RETRACTED ARTICLE: Improving the measurement of alexithymia in autistic adults: a psychometric investigation and refinement of the twenty-item Toronto Alexithymia ScaleMolecular Autism - - 2021
Zachary J. Williams, Katherine Gotham
AbstractBackgroundAlexithymia, a personality trait characterized by difficulties interpreting one’s own emotional states, is commonly elevated in autistic adults, and a growing body of literature suggests that this trait underlies a number of cognitive and emotional differences previously attributed to autism, such as difficulties in facial emotion recognition and reduced empathy. Although questionnaires such as the twenty-item Toronto Alexithymia Scale (TAS-20) are frequently used to measure alexithymia in the autistic population, few studies have attempted to determine the psychometric properties of these questionnaires in autistic adults, including whether differential item functioning (I-DIF) exists between autistic and general population adults.
MethodsWe conducted an in-depth psychometric analysis of the TAS-20 in a large sample of 743 verbal autistic adults recruited from the Simons Foundation SPARK participant pool and 721 general population controls enrolled in a large international psychological study (the Human Penguin Project). The factor structure of the TAS-20 was examined using confirmatory factor analysis, and item response theory was used to further refine the scale based on local model misfit and I-DIF between the groups. Correlations between alexithymia and other clinical outcomes such as autistic traits, anxiety, and quality-of-life were used to assess the nomological validity of the revised alexithymia scale in the SPARK sample.
ResultsThe TAS-20 did not exhibit adequate global model fit in either the autistic or general population samples. Empirically driven item reduction was undertaken, resulting in an eight-item unidimensional scale (TAS-8) with sound psychometric properties and practically ignorable I-DIF between diagnostic groups. Correlational analyses indicated that TAS-8 scores meaningfully predict autistic trait levels, anxiety and depression symptoms, and quality of life, even after controlling for trait neuroticism.
LimitationsLimitations of the current study include a sample of autistic adults that was overwhelmingly female, later-diagnosed, and well-educated; clinical and control groups drawn from different studies with variable measures; and an inability to test several other important psychometric characteristics of the TAS-8, including sensitivity to change and I-DIF across multiple administrations.
ConclusionsThese results indicate the potential of the TAS-8 as a psychometrically robust tool to measure alexithymia in both autistic and non-autistic adults. A free online score calculator has been created to facilitate the use of norm-referenced TAS-8 latent trait scores in research applications (available athttp://asdmeasures.shinyapps.io/TAS8_Score).
Effects of multiple-dose intranasal oxytocin administration on social responsiveness in children with autism: a randomized, placebo-controlled trialMolecular Autism - Tập 14 - Trang 1-13 - 2023
Nicky Daniels, Matthijs Moerkerke, Jean Steyaert, Annelies Bamps, Edward Debbaut, Jellina Prinsen, Tiffany Tang, Stephanie Van der Donck, Bart Boets, Kaat Alaerts
Intranasal administration of oxytocin is increasingly explored as a new approach to facilitate social development and reduce disability associated with a diagnosis of autism spectrum disorder (ASD). The efficacy of multiple-dose oxytocin administration in children with ASD is, however, not well established. A double-blind, randomized, placebo-controlled trial with parallel design explored the effects of a 4-week intranasal oxytocin administration (12 IU, twice daily) on parent-rated social responsiveness (Social Responsiveness Scale: SRS-2) in pre-pubertal school-aged children (aged 8–12 years, 61 boys, 16 girls). Secondary outcomes included a questionnaire-based assessment of repetitive behaviors, anxiety, and attachment. Effects of oxytocin were assessed immediately after the administration period and at a follow-up, 4 weeks after the last administration. The double-blind phase was followed by a 4-week single-blind phase during which all participants received intranasal oxytocin. In the double-blind phase, both the oxytocin and placebo group displayed significant pre-to-post-improvements in social responsiveness and secondary questionnaires, but improvements were not specific to the intranasal oxytocin. Notably, in the single-blind phase, participants who were first allocated to intranasal placebo and later changed to intranasal oxytocin displayed a significant improvement in social responsiveness, over and above the placebo-induced improvements noted in the first phase. Participants receiving oxytocin in the first phase also showed a significant further improvement upon receiving a second course of oxytocin, but only at the 4-week follow-up. Further, exploratory moderator analyses indicated that children who received psychosocial trainings (3 or more sessions per month) along with oxytocin administration displayed a more pronounced improvement in social responsiveness. Future studies using larger cohorts and more explicitly controlled concurrent psychosocial trainings are warranted to further explore the preliminary moderator effects, also including understudied populations within the autism spectrum, such as children with co-occurring intellectual disabilities. Four weeks of oxytocin administration did not induce treatment-specific improvements in social responsiveness in school-aged children with ASD. Future studies are warranted to further explore the clinical efficacy of oxytocin administration paired with targeted psychosocial trainings that stimulate socio-communicative behaviors. Trial registration The trial was registered with the European Clinical Trial Registry (EudraCT 2018-000769-35) on June 7th, 2018 (
https://www.clinicaltrialsregister.eu/ctr-search/trial/2018-000769-35/BE
).
Review of neuroimaging in autism spectrum disorders: what have we learned and where we go from hereMolecular Autism - Tập 2 - Trang 1-9 - 2011
Evdokia Anagnostou, Margot J Taylor
Autism spectrum disorder (ASD) refers to a syndrome of social communication deficits and repetitive behaviors or restrictive interests. It remains a behaviorally defined syndrome with no reliable biological markers. The goal of this review is to summarize the available neuroimaging data and examine their implication for our understanding of the neurobiology of ASD. Although there is variability in the literature on structural magnetic resonance literature (MRI), there is evidence of volume abnormalities in both grey and white matter, with a suggestion of some region-specific differences. Early brain overgrowth is probably the most replicated finding in a subgroup of people with ASD, and new techniques, such as cortical-thickness measurements and surface morphometry have begun to elucidate in more detail the patterns of abnormalities as they evolve with age, and are implicating specific neuroanatomical or neurodevelopmental processes. Functional MRI and diffusion tensor imaging techniques suggest that such volume abnormalities are associated with atypical functional and structural connectivity in the brain, and researchers have begun to use magnetic resonance spectroscopy (MRS) techniques to explore the neurochemical substrate of such abnormalities. The data from multiple imaging methods suggests that ASD is associated with an atypically connected brain. We now need to further clarify such atypicalities, and start interpreting them in the context of what we already know about typical neurodevelopmental processes including migration and organization of the cortex. Such an approach will allow us to relate imaging findings not only to behavior, but also to genes and their expression, which may be related to such processes, and to further our understanding of the nature of neurobiologic abnormalities in ASD.
Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndromeMolecular Autism - Tập 2 - Trang 1-13 - 2011
Claudia M Greco, Celestine S Navarro, Michael R Hunsaker, Izumi Maezawa, John F Shuler, Flora Tassone, Mary Delany, Jacky W Au, Robert F Berman, Lee-Way Jin, Cynthia Schumann, Paul J Hagerman, Randi J Hagerman
Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS.
Genetic and morphological estimates of androgen exposure predict social deficits in multiple neurodevelopmental disorder cohortsMolecular Autism - Tập 12 - Trang 1-18 - 2021
Brooke G. McKenna, Yongchao Huang, Kévin Vervier, Dabney Hofammann, Mary Cafferata, Seima Al-Momani, Florencia Lowenthal, Angela Zhang, Jin-Young Koh, Savantha Thenuwara, Leo Brueggeman, Ethan Bahl, Tanner Koomar, Natalie Pottschmidt, Taylor Kalmus, Lucas Casten, Taylor R. Thomas, Jacob J. Michaelson
Neurodevelopmental disorders (NDDs) such as autism spectrum disorder (ASD) display a strong male bias. Androgen exposure is profoundly increased in typical male development, but it also varies within the sexes, and previous work has sought to connect morphological proxies of androgen exposure, including digit ratio and facial morphology, to neurodevelopmental outcomes. The results of these studies have been mixed, and the relationships between androgen exposure and behavior remain unclear. Here, we measured both digit ratio masculinity (DRM) and facial landmark masculinity (FLM) in the same neurodevelopmental cohort (N = 763) and compared these proxies of androgen exposure to clinical and parent-reported features as well as polygenic risk scores. We found that FLM was significantly associated with NDD diagnosis (ASD, ADHD, ID; all
$$p<0.05$$
), while DRM was not. When testing for association with parent-reported problems, we found that both FLM and DRM were positively associated with concerns about social behavior (
$$\rho =0.19$$
,
$$p=0.004$$
;
$$\rho =0.2$$
,
$$p=0.004$$
, respectively). Furthermore, we found evidence via polygenic risk scores (PRS) that DRM indexes masculinity via testosterone levels (
$$t=4.0$$
,
$$p=8.8\times 10^{-5}$$
), while FLM indexes masculinity through a negative relationship with sex hormone binding globulin (SHBG) levels (
$$t=-3.3$$
,
$$p=0.001$$
). Finally, using the SPARK cohort (N = 9419) we replicated the observed relationship between polygenic estimates of testosterone, SHBG, and social functioning (
$$t=-2.3$$
,
$$p=0.02$$
, and
$$t=4.2$$
,
$$p={3.2\times 10^{-5}}$$
for testosterone and SHBG, respectively). Remarkably, when considered over the extremes of each variable, these quantitative sex effects on social functioning were comparable to the effect of binary sex itself (binary male:
$$-0.22\pm 0.05$$
; testosterone:
$$-0.35\pm 0.15$$
from 0.1%-ile to 99.9%-ile; SHBG:
$$0.64\pm 0.15$$
from 0.1%-ile to 99.9%-ile). In the devGenes and SPARK cohorts, our analyses rely on indirect, rather than direct measurement of androgens and related molecules. These findings and their replication in the large SPARK cohort lend support to the hypothesis that increasing net androgen exposure diminishes capacity for social functioning in both males and females.
Complex nature of apparently balanced chromosomal rearrangements in patients with autism spectrum disorderMolecular Autism - Tập 6 - Trang 1-14 - 2015
Anne-Claude Tabet, Alain Verloes, Marion Pilorge, Elsa Delaby, Richard Delorme, Gudrun Nygren, Françoise Devillard, Marion Gérard, Sandrine Passemard, Delphine Héron, Jean-Pierre Siffroi, Aurelia Jacquette, Andrée Delahaye, Laurence Perrin, Céline Dupont, Azzedine Aboura, Pierre Bitoun, Mary Coleman, Marion Leboyer, Christopher Gillberg, Brigitte Benzacken, Catalina Betancur
Apparently balanced chromosomal rearrangements can be associated with an abnormal phenotype, including intellectual disability and autism spectrum disorder (ASD). Genome-wide microarrays reveal cryptic genomic imbalances, related or not to the breakpoints, in 25% to 50% of patients with an abnormal phenotype carrying a microscopically balanced chromosomal rearrangement. Here we performed microarray analysis of 18 patients with ASD carrying balanced chromosomal abnormalities to identify submicroscopic imbalances implicated in abnormal neurodevelopment. Eighteen patients with ASD carrying apparently balanced chromosomal abnormalities were screened using single nucleotide polymorphism (SNP) arrays. Nine rearrangements were de novo, seven inherited, and two of unknown inheritance. Genomic imbalances were confirmed by fluorescence in situ hybridization and quantitative PCR. We detected clinically significant de novo copy number variants in four patients (22%), including three with de novo rearrangements and one with an inherited abnormality. The sizes ranged from 3.3 to 4.9 Mb; three were related to the breakpoint regions and one occurred elsewhere. We report a patient with a duplication of the Wolf-Hirschhorn syndrome critical region, contributing to the delineation of this rare genomic disorder. The patient has a chromosome 4p inverted duplication deletion, with a 0.5 Mb deletion of terminal 4p and a 4.2 Mb duplication of 4p16.2p16.3. The other cases included an apparently balanced de novo translocation t(5;18)(q12;p11.2) with a 4.2 Mb deletion at the 18p breakpoint, a subject with de novo pericentric inversion inv(11)(p14q23.2) in whom the array revealed a de novo 4.9 Mb deletion in 7q21.3q22.1, and a patient with a maternal inv(2)(q14.2q37.3) with a de novo 3.3 Mb terminal 2q deletion and a 4.2 Mb duplication at the proximal breakpoint. In addition, we identified a rare de novo deletion of unknown significance on a chromosome unrelated to the initial rearrangement, disrupting a single gene, RFX3. These findings underscore the utility of SNP arrays for investigating apparently balanced chromosomal abnormalities in subjects with ASD or related neurodevelopmental disorders in both clinical and research settings.
Altered functional connectivity of the amygdaloid input nuclei in adolescents and young adults with autism spectrum disorder: a resting state fMRI studyMolecular Autism - Tập 7 - Trang 1-13 - 2016
Annika Rausch, Wei Zhang, Koen V. Haak, Maarten Mennes, Erno J. Hermans, Erik van Oort, Guido van Wingen, Christian F. Beckmann, Jan K. Buitelaar, Wouter B. Groen
Amygdala dysfunction is hypothesized to underlie the social deficits observed in autism spectrum disorders (ASD). However, the neurobiological basis of this hypothesis is underspecified because it is unknown whether ASD relates to abnormalities of the amygdaloid input or output nuclei. Here, we investigated the functional connectivity of the amygdaloid social-perceptual input nuclei and emotion-regulation output nuclei in ASD versus controls. We collected resting state functional magnetic resonance imaging (fMRI) data, tailored to provide optimal sensitivity in the amygdala as well as the neocortex, in 20 adolescents and young adults with ASD and 25 matched controls. We performed a regular correlation analysis between the entire amygdala (EA) and the whole brain and used a partial correlation analysis to investigate whole-brain functional connectivity uniquely related to each of the amygdaloid subregions. Between-group comparison of regular EA correlations showed significantly reduced connectivity in visuospatial and superior parietal areas in ASD compared to controls. Partial correlation analysis revealed that this effect was driven by the left superficial and right laterobasal input subregions, but not the centromedial output nuclei. These results indicate reduced connectivity of specifically the amygdaloid sensory input channels in ASD, suggesting that abnormal amygdalo-cortical connectivity can be traced down to the socio-perceptual pathways.
Sự kéo dài và các yếu tố dự đoán hành vi tự gây thương tích ở người tự kỷ: một nghiên cứu đoàn hệ dài hạn mười năm Dịch bởi AI Molecular Autism - - 2020
Catherine Laverty, Chris Oliver, Joanna Moss, Lisa Nelson, Caroline Richards
Tóm tắt
Đặt vấn đề
Các hành vi tự gây thương tích, chẳng hạn như đập đầu, kéo tóc, cạy da và cào xước, rất phổ biến ở những người mắc chứng tự kỷ. Mặc dù tỷ lệ xảy ra cao, nhưng vẫn thiếu nghiên cứu dài hạn để cải thiện các mô hình rủi ro và cơ chế, cũng như thông tin cho việc lập kế hoạch dịch vụ. Trong nghiên cứu dài hạn này, chúng tôi đã điều tra hành vi tự gây thương tích ở một nhóm cá nhân mắc chứng tự kỷ trong suốt 10 năm nhằm xác định các đặc điểm hành vi và nhân khẩu học liên quan đến việc tự gây thương tích kéo dài.
Phương pháp
Các người chăm sóc của 67 cá nhân mắc chứng tự kỷ đã hoàn thành bảng câu hỏi liên quan đến sự hiện diện của hành vi tự gây thương tích và các yếu tố rủi ro liên quan tại T1 (tuổi trung bình [SD] là 13.4 [7.7] năm) và T3 (tuổi trung bình [SD] là 23.9 [7.7] năm) 10 năm sau. Bốn mươi sáu cá nhân trong số này cũng đã tham gia tại T2 (3 năm sau khi tham gia ban đầu). Phân tích đã đánh giá các yếu tố rủi ro nhân khẩu học và hành vi cho hành vi tự gây thương tích, cũng như giá trị dự đoán của các yếu tố được đánh giá tại T1 và T2.
Kết quả
Hành vi tự gây thương tích kéo dài ở 44% cá nhân trong suốt 10 năm, với các đặc điểm hành vi như tính bốc đồng (p < .001) và tình trạng hoạt động thái quá (p = .002), được xác định là các yếu tố rủi ro cho sự kéo dài. Một mô hình dự đoán hành vi tự gây thương tích được xây dựng từ phân tích LASSO, với tính bốc đồng cơ bản, sở thích và vui vẻ, hành vi điển hình, giao tiếp xã hội và sự thích ứng là những yếu tố dự đoán hành vi tự gây thương tích trong suốt 10 năm.
Kết luận
Trong nghiên cứu dài hạn độc nhất này về sự kéo dài của hành vi tự gây thương tích ở một mẫu không phải lâm sàng của những cá nhân mắc chứng tự kỷ trong suốt 10 năm, chúng tôi đã xác định được một hồ sơ đặc trưng hành vi mới, mạnh mẽ và ổn định liên quan đến hành vi tự gây thương tích kéo dài. Những phát hiện này hỗ trợ một chiến lược can thiệp sớm nhắm vào những cá nhân được xác định có nguy cơ cao hơn trong việc phát triển hành vi tự gây thương tích.
Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patternsMolecular Autism - Tập 11 - Trang 1-16 - 2020
Shreya Das Sharma, Rakhi Pal, Bharath Kumar Reddy, Bhuvaneish T. Selvaraj, Nisha Raj, Krishna Kumar Samaga, Durga J. Srinivasan, Loren Ornelas, Dhruv Sareen, Matthew R. Livesey, Gary J. Bassell, Clive N. Svendsen, Peter C. Kind, Siddharthan Chandran, Sumantra Chattarji, David J. A. Wyllie
Fragile X syndrome (FXS), a neurodevelopmental disorder, is a leading monogenetic cause of intellectual disability and autism spectrum disorder. Notwithstanding the extensive studies using rodent and other pre-clinical models of FXS, which have provided detailed mechanistic insights into the pathophysiology of this disorder, it is only relatively recently that human stem cell-derived neurons have been employed as a model system to further our understanding of the pathophysiological events that may underlie FXS. Our study assesses the physiological properties of human pluripotent stem cell-derived cortical neurons lacking fragile X mental retardation protein (FMRP). Electrophysiological whole-cell voltage- and current-clamp recordings were performed on two control and three FXS patient lines of human cortical neurons derived from induced pluripotent stem cells. In addition, we also describe the properties of an isogenic pair of lines in one of which FMR1 gene expression has been silenced. Neurons lacking FMRP displayed bursts of spontaneous action potential firing that were more frequent but shorter in duration compared to those recorded from neurons expressing FMRP. Inhibition of large conductance Ca2+-activated K+ currents and the persistent Na+ current in control neurons phenocopies action potential bursting observed in neurons lacking FMRP, while in neurons lacking FMRP pharmacological potentiation of voltage-dependent Na+ channels phenocopies action potential bursting observed in control neurons. Notwithstanding the changes in spontaneous action potential firing, we did not observe any differences in the intrinsic properties of neurons in any of the lines examined. Moreover, we did not detect any differences in the properties of miniature excitatory postsynaptic currents in any of the lines. Pharmacological manipulations can alter the action potential burst profiles in both control and FMRP-null human cortical neurons, making them appear like their genetic counterpart. Our studies indicate that FMRP targets that have been found in rodent models of FXS are also potential targets in a human-based model system, and we suggest potential mechanisms by which activity is altered.
Autistic traits and individual brain differences: functional network efficiency reflects attentional and social impairments, structural nodal efficiencies index systemising and theory-of-mind skillsMolecular Autism - Tập 12 Số 1 - 2021
Subhadip Paul, Aditi Arora, Rashi Midha, Dinh Vu, Prasun K. Roy, Matthew K. Belmonte
Abstract
Background
Autism is characterised not only by impaired social cognitive ‘empathising’ but also by superior rule-based ‘systemising’. These cognitive domains intertwine within the categorical diagnosis of autism, yet behavioural genetics suggest largely independent heritability, and separable brain mechanisms. We sought to determine whether quantitative behavioural measures of autistic traits are dimensionally associated with structural and functional brain network integrity, and whether brain bases of autistic traits vary independently across individuals.
Methods
Thirty right-handed neurotypical adults (12 females) were administered psychometric (Social Responsiveness Scale, Autism Spectrum Quotient and Systemising Quotient) and behavioural (Attention Network Test and theory-of-mind reaction time) measures of autistic traits, and structurally (diffusion tensor imaging) and functionally (500 s of 2 Hz eyes-closed resting fMRI) derived graph-theoretic measures of efficiency of information integration were computed throughout the brain and within subregions.
Results
Social impairment was positively associated with functional efficiency (r = .47, p = .006), globally and within temporo-parietal and prefrontal cortices. Delayed orienting of attention likewise was associated with greater functional efficiency (r = − .46, p = .0133). Systemising was positively associated with global structural efficiency (r = .38, p = 0.018), driven specifically by temporal pole; theory-of-mind reaction time was related to structural efficiency (r = − .40, p = 0.0153) within right supramarginal gyrus.
Limitations
Interpretation of these relationships is complicated by the many senses of the term ‘connectivity’, including functional, structural and computational; by the approximation inherent in group functional anatomical parcellations when confronted with individual variation in functional anatomy; and by the validity, sensitivity and specificity of the several survey and experimental behavioural measures applied as correlates of brain structure and function.
Conclusions
Functional connectivities highlight distributed networks associated with domain-general properties such as attentional orienting and social cognition broadly, associating more impaired behaviour with more efficient brain networks that may reflect heightened feedforward information flow subserving autistic strengths and deficits alike. Structural connectivity results highlight specific anatomical nodes of convergence, reflecting cognitive and neuroanatomical independence of systemising and theory-of-mind. In addition, this work shows that individual differences in theory-of-mind related to brain structure can be measured behaviourally, and offers neuroanatomical evidence to pin down the slippery construct of ‘systemising’ as the capacity to construct invariant contextual associations.
