Single-case and group research studies were evaluated according to specific primary and secondary quality indicators including participant characteristics, clarity with which the independent variable was described, inter-observer agreement, fidelity, generalization and/or maintenance, and social validity. Studies subsequently received a quality rating of high, acceptable or unacceptable. Following this process, studies were categorized as strong, adequate or weak research. The first author independently evaluated all full-text reviews. The second author blindly and independently rated two of the nine selected texts (corresponding to 20% of sample) according to identical primary and secondary quality indicators. Inter-rater reliability was calculated and demonstrated 92% agreement. Discrepancies were solved through discussion as well as reference to the original documentation. The empirical strength of each study was categorized as promising or established based on the outcome of the quality rating process.
All nine full-text reviews targeted social communication outcomes, as stipulated within eligibility criteria. The majority of studies provided a clear operational definition of target outcomes based on the measurement of social initiations (Loncola & Craig-Unkefer, 2005; Vincent et al., 2018; Watkins et al., 2019b) and responses (Loncola & Craig-Unkefer, 2005; Watkins et al., 2019b) by target participants with ASD towards peers or adults within play. Ben-Sasson et al. (2012) also examined the frequency of positive and negative social interactions alongside social responsive scales whilst other studies focused specifically on initiations of joint attention behaviours (Chang et al., 2016b; Goods et al., 2013; Lawton & Kasari, 2012). However, social communication outcomes were less clear within some studies (Beadle-Brown et al., 2018; Thomas & Smith, 2004) in particular when dependent measures were based on generic social communication subscales (Beadle-Brown et al., 2018) and social interaction (Thomas & Smith, 2004).
target spectrum's handbook for general studies pdf download
Notably, there is a prominent sex difference in the prevalence of ASD, with prevalences of 2.8% in males and 0.65% in females and a male-to-female ratio of 4.3:1.51,52 This suggests that unknown biological factors may play a role.53,54,55,56 Moreover, a recent study showed an increased female-to-male odds ratio for ASD comorbidities and showed that comorbidity occurrence was associated with the age at first autism diagnosis.57 There may be differences in gene expression induced by gonadal hormones or sex chromosomes in mammals.58 In the brain, more genes are expressed from the X chromosome than from the Y chromosome. The mutations in the X chromosome are generally associated with intellectual disability syndrome, which is more prevalent in males than in females.59,60 The earliest studies on the rare variant of ASD have also tended to focus on the contributions of chromosomal abnormalities in girls. A rare LGD mutation has been found in the NLGN4 and NLGN3 genes, both of which are located on the X chromosome.61 As an X-linked neurodevelopment disorder, Rett syndrome almost exclusively influences females. One possibility is that mutations in Rett syndrome occur almost exclusively on the paternally derived X chromosome and are lethal in male embryos.62 In general, the contribution of gender aetiology to autism remains largely unexplained. Human studies have only identified minor sex variations in cerebral cortical gene expression.63,64,65,66 Resolving sex differences is a significant aspect in the process of ASD and shows great potential for the development of widely applicable therapies. Many psychiatric disorders, including ASD, will probably be better understood if key sex differences in cellular and molecular events during brain differentiation can be identified.
The majority of genome-wide association studies have concentrated on protein-coding regions, disregarding non-coding RNA. Because non-coding RNAs primarily target transcripts and rarely interact directly with DNA, they are considered nonclassical epigenetic pathways.93,273 Posttranscriptional regulation by non-coding RNAs, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), is associated with ASD. miRNAs are short non-coding RNA molecules that regulate the expression of most genes by blocking protein synthesis or increasing mRNA degradation at the posttranscriptional level. A preliminary assessment suggested that autism does not induce global dysfunction of miRNA expression, as only 28 of 466 miRNAs were significantly altered in postmortem cerebellar cortex tissue of ASD patients.274 Interestingly, the predicted targets of the differentially expressed miRNAs were enriched with genes related to neurobiology, the cell cycle, and cell signalling and largely overlapped with genes previously identified via differential mRNA expression analysis of ASD patients.30,275 Considering that miRNAs can be delivered into cells without being integrated into the host genome, miRNA-based therapy is a prospect strategy for the treatment of ASD.237 Highly expressed miRNAs in ASD patients can be downregulated by miRNA antagonist treatment (i.e., miRNA-inhibitory therapy), while miRNA mimic replacement therapy can compensate for weakly expressed miRNAs.276 Compared with mRNAs, lncRNAs exhibited higher tissue-specific expression, and a considerable number of lncRNAs were confined to the brain.277 The evolution of lncRNA-specific and synaptic function-enriched gene expression in primates suggests that this category of RNAs may have a broad range of roles in the brain and may help to elucidate the aetiology of ASD.31,278,279
In animal studies, mice with heterozygous knockout of miR-137 show repetitive behaviours and social behavioural deficits.280 Another example of the use of miRNA profile screens in a genetic model of ASD comes from a study on Mecp2-knockout mice. Expression profiling of miRNAs in the cerebella of Mecp2-knockout mice revealed the downregulation of a subset of miRNAs.280 Moreover, some of these miRNAs targeted BDNF, which is consistent with the finding that miR-132 targets MeCP2 and BDNF in vitro and is downregulated in the cortices of Mecp2-knockout mice.281,282 Therefore, the regulatory loop including BDNF, miR-132 and MeCP2 may be involved in ASD.237,282 The deletions in regions of differentially expressed lncRNAs are similar to those reported for miRNAs and mRNAs.30 BC1 is an lncRNA whose deletion in the mouse cortex can cause social dysfunction. The underlying mechanism is that BC1 tends to increase the affinity of FMRP and CYFIPI, both of which are ASD risk genes.168,283,284
In summary, dysregulation of immunoregulatory signalling molecules, including cytokines, microglial complement, MET, and MHCI, is an important link in the pathological process of ASD that possibly regulates synaptic morphology and plasticity in the CNS through common downstream pathways. Among them, mTOR serves as a focal point for integrating immunological signalling in the brain, cytokine signalling, perinatal environmental exposures, and chronic immune disorders. Determining whether and how immune contributions concentrate on the common mTOR pathway in future studies will be critical for our understanding of the importance of mTOR in different aspects, not just from an immune perspective, as well as for future targeted drug development.
For nearly two decades, an increasing number of studies on the modulation of circuits and neurotransmitter systems have gained insight into different brain areas and circuits involved in particular behavioural states. Nevertheless, it is unclear to what extent the mouse phenotypes recapitulate the relationships among neural circuits in autism. It should be noted that the human brain with its multimodal structure has undergone dramatic changes in brain regions such as the frontal and temporal lobes during evolution. Therefore, more comparative studies between primate and mouse models are required to precisely correlate neuroanatomical features with candidate brain circuits involved in ASD pathogenesis. More importantly, identification of molecular mechanisms that are specific to social behaviours and circuits is needed. Such information will be essential for developing targeted treatments aimed at ASD.
Physical intervention is usually considered as a priority because many young autistic children have difficulty communicating and interacting with others. Music therapy, cognitive behavioural therapy (CBT) and social behavioural therapy (SBT) have all showed promise in helping autistic patients improve their social interaction and verbal communication.50,452 One potential pathway by which music therapy affects ASD is by changing the structural and functional connectivity of the cortex to achieve a greater degree of multisensory integration across cortical and subcortical regeions during early development.453 CBT is a commonly used psychotherapeutic intervention and can both target core symptoms and treat comorbid anxiety and depression symptoms of ASD.454,455 SBT targets emotional regulation, social skills and functional communication, with an emphasis on independence and quality of life. Considering that the behavioural symptoms of ASD appear at a fairly early stage of development, intervening before symptoms appear may lead to better outcomes. Although treatments vary widely around the world, they generally follow a typical developmental psychology sequence that emphasizes play, social interaction, and communication with children. It is worth noting that clinical services should not be solely diagnosis oriented but should provide step-by-step specific interventions.175
Because the pathogenetic and pathological mechanisms are still unclear, there is no effective treatment drug for the eradication of autism that has been officially approved. Several drugs targeting autism are under study (Table 3) and clinical trials (Table 4). At present, clinical drug treatment of autism generally involves appropriate amounts of atypical antipsychotics, antidepressants, and sleep disorder-improving drugs according to the core symptoms of children.50 2ff7e9595c
Comments