately 30 to 50% of the etiologies can be identified when using a combination of available genetic testing. Many of these gene mutations are either core components of the Wnt signaling pathway or their modulators. The full mutation of the fragile X mental retardation 1 (FMR1) gene leads to fragile X syndrome (FXS), the most common cause of monogenic origin of ASD, accounting for ~ 2% of the cases. There is an overlap of molecular mechanisms in those with idiopathic ASD and those with FXS, an interaction between various signaling pathways is suggested during the development of the autistic brain. This review summarizes the cross talk between neurobiological pathways found in ASD and FXS. These signaling pathways are currently under evaluation to target specific treatments in search of the reversal of the molecular abnormalities found in both idiopathic ASD and FXS.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13311-020-00968-6.Key Words: Autism spectrum disorders, fragile X syndrome, targeted treatments, Wnt, retinoic acid, mTOR, ERK/MAPK, signaling cross talk, endocannabinoid system, neurodevelopmental disorders     

Autism spectrum disorder and underlying brain mechanism in the oculoauriculovertebral spectrum

As part of a multidisciplinary study, the rate of autism spectrum disorder (ASD), learning disability (LD), and brain abnormalities was examined in 20 participants (12 males, 8 females; age range 8mo-17y, mean age 8y 1mo) diagnosed as falling within the oculoauriculovertebral spectrum (OAV). A neuropsychiatric examination was performed, including standardized autism diagnostic interviews. Two individuals met diagnostic criteria for autism, one for autistic-like condition, and five for autistic traits. Four patients had mild LD, three severe LD, two profound LD, and two borderline intellectual functioning. Neuroimaging indicated cerebral abnormalities in more than half of the patients. Abnormalities of white/grey matter were found in more than half of examined individuals; enlargement of ventricles in more than a third. Results indicate that at least a subgroup of ASD may be associated with errors in early embryonic brain development. Awareness of the coexistence of OAV/ASD is important in habilitation care of individuals with OAV.     

Speech Preference is Associated with Autistic-Like Behavior in 18-Months-Olds at Risk for Autism Spectrum Disorder

We examined whether infants’ preference for speech at 12 months is associated with autistic-like behaviors at 18 months in infants who are at increased risk for autism spectrum disorder (ASD) because they have an older sibling diagnosed with ASD and in low-risk infants. Only low-risk infants listened significantly longer to speech than to nonspeech at 12 months. In both groups, relative preference for speech correlated positively with general cognitive ability at 12 months. However, in high-risk infants only, preference for speech was associated with autistic-like behavior at 18 months, while in low-risk infants, preference for speech correlated with language abilities. This suggests that in children at risk for ASD an atypical species-specific bias for speech may underlie atypical social development.     

Hypomelanosis of Ito in Three Cases with Autism and Autistic-like Conditions

Two girls and a boy showing autistic behaviour and fulfilling the criteria for autistic disorder, Asperger syndrome or atypical autism were diagnosed as having hypomelanosis of Ito syndrome. It is suggested that skin changes indicating underlying neurocutaneous disorders be meticulously looked for in all cases with autism and autistic-like conditions.     

Mood symptoms and suicidality across the autism spectrum

BackgroundAutism spectrum is a psychopathological dimension which encompasses a wide range of clinical presentations: from subthreshold forms and autistic traits (AT), that can be found in the general population, to full-blown autism spectrum disorder (ASD). Many studies reported high rates of comorbidity between both ASD and AT and mood disorders, as well as a high prevalence of suicidal ideation among patients with ASD/AT. The aim of this study was to investigate the presence of mood symptoms and suicidal ideation and behaviors in patients with full-blown ASD and in subjects with AT, as well in a healthy control (HC) group, with a specific focus on which of the autistic features may be predictive of suicidal ideation and behaviors.MethodsWe recruited 262 adult subjects: 34 with ASD without intellectual impairment or language disability (ASD group), 68 fulfilling only one symptom criterion for ASD according to DSM-5 but who do not meet criteria for a full-blown diagnosis of ASD (AT group), and 160 HC. All subjects were assessed with the Structured Clinical Interview for DSM-5 (SCID-5); in addition, they were asked to fill two questionnaires: The Mood Spectrum, Self-report (MOODS-SR) and the Adult Autism Subthreshold Spectrum (AdAS Spectrum).ResultsASD subjects reported significantly higher AdAS Spectrum and MOODS-SR total scores, as well as higher MOODS-SR depressive component total scores, when compared with AT and HC subjects. AT subjects scored significantly higher than the HC group. No significant differences were reported between ASD and AT subjects for the suicidality score according to MOODS-SR, despite both groups scored significantly higher than the HC group. The strongest predictor of suicidality score were MOODS-SR depressive component score and AdAS Spectrum Restricted interests and rumination domain score.ConclusionsOur results highlight a correlation between autism and mood spectrum, as well as between suicidality and both ASD and AT. Subthreshold forms of ASD should be accurately investigated due to their relationship with suicidal thoughts and behaviors.     

Neuropsychiatric Assessmenit of Children with Autism: A Population-Based Study

Thirty-five children with autistic disorder and 17 with autistic-like conditions underwent an exhaustive neurobiological evaluation, and the findings were contrasted with those obtained from various comparison groups. Almost 90 per cent of the children with autistic disorder and autistic-like conditions had major indications of brain damage or dysfunction. Some of those who did not show such abnormalities had a first-degree relative with Asperger syndrome. The rate of abnormality was similar to that of severely mentally retarded children, but in excess of that of normal children. Within the autism group, abnormality rate did not correlate with degree of mental retardation. It is concluded that autism has multiple biological aetiologies and that autistic symptoms in a child should always prompt a thorough medical/neurobiological evaluation.     

Gender-specific behavioral and immunological alterations in an animal model of autism induced by prenatal exposure to valproic acid

Autism is a severe behavioral disorder characterized by pervasive impairments in social interactions, deficits in verbal and non-verbal communication, and stereotyped behaviors, with a four times higher incidence in boys than in girls. The core symptoms are frequently accompanied by a spectrum of neurobehavioral and immunological derangements, including: aberrant sensitivity to sensory stimulation, anxiety, and decreased cellular immune capacity. Recently, a new potential rodent model of autism induced by prenatal exposure to valproic acid (VPA rats) has been proposed. In order to determine if gender has an influence on alterations observed in VPA rats, male and female rats have been evaluated in a battery of behavioral, immunological, and endocrinological tests. A plethora of aberrations has been found in male VPA rats: lower sensitivity to pain, increased repetitive/stereotypic-like activity, higher anxiety, decreased level of social interaction, increased basal level of corticosterone, decreased weight of the thymus, decreased splenocytes proliferative response to concanavaline A, lower IFN-gamma/IL-10 ratio, and increased production of NO by peritoneal macrophages. Female VPA rats exhibited only increased repetitive/stereotypic-like activity and decreased IFN-gamma/IL-10 ratio. Sexual dimorphism characteristics for measured parameters have been observed in both groups of animals, except social interaction in VPA rats. Our results confirm existence of similarities between the observed pattern of aberrations in VPA rats and features of disturbed behavior and immune function in autistic patients, and suggest that they are gender-specific, which is intriguing in light of disproportion in boys to girls ratio in autism.     

Increasing astrogenesis in the developing hippocampus induces autistic-like behavior in mice via enhancing inhibitory synaptic transmission

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized primarily by impaired social communication and rigid, repetitive, and stereotyped behaviors. Many studies implicate abnormal synapse development and the resultant abnormalities in synaptic excitatory–inhibitory (E/I) balance may underlie many features of the disease, suggesting aberrant neuronal connections and networks are prone to occur in the developing autistic brain. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function during a critical developmental period may also contribute to the pathogenesis of ASD. Here, we report that increasing hippocampal astrogenesis during development induces autistic-like behavior in mice and a concurrent decreased E/I ratio in the hippocampus that results from enhanced GABAergic transmission in CA1 pyramidal neurons. Suppressing the aberrantly elevated GABAergic synaptic transmission in hippocampal CA1 area rescues autistic-like behavior and restores the E/I balance. Thus, we provide direct evidence for a developmental role of astrocytes in driving the behavioral phenotypes of ASD, and our results support that targeting the altered GABAergic neurotransmission may represent a promising therapeutic strategy for ASD.     

It’s not really lying. Autism spectrum disorder relates to lower recognition of other-oriented lies through a decrease in perceived intentionality of the liar

BackgroundThere is mixed evidence regarding how persons with ASD deal with deception. Some studies show that autism is related to difficulties in lying, others show no differences between individuals with ASD and typically developing persons in use of deception. It may be that individuals with ASD have difficulties in understanding what lying is.MethodIn Study 1 (N = 66) we matched a sample of individuals clinically diagnosed with autism spectrum disorder with typically developing individuals. Study 2 (N = 256) was conducted with participants from the general population. We asked participants to evaluate deceitfulness of protagonists’ behavior in stories presenting other-oriented and self-oriented lying.ResultsThe results suggest that the higher the autistic traits, the less individuals perceive the liar as behaving intentionally. In the case of more complex, other-oriented lies, autistic traits indirectly relate to recognition of lies through attribution of intentionality.ConclusionThese findings show how autistic traits relate to understanding of lying and suggest that it might be interesting to test training among individuals with ASD aimed at learning how to recognize deception.     

Neurologic treatment strategies in autism: an overview of medical intervention strategies

Child neurologists are likely to be caring for an increasing number of patients with autistic spectrum disorder (ASD). ASD may occur in as many as 1/100 to 1/200 births. It appears to be a multifactorial disease, with many phenotypes or subgroups. No simple treatment is currently approved for curing or managing core symptoms of autism. We rationally propose a symptom-based review of what treatments may offer relief to specific subtypes of clinical behaviors seen in autism. There is a lack of clinically based evidence on which to universally recommend a rational clinical algorithm for treatment; we suggest that rational pharmacotherapy may offer symptomatic relief to core areas of dysfunction in the autistic population. Future research into rational medical treatment options is desperately needed.     

Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex

Until recently, the neuropsychiatric phenotype of tuberous sclerosis complex (TSC) was presumed to be caused by the structural brain abnormalities and/or seizures seen in the disorder. However, advances in the molecular biology of the disorder have shown that TSC is a mammalian target of rapamycin (mTOR) overactivation syndrome, and that direct molecular pathways exist between gene mutation and cognitive/neurodevelopmental phenotype. Molecularly-targeted treatments using mTOR inhibitors (such as rapamycin) are showing great promise for the physical and neurological phenotype of TSC. Pre-clinical and early-phase clinical studies of the cognitive and neurodevelopmental features of TSC suggest that some of the neuropsychiatric phenotypes might also be reversible, even in adults with the disorder. TSC, fragile X, neurofibromatosis type 1, and disorders associated with phosphatase and tensin homo (PTEN) mutations, all signal through the mTOR signaling pathway, with the TSC1-TSC2 protein complex as a molecular switchboard at its center. Together, these disorders represent as much as 14% of autism spectrum disorders (ASD). Therefore, we suggest that this signaling pathway is a key to the underlying pathophysiology of a significant subset of individuals with ASD. The study of molecularly targeted treatments in TSC and related disorders, therefore, may be of scientific and clinical value not only to those with TSC, but to a larger population that may have a neuropsychiatric phenotype attributable to mTOR overactivation or dysregulation.     

DSM-5 criteria for autism spectrum disorder maximizes diagnostic sensitivity and specificity in preschool children

Purpose

The criteria for autism spectrum disorder (ASD) were revised in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM). The objective of this study was to compare the sensitivity and specificity of DSM-IV-Text Revision (DSM-IV-TR) and DSM-5 definitions of ASD in a community-based sample of preschool children.

Methods

Children between 2 and 5 years of age were enrolled in the Study to Explore Early Development-Phase 2 (SEED2) and received a comprehensive developmental evaluation. The clinician(s) who evaluated the child completed two diagnostic checklists that indicated the presence and severity of DSM-IV-TR and DSM-5 criteria. Definitions for DSM-5 ASD, DSM-IV-TR autistic disorder, and DSM-IV-TR Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS) were created from the diagnostic checklists.

Results

773 children met SEED2 criteria for ASD and 288 met criteria for another developmental disorder (DD). Agreement between DSM-5 and DSM-IV-TR definitions of ASD were good for autistic disorder (0.78) and moderate for PDD-NOS (0.57 and 0.59). Children who met DSM-IV-TR autistic disorder but not DSM-5 ASD (n = 71) were more likely to have mild ASD symptoms, or symptoms accounted for by another disorder. Children who met PDD-NOS but not DSM-5 ASD (n = 66), or vice versa (n = 120) were less likely to have intellectual disability and more likely to be female. Sensitivity and specificity were best balanced with DSM-5 ASD criteria (0.95 and 0.78, respectively).

Conclusions

The DSM-5 definition of ASD maximizes diagnostic sensitivity and specificity in the SEED2 sample. These findings support the DSM-5 conceptualization of ASD in preschool children.

     

Validation of the phenomenon of autistic regression using home videotapes

CONTEXT: To date, there has been no objective validation of the phenomenon of autistic regression early in life. OBJECTIVE: To validate parental report of autistic regression using behavioral data coded from home videotapes of children with autism spectrum disorder (ASD) vs typical development taken at 12 and 24 months of age. DESIGN: Home videotapes of 56 children's first and second birthday parties were collected from parents of young children with ASD with and without a reported history of regression and typically developing children. Child behaviors were coded by raters blind to child diagnosis and regression history. A parent interview that elicited information about parents' recall of early symptoms from birth was also administered. SETTING: Participants were recruited from a multidisciplinary study of autism conducted at a major university. PARTICIPANTS: Fifteen children with ASD with a history of regression, 21 children with ASD with early-onset autism, and 20 typically developing children and their parents participated. MAIN OUTCOME MEASURES: Observations of children's communicative, social, affective, repetitive behaviors, and toy play coded from videotapes of the toddlers' first and second birthday parties. RESULTS: Analyses revealed that infants with ASD with regression show similar use of joint attention and more frequent use of words and babble compared with typical infants at 12 months of age. In contrast, infants with ASD with early onset of symptoms and no regression displayed fewer joint attention and communicative behaviors at 12 months of age. By 24 months of age, both groups of toddlers with ASD displayed fewer instances of word use, vocalizations, declarative pointing, social gaze, and orienting to name as compared with typically developing 24-month-olds. Parent interview data suggested that some children with regression displayed difficulties in regulatory behavior before the regression occurred. CONCLUSION: This study validates the existence of early autistic regression.     

Psychopathological symptoms associated with psychosocial functioning in children and adolescents with autism spectrum disorders and their typically developing peers

Children and adolescents with autism have increased prevalence of psychosocial disabilities. Studies in autism indicate that key psychosocial factors including adaptive functioning, school absence, special needs education, frequency of peer socialization and participation in organized leisure activities may differ in their relationship with autistic, internalizing and externalizing symptoms, but the findings are so far mixed. Therefore, we examined if these measures of psychosocial functioning displayed specific associations with autistic, internalizing and/or externalizing symptoms in 61 children with autism aged 7–14 years compared to 61 typically developing controls. Multiple linear regression analyses across all participants showed that lower adaptive functioning, frequency of peer socialization and participation in leisure activities were driven by more social communication problems and not internalizing, externalizing or autistic-like symptoms including rigidity, stereotypy and sensory sensitivity. Notably, increased school absence was specifically driven by more internalizing symptoms and not autistic or externalizing symptoms. These associations were observed across all participants, both children with autism and their typically developing peers, and therefore appear to be dimensional and general in nature. Within the autism group, children who received special needs education displayed fewer social communication problems compared to those who attended regular education, while a developmental history of social interaction problems was related to lower adaptive functioning. Our findings suggest that social communication problems are more critical for psychosocial functioning than other autistic-like behaviors, internalizing or externalizing symptoms but that efforts to reduce school absence specifically need to target internalizing symptoms and not autistic-like or externalizing symptoms.     

Autistic traits modulate conscious and nonconscious face perception

Difficulty with emotion perception is a core feature of autism spectrum disorder (ASD) that is also associated with the broader autism phenotype. The current study explored the neural underpinnings of conscious and nonconscious perceptions of affect in typically developing individuals with varying levels of autistic-like traits, as measured by the Autism Quotient (AQ). We investigated the relationship between autistic traits and face processing efficiency using event-related potentials (ERPs). In 20 typically developing adults, we utilized ERPs (the P100, N170, and P300) to measure differences in face processing for emotional faces that were presented either (a) too quickly to reach conscious awareness (16 ms) or (b) slowly enough to be consciously observed (200 ms). All individuals evidenced increased P100 and P300 amplitude and shorter N170 latencies for nonconscious versus consciously presented faces. Individuals with high AQ scores evidenced delayed ERP components. Nonconsciously perceived emotional faces elicited enhanced neural responses regardless of AQ score. Higher levels of autistic traits were associated with inefficient face perception (i.e., longer latency of ERP components). This delay parallels processing delays observed in ASD. These data suggest that inefficient social perception is present in individuals with subclinical levels of social impairment.     

Vitamin A supplementation ameliorates motor incoordination via modulating RORα in the cerebellum in a valproic acid-treated rat autism model with vitamin A deficiency

Motor dysfunctions are common comorbidities among autism spectrum disorder (ASD) patients. Abnormal cerebellar development throughout critical periods may have an effect on motor functions and result in motor impairments. Vitamin A (VA) plays a crucial role in the developing process of the nervous system. The correlation of VA deficiency (VAD) and ASD with motor dysfunctions, however, is not clear. Therefore, we built rat models with different VA levels based on the valproic acid (VPA)-treated autism model. ASD rats with VAD showed aggravated motor coordination abnormalities, Purkinje cell loss and impaired dendritic arborization of Purkinje cells compared to ASD rats with normal VA levels (VA normal, VAN). Additionally, the expression levels of retinoid-related orphan receptor α (RORα) and retinoic acid receptor α (RARα) were lower in the cerebellum of ASD rats with VAD than in those of ASD rats with VAN. VA supplementation (VAS) effectively improved motor coordination and cerebellar Purkinje cell abnormalities in ASD rats with VAD. Furthermore, the results of chromatin immunoprecipitation (ChIP) assays confirmed that the enrichment of RARα was detected on the RORα promoter in the cerebellum and that VAS could upregulate the binding capacity of RARα for RORα promoters. These results showed that VAD in autism might result in cerebellar impairments and be a factor aggravating a subtype of ASD with motor comorbidities. The therapeutic effect of VAS on motor deficits and Purkinje neuron impairments in autism might be due to the regulation of RORα by RARα.