Publications by authors named "James McPartland"

106 Publications

Long-term Follow-up of Preoperative Infant Event-related Potentials in School-age Children with Craniosynostosis.

Plast Reconstr Surg Glob Open 2021 Oct 4;9(10):e3844. Epub 2021 Oct 4.

Section of Plastic and Reconstructive Surgery, Department of Surgery, Yale University School of Medicine, New Haven, Conn.

Background: Previous studies demonstrated impaired auditory processing in children with sagittal and metopic craniosynostosis before surgical correction. This study investigated whether worse presurgical neural response as assessed by event-related potentials (ERP) was predictive of poorer school-age neurocognition.

Methods: Preoperative infant ERP was recorded in 15 sagittal and 18 metopic patients. Mismatch negativity and P150 paradigms were derived from ERP recordings, as previously published. Of those, 13 sagittal and 13 metopic patients returned for neurocognitive evaluation 6 or more years later. ERP was correlated to neurocognitive outcomes using Spearman's correlations controlling for age. Two-tailed t-tests were used to evaluate the influence of age at the time of surgery (6 months) and morphologic severity on neurocognitive outcomes.

Results: In the sagittal group, no significant correlations were found between preoperative mismatch negativity or P150 amplitudes and neurocognitive outcomes. Although no correlation was found between mismatch negativity and neurocognitive outcome in the metopic group, those with lower P150 amplitudes had higher scores in performance IQ (r = -0.877, P < 0.001) and full-scale IQ (r = -0.893, < 0.001). Morphologic severity and neurocognitive outcomes showed no relationship in the sagittal or metopic groups. Patients who received surgery at less than 6 months had higher full-scale IQ (109.69 versus 95.92, = 0.025), visuomotor integration (103.15 versus 90.46, = 0.041), and visual perception scores (105.69 versus 96.08, = 0.033).

Conclusions: Preoperative infant ERP does not correlate with school-age neurocognitive outcomes. Earlier age at the time of surgery was associated with improved neurocognitive outcomes.
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http://dx.doi.org/10.1097/GOX.0000000000003844DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8489894PMC
October 2021

Resting state EEG in youth with ASD: age, sex, and relation to phenotype.

J Neurodev Disord 2021 09 13;13(1):33. Epub 2021 Sep 13.

Center on Child Health, Behavior and Development, Seattle Children's Research Institute, 1920 Terry Ave, CURE-03, Seattle, WA, 98101, USA.

Background: Identification of ASD biomarkers is a key priority for understanding etiology, facilitating early diagnosis, monitoring developmental trajectories, and targeting treatment efforts. Efforts have included exploration of resting state encephalography (EEG), which has a variety of relevant neurodevelopmental correlates and can be collected with minimal burden. However, EEG biomarkers may not be equally valid across the autism spectrum, as ASD is strikingly heterogeneous and individual differences may moderate EEG-behavior associations. Biological sex is a particularly important potential moderator, as females with ASD appear to differ from males with ASD in important ways that may influence biomarker accuracy.

Methods: We examined effects of biological sex, age, and ASD diagnosis on resting state EEG among a large, sex-balanced sample of youth with (N = 142, 43% female) and without (N = 138, 49% female) ASD collected across four research sites. Absolute power was extracted across five frequency bands and nine brain regions, and effects of sex, age, and diagnosis were analyzed using mixed-effects linear regression models. Exploratory partial correlations were computed to examine EEG-behavior associations in ASD, with emphasis on possible sex differences in associations.

Results: Decreased EEG power across multiple frequencies was associated with female sex and older age. Youth with ASD displayed decreased alpha power relative to peers without ASD, suggesting increased neural activation during rest. Associations between EEG and behavior varied by sex. Whereas power across various frequencies correlated with social skills, nonverbal IQ, and repetitive behavior for males with ASD, no such associations were observed for females with ASD.

Conclusions: Research using EEG as a possible ASD biomarker must consider individual differences among participants, as these features influence baseline EEG measures and moderate associations between EEG and important behavioral outcomes. Failure to consider factors such as biological sex in such research risks defining biomarkers that misrepresent females with ASD, hindering understanding of the neurobiology, development, and intervention response of this important population.
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http://dx.doi.org/10.1186/s11689-021-09390-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8439051PMC
September 2021

Brief Report: Preliminary Evidence of the N170 as a Biomarker of Response to Treatment in Autism Spectrum Disorder.

Front Psychiatry 2021 29;12:709382. Epub 2021 Jun 29.

Child Study Center, Yale School of Medicine, New Haven, CT, United States.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by primary difficulties in social function. Individuals with ASD display slowed neural processing of faces, as indexed by the latency of the N170, a face-sensitive event-related potential. Currently, there are no objective biomarkers of ASD useful in clinical care or research. Efficacy of behavioral treatment is currently evaluated through subjective clinical impressions. To explore whether the N170 might have utility as an objective index of treatment response, we examined N170 before and after receipt of an empirically validated behavioral treatment in children with ASD. Electroencephalography (EEG) data were obtained on a preliminary cohort of preschool-aged children with ASD before and after a 16-week course of PRT and in a subset of participants in waitlist control (16-weeks before the start of PRT) and follow-up (16-weeks after the end of PRT). EEG was recorded while participants viewed computer-generated faces with neutral and fearful affect. Significant reductions in N170 latency to faces were observed following 16 weeks of PRT intervention. Change in N170 latency was not observed in the waitlist-control condition. This exploratory study offers suggestive evidence that N170 latency may index response to behavioral treatment. Future, more rigorous, studies in larger samples are indicated to evaluate whether the N170 may be useful as a biomarker of treatment response.
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http://dx.doi.org/10.3389/fpsyt.2021.709382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8275957PMC
June 2021

Face perception predicts affective theory of mind in autism spectrum disorder but not schizophrenia or typical development.

J Abnorm Psychol 2021 May;130(4):413-422

Yale Child Study Center.

Autism spectrum disorder (ASD) and schizophrenia spectrum disorder (SCZ) have overlapping symptomatology related to difficulties with social cognition. Yet, few studies have directly compared social cognition in ASD, SCZ, and typical development (TD). The current study examined individual differences in face recognition and its relation to affective theory of mind (ToM) in each diagnostic group. Adults with ASD (n = 31), SCZ (n = 43), and TD (n = 47) between the ages of 18 and 48 years-old with full scale IQ above 80 participated in this study. The Reading the Mind in the Eyes Test (RMET) measured affective ToM, and the Benton Facial Recognition Test (BFRT) measured face perception. Adults with ASD and SCZ did not differ in their affective ToM abilities, and both groups showed affective ToM difficulties compared with TD. However, better face recognition ability uniquely predicted better affective ToM ability in ASD. Results suggest that affective ToM difficulties may relate to face processing in ASD but not SCZ. By clarifying the complex nature of individual differences in affective ToM and face recognition difficulties in these disorders, the present study suggests there may be divergent mechanisms underlying pathways to social dysfunction in ASD compared with SCZ. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/abn0000621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244155PMC
May 2021

Drug development for Autism Spectrum Disorder (ASD): Progress, challenges, and future directions.

Eur Neuropsychopharmacol 2021 Jul 19;48:3-31. Epub 2021 Jun 19.

Department of Psychiatry, Columbia University, New York, NY, United States.

In 2017, facing lack of progress and failures encountered in targeted drug development for Autism Spectrum Disorder (ASD) and related neurodevelopmental disorders, the ISCTM with the ECNP created the ASD Working Group charged to identify barriers to progress and recommending research strategies for the field to gain traction. Working Group international academic, regulatory and industry representatives held multiple in-person meetings, teleconferences, and subgroup communications to gather a wide range of perspectives on lessons learned from extant studies, current challenges, and paths for fundamental advances in ASD therapeutics. This overview delineates the barriers identified, and outlines major goals for next generation biomedical intervention development in ASD. Current challenges for ASD research are many: heterogeneity, lack of validated biomarkers, need for improved endpoints, prioritizing molecular targets, comorbidities, and more. The Working Group emphasized cautious but unwavering optimism for therapeutic progress for ASD core features given advances in the basic neuroscience of ASD and related disorders. Leveraging genetic data, intermediate phenotypes, digital phenotyping, big database discovery, refined endpoints, and earlier intervention, the prospects for breakthrough treatments are substantial. Recommendations include new priorities for expanded research funding to overcome challenges in translational clinical ASD therapeutic research.
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http://dx.doi.org/10.1016/j.euroneuro.2021.05.010DOI Listing
July 2021

Impact of autism genetic risk on brain connectivity: a mechanism for the female protective effect.

Brain 2021 May 29. Epub 2021 May 29.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.

The biological mechanisms underlying the greater prevalence of autism spectrum disorder in males than females remain poorly understood. One hypothesis posits that this female protective effect arises from genetic load for autism spectrum disorder differentially impacting male and female brains. To test this hypothesis, we investigated the impact of cumulative genetic risk for autism spectrum disorder on functional brain connectivity in a balanced sample of boys and girls with autism spectrum disorder and typically developing boys and girls (127 youth, ages 8-17). Brain connectivity analyses focused on the salience network, a core intrinsic functional connectivity network which has previously been implicated in autism spectrum disorder. The effects of polygenic risk on salience network functional connectivity were significantly modulated by participant sex, with genetic load for autism spectrum disorder influencing functional connectivity in boys with and without autism spectrum disorder but not girls. These findings support the hypothesis that autism spectrum disorder risk genes interact with sex differential processes, thereby contributing to the male bias in autism prevalence and proposing an underlying neurobiological mechanism for the female protective effect.
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http://dx.doi.org/10.1093/brain/awab204DOI Listing
May 2021

Looking Back at the Next 40 Years of ASD Neuroscience Research.

J Autism Dev Disord 2021 Dec 27;51(12):4333-4353. Epub 2021 May 27.

Child Study Center, Yale School of Medicine, New Haven, CT, 06520, USA.

During the last 40 years, neuroscience has become one of the most central and most productive approaches to investigating autism. In this commentary, we assemble a group of established investigators and trainees to review key advances and anticipated developments in neuroscience research across five modalities most commonly employed in autism research: magnetic resonance imaging, functional near infrared spectroscopy, positron emission tomography, electroencephalography, and transcranial magnetic stimulation. Broadly, neuroscience research has provided important insights into brain systems involved in autism but not yet mechanistic understanding. Methodological advancements are expected to proffer deeper understanding of neural circuitry associated with function and dysfunction during the next 40 years.
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http://dx.doi.org/10.1007/s10803-021-05095-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8542594PMC
December 2021

Refining biomarker evaluation in ASD.

Eur Neuropsychopharmacol 2021 Jul 29;48:34-36. Epub 2021 Apr 29.

Professor of Child Psychiatry and Psychology, Yale Child Study Center, 230 South Frontage Road, New Haven, CT 06520, United States. Electronic address:

This commentary reflects on reasonable biomarker expectations in ASD by addressing three key questions: What is a biomarker? What is required for a biomarker in ASD? How can biomarkers be useful in ASD? In addressing these queries, a path forward emerges based on clear definition of the objective for any given ASD biomarker and evaluation of each biomarker relative to current best practices.
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http://dx.doi.org/10.1016/j.euroneuro.2021.03.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8238819PMC
July 2021

Modeling temporal dynamics of face processing in youth and adults.

Soc Neurosci 2021 Aug 17;16(4):345-361. Epub 2021 May 17.

Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA, USA.

A hierarchical model of temporal dynamics was examined in adults ( = 34) and youth ( = 46) across the stages of face processing during the perception of static and dynamic faces. Three ERP components (P100, N170, N250) and spectral power in the mu range were extracted, corresponding to cognitive stages of face processing: low-level vision processing, structural encoding, higher-order processing, and action understanding. Youth and adults exhibited similar yet distinct patterns of hierarchical temporal dynamics such that earlier cognitive stages predicted later stages, directly and indirectly. However, latent factors indicated unique profiles related to behavioral performance for adults and youth and age as a continuous factor. The application of path analysis to electrophysiological data can yield novel insights into the cortical dynamics of social information processing.
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http://dx.doi.org/10.1080/17470919.2021.1920050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324546PMC
August 2021

A neurogenetic analysis of female autism.

Brain 2021 07;144(6):1911-1926

Department of Pediatrics, Yale School of Medicine, New Haven, CT 06510, USA.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.
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http://dx.doi.org/10.1093/brain/awab064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320285PMC
July 2021

The N170 event-related potential reflects delayed neural response to faces when visual attention is directed to the eyes in youths with ASD.

Autism Res 2021 07 22;14(7):1347-1356. Epub 2021 Mar 22.

Child Study Center, Yale School of Medicine, New Haven, Connecticut, USA.

Atypical neural response to faces is thought to contribute to social deficits in autism spectrum disorder (ASD). Compared to typically developing (TD) controls, individuals with ASD exhibit delayed brain responses to upright faces at a face-sensitive event-related potential (ERP), the N170. Given observed differences in patterns of visual attention to faces, it is not known whether slowed neural processing may simply reflect atypical looking to faces. The present study manipulated visual attention to facial features to examine whether directed attention to the eyes normalizes N170 latency in ASD. ERPs were recorded in 30 children and adolescents with ASD as well as 26 TD children and adolescents. Results replicated prior findings of shorter N170 latency to the eye region of the face in TD individuals. In contrast, those with ASD did not demonstrate modulation of N170 latency by point of regard to the face. Group differences in latency were most pronounced when attention was directed to the eyes. Results suggest that well-replicated findings of N170 delays in ASD do not simply reflect atypical patterns of visual engagement with experimental stimuli. These findings add to a body of evidence indicating that N170 delays are a promising marker of atypical neural response to social information in ASD. LAY SUMMARY: This study looks at how children's and adolescents' brains respond when looking at different parts of a face. Typically developing children and adolescents processed eyes faster than other parts of the face, whereas this pattern was not seen in ASD. Children and adolescents with ASD processed eyes more slowly than typically developing children. These findings suggest that observed inefficiencies in face processing in ASD are not simply reflective of failure to attend to the eyes.
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http://dx.doi.org/10.1002/aur.2505DOI Listing
July 2021

The gap between IQ and adaptive functioning in autism spectrum disorder: Disentangling diagnostic and sex differences.

Autism 2021 08 15;25(6):1565-1579. Epub 2021 Mar 15.

Department of Speech, Language, and Hearing Sciences, The George Washington University, Washington, DC, USA.

Lay Abstract: Adaptive functioning refers to skills that are vital to success in day-to-day life, including daily living (e.g. grocery shopping, food preparation, transportation use), communication (e.g. verbal expression of needs), and socialization skills (e.g. interpersonal skills, including expressing and recognizing emotions, and understanding turn-taking in conversation). Among autistic individuals without intellectual disability, adaptive functioning is not commensurate with intellectual ability (IQ), and instead a gap exists between these individuals' intellectual ability and their adaptive skills. Further, these autistic individuals show a widening of this gap with increasing age. Existing studies of the gap between IQ and adaptive functioning have studied predominantly male samples. Thus, we do not know if the gap also exists in autistic females. We therefore looked at adaptive functioning and the gap between IQ and adaptive functioning in a large sample of autistic girls and boys without intellectual disability. To disentangle effects of group (autistic vs typically developing) from effects of sex (girls vs boys), we compared autistic girls and boys to one another as well as to their same-sex typically developing peers. Analyses took into consideration differences in IQ between autistic and typically developing youth. We found autistic girls, like autistic boys, show lower adaptive functioning than their same-sex typically developing peers. Results underscore the need to evaluate adaptive functioning in autistic individuals without intellectual disability and to provide necessary supports. The large gap between intellectual ability and socialization skills, in particular, may be of critical importance in improving our understanding of outcomes and mental health difficulties among autistic females.
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http://dx.doi.org/10.1177/1362361321995620DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8324508PMC
August 2021

Language and Aggressive Behaviors in Male and Female Youth with Autism Spectrum Disorder.

J Autism Dev Disord 2022 Jan 8;52(1):454-462. Epub 2021 Mar 8.

Center on Child Health, Behavior and Development, Seattle Children's Research Institute, 2001 8th Ave, Suite 400, Seattle, WA, 98121, USA.

Aggressive behaviors are common among youth with autism spectrum disorder (ASD) and correlate with pervasive social-emotional difficulties. Communication skill is an important correlate of disruptive behavior in typical development, and clarification of links between communication and aggression in ASD may inform intervention methods. We investigate child/family factors and communication in relation to aggression among 145 individuals with ASD (65 female; ages 8-17 years). Overall, more severe aggression was associated with younger age, lower family income, and difficulties with communication skills. However, this pattern of results was driven by males, and aggression was unrelated to child or family characteristics for females. Future work should incorporate these predictors in conjunction with broader contextual factors to understand aggressive behavior in females with ASD.
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http://dx.doi.org/10.1007/s10803-020-04773-0DOI Listing
January 2022

Eye see what you're saying: Contrastive use of beat gesture and pitch accent affects online interpretation of spoken discourse.

J Exp Psychol Learn Mem Cogn 2021 Sep 4;47(9):1494-1526. Epub 2021 Feb 4.

Child Study Center.

Cues to prominence such as beat gesture and contrastive pitch accent play an important role in constraining what is remembered. However, it is currently unclear how beat gesture affects online discourse processing alone and in combination with contrastive accenting. Using an adaptation of the visual world eye-tracking paradigm, we orthogonally manipulated the presence of these cues and their felicity (match) with contrast within local (sentence-level) and global (experiment-level) referential contexts. In Experiment 1, in which beat gesture and contrastive accenting were always globally felicitous with the context of filler referring expressions, beat gesture increased anticipation of both target and competitor referents of locally infelicitous critical referring expressions differing in color and shape, whereas contrastive accenting hindered resolution of these expressions. In Experiment 2, in which beat gesture and contrastive accenting were always globally infelicitous with the context of filler referring expressions, beat gesture increased anticipation of both target and competitor referents of locally felicitous critical referring expressions contrasting in color, whereas contrastive accenting did not affect their interpretation. Taken together, these findings indicate that local and global felicity of cues to prominence with contrast affects their interpretation during online spoken discourse processing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/xlm0000986DOI Listing
September 2021

First-Hand Accounts of Interoceptive Difficulties in Autistic Adults.

J Autism Dev Disord 2021 Oct 3;51(10):3483-3491. Epub 2021 Jan 3.

Child Study Center, Yale University, 230 S. Frontage Rd, New Haven, CT, 06511, USA.

Interoceptive awareness refers to one's ability to detect, discriminate, and regulate internal bodily and mental processes. Interoceptive challenges in ASD remain under researched and poorly understood. In this study, we analyzed texts of adults who self-identify as autistic describing their interoceptive challenges. Many individuals described limited awareness of hunger, satiation, or thirst, which contributed to eating disordered behavior in some instances. Others described limited awareness or difficulty understanding affective arousal, pain or illness, and difficulty differentiating benign body signals from signals that represent medical concerns. Findings from this study call for increased research attention on this topic, and a need for valid and objective measures for assessing interoception in ASD.
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http://dx.doi.org/10.1007/s10803-020-04811-xDOI Listing
October 2021

Adaptive and Maladaptive Bodily Awareness: Distinguishing Interoceptive Sensibility and Interoceptive Attention from Anxiety-Induced Somatization in Autism and Alexithymia.

Autism Res 2021 02 18;14(2):240-247. Epub 2020 Dec 18.

Child Study Center, Yale University, New Haven, CT, USA.

There is growing interest in "interoception" (i.e., detection and interpretation of internal body signals) as a relevant mechanism contributing to certain symptoms and features of autism spectrum disorder (ASD) and alexithymia. However, inconsistent measurement and operationalization of interoception has led to confusion and inconsistent findings in the literature. In this commentary, we present alternative interpretations of findings from existing studies to demonstrate that ASD and alexithymia are conditions associated with reduced adaptive forms of interoceptive attention (i.e., attention toward bodily signals) but heightened maladaptive forms of interoceptive attention related to anxiety-induced somatization. Differentiating adaptive and maladaptive forms of interoceptive attention reveals a clearer pattern of findings in the research literature for further investigation of interoceptive processes that are involved in the neurobiology of ASD. However, interoception is a complex and multi-faceted construct that requires continual refinement in conceptualization and operationalization. Interoception research may benefit from self-report measures that clearly differentiate adaptive and maladaptive forms of bodily awareness. LAY SUMMARY: Some research suggests that autistic people have difficulty understanding bodily feelings such as hunger, illness, or emotions, whereas some studies have reported the opposite pattern of findings. We argue that this latter subset of studies reached false conclusions from using measures of bodily awareness that largely measure physical symptoms of anxiety. While attention to unpleasant bodily signals is an important ability necessary for maintaining healthy bodily functioning, excessive attention, and worry toward bodily signals can increase anxiety and be harmful.
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http://dx.doi.org/10.1002/aur.2458DOI Listing
February 2021

Low-motion fMRI data can be obtained in pediatric participants undergoing a 60-minute scan protocol.

Sci Rep 2020 12 14;10(1):21855. Epub 2020 Dec 14.

Interdepartmental Neuroscience Program, Yale School of Medicine, New Haven, CT, USA.

Performing functional magnetic resonance imaging (fMRI) scans of children can be a difficult task, as participants tend to move while being scanned. Head motion represents a significant confound in fMRI connectivity analyses. One approach to limit motion has been to use shorter MRI protocols, though this reduces the reliability of results. Hence, there is a need to implement methods to achieve high-quality, low-motion data while not sacrificing data quantity. Here we show that by using a mock scan protocol prior to a scan, in conjunction with other in-scan steps (weighted blanket and incentive system), it is possible to achieve low-motion fMRI data in pediatric participants (age range: 7-17 years old) undergoing a 60 min MRI session. We also observe that motion is low during the MRI protocol in a separate replication group of participants, including some with autism spectrum disorder. Collectively, the results indicate it is possible to conduct long scan protocols in difficult-to-scan populations and still achieve high-quality data, thus potentially allowing more reliable fMRI findings.
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http://dx.doi.org/10.1038/s41598-020-78885-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736342PMC
December 2020

Do Biological Sex and Early Developmental Milestones Predict the Age of First Concerns and Eventual Diagnosis in Autism Spectrum Disorder?

Autism Res 2021 01 4;14(1):156-168. Epub 2020 Dec 4.

University of Virginia, Department of Neurology, Charlottesville, Virginia, USA.

Despite advances in early detection, the average age of autism spectrum disorder (ASD) diagnosis exceeds 4 years and is often later in females. In typical development, biological sex predicts inter-individual variation across multiple developmental milestones, with females often exhibiting earlier progression. The goal of this study was to examine sex differences in caregiver-reported developmental milestones (first word, phrase, walking) and their contribution to timing of initial concerns expressed by caregivers and eventual age of diagnosis. 195 (105 males) children and adolescents aged 8 to 17 years with a clinical diagnosis of ASD were recruited to the study (mean IQ = 99.76). While developmental milestones did not predict timing of diagnosis or age parents first expressed concerns, females had earlier first words and phrases than males. There was a marginal difference in the age of diagnosis, with females receiving their diagnosis 1 year later than males. Despite sex differences in developmental milestones and diagnostic variables, IQ was the most significant predictor in the timing of initial concerns and eventual diagnosis, suggesting children with lower IQ, regardless of sex, are identified and diagnosed earlier. Overall, biological sex and developmental milestones did not account for a large proportion of variance for the eventual age of ASD diagnosis, suggesting other factors (such as IQ and the timing of initial concerns) are potentially more influential. LAY SUMMARY: In this study, a later age of diagnosis in females having ASD was confirmed; however, biological sex was not the stronger predictor of age of diagnosis. Parents reported that females learned language more quickly than males, and parents noted their first concerns when females were older than males. In this sample, the strongest predictor of age of diagnosis was the age of first concerns.
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http://dx.doi.org/10.1002/aur.2446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023413PMC
January 2021

Contrast Is in the Eye of the Beholder: Infelicitous Beat Gesture Increases Cognitive Load During Online Spoken Discourse Comprehension.

Cogn Sci 2020 10;44(10):e12912

Department of Child Psychiatry, Yale University.

We investigated how two cues to contrast-beat gesture and contrastive pitch accenting-affect comprehenders' cognitive load during processing of spoken referring expressions. In two visual-world experiments, we orthogonally manipulated the presence of these cues and their felicity, or fit, with the local (sentence-level) referential context in critical referring expressions while comprehenders' task-evoked pupillary responses (TEPRs) were examined. In Experiment 1, beat gesture and contrastive accenting always matched the referential context of filler referring expressions and were therefore relatively felicitous on the global (experiment) level, whereas in Experiment 2, beat gesture and contrastive accenting never fit the referential context of filler referring expressions and were therefore infelicitous on the global level. The results revealed that both beat gesture and contrastive accenting increased comprehenders' cognitive load. For beat gesture, this increase in cognitive load was driven by both local and global infelicity. For contrastive accenting, this increase in cognitive load was unaffected when cues were globally felicitous but exacerbated when cues were globally infelicitous. Together, these results suggest that comprehenders' cognitive resources are taxed by processing infelicitous use of beat gesture and contrastive accenting to convey contrast on both the local and global levels.
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http://dx.doi.org/10.1111/cogs.12912DOI Listing
October 2020

Neurologic Characterization of Craniosynostosis: Can Direct Brain Recordings Predict Language Development?

J Craniofac Surg 2021 Jan-Feb 01;32(1):78-82

Yale School of Medicine.

Purpose: Nonsyndromic craniosynostosis (NSC) is associated with language deficits. Conventional tests, such as the Bayley Scales of Infant Development (BSID), may not reflect accurate long-term cognition. Alternatively, mismatch negativity (MMN) waves recorded via electroencephalogram (EEG) measure neural responses to speech and may objectively predict language development. This study aimed to (1) correlate infant MMN to future language achievement and (2) compare MMN among subtypes of NSC.

Methods: Pre and postoperatively (mean operative age 9.5 months), NSC participants received the BSID and EEG phoneme-discrimination paradigm(80 dB,250 Hz). The MMN was the largest negative amplitude in the difference wave 80 to 300 ms after stimuli. To measure cognitive outcome, patients completed a neurodevelopmental battery (Wechsler-Abbreviated Scale of Intelligence and Wechsler-Fundamentals) at >6 years of age.

Results: Eleven NSC patients with EEG testing in infancy were neurocognitively tested (average age 8.0 years; 27% female; 55% sagittal, 27% metopic, 9% unicoronal, 9% sagittal/metopic). The left frontal cluster MMN strongly correlated with word-reading (r = 0.713, P = 0.031), reading-comprehension (r = 0.745, P = 0.021), and language-composites (r = 0.0771, P = 0.015). Conversely, BSID scores did not yield significant predictive value (r < 0.5, P > 0.05). Follow-up event related potentials (ERP) comparison included 39 normal control, 18 sagittal, 17 metopic, 6 unilateral-coronal infants. Preoperatively, sagittal (P = 0.003) and metopic (P = 0.003) patients had attenuated left frontal MMN compared to controls. Postoperatively, the sagittal cohort was normalized to controls while metopic patients retained attenuations (P = 0.041).

Conclusion: ERP assessment in NSC had significantly better predictive value for future neurocognition than the BSID. Preoperatively, sagittal and metopic patients had attenuated neural response to language; postoperatively, sagittal patients had improved responses in comparison to metopic patients. Use of ERP assessment may help tailor treatment for language deficits earlier in development.
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http://dx.doi.org/10.1097/SCS.0000000000007004DOI Listing
June 2021

N400 amplitude, latency, and variability reflect temporal integration of beat gesture and pitch accent during language processing.

Brain Res 2020 11 17;1747:147059. Epub 2020 Aug 17.

Yale University, United States.

This study examines how across-trial (average) and trial-by-trial (variability in) amplitude and latency of the N400 event-related potential (ERP) reflect temporal integration of pitch accent and beat gesture. Thirty native English speakers viewed videos of a talker producing sentences with beat gesture co-occurring with a pitch accented focus word (synchronous), beat gesture co-occurring with the onset of a subsequent non-focused word (asynchronous), or the absence of beat gesture (no beat). Across trials, increased amplitude and earlier latency were observed when beat gesture was temporally asynchronous with pitch accenting than when it was temporally synchronous with pitch accenting or absent. Moreover, temporal asynchrony of beat gesture relative to pitch accent increased trial-by-trial variability of N400 amplitude and latency and influenced the relationship between across-trial and trial-by-trial N400 latency. These results indicate that across-trial and trial-by-trial amplitude and latency of the N400 ERP reflect temporal integration of beat gesture and pitch accent during language comprehension, supporting extension of the integrated systems hypothesis of gesture-speech processing and neural noise theories to focus processing in typical adult populations.
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http://dx.doi.org/10.1016/j.brainres.2020.147059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493208PMC
November 2020

Research and training in autism spectrum disorder to catalyze the next genomic and neuroscience revolutions.

Mol Psychiatry 2021 05;26(5):1429-1431

Child Study Center, Yale University School of Medicine, New Haven, CT, USA.

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http://dx.doi.org/10.1038/s41380-020-0830-5DOI Listing
May 2021

Autism Spectrum Disorder and Schizophrenia Are Better Differentiated by Positive Symptoms Than Negative Symptoms.

Front Psychiatry 2020 11;11:548. Epub 2020 Jun 11.

Child Study Center, Yale University School of Medicine, New Haven, CT, United States.

Autism spectrum disorder (ASD) and schizophrenia (SZ) are heterogenous neurodevelopmental disorders that overlap in symptom presentation. The purpose of this study was to specify overlapping symptom domains and to identify symptoms that can reliably differentiate adults with ASD (n = 53), SZ (n = 39), and typical development (TD; n = 40). All participants regardless of diagnosis were administered gold-standard diagnostic assessments of ASD and SZ characteristics including the Autism Diagnostic Observation Schedule (ADOS-2) and the Positive and Negative Syndrome Scale (PANSS). Sensitivity and specificity of the ADOS were assessed using diagnostic cut-off scores. The degree of symptom overlap on these measures between participant groups was analyzed using Analyses of Variance (ANOVAs), Receiver Operating Characteristic (ROC) Curves, and Analyses of Covariance (ANCOVAs) to control for group differences in IQ and sex distributions. The ADOS reliably discriminated ASD and TD adults, but there was a high rate of "false positives" in SZ patients who did not meet the DSM-5 criteria for ASD. To identify the reasons for low specificity in the SZ sample, we categorized ASD and SZ symptoms into 'positive' (presence of atypical behaviors) and 'negative' (absence of typical behaviors) symptoms. ASD and SZ groups overlapped on negative symptoms largely related to the absence of typical social and communicative behaviors, whereas disorder-specific positive symptoms differentiated ASD and SZ. For example, those with ASD scored higher on restricted and repetitive behaviors and stereotyped language, whereas those with SZ scored higher on psychotic symptoms such as delusions and hallucinations. These results suggest that, when making a differential diagnosis between ASD and SZ, clinicians may benefit from focusing on the presence or absence of positive ASD and SZ symptoms. Standardized measures to classify ASD symptoms into positive and negative symptoms have not yet been developed but represent a potentially viable clinical tool.
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http://dx.doi.org/10.3389/fpsyt.2020.00548DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7301837PMC
June 2020

Neural responsivity to social rewards in autistic female youth.

Transl Psychiatry 2020 06 2;10(1):178. Epub 2020 Jun 2.

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, USA.

Autism is hypothesized to be in part driven by a reduced sensitivity to the inherently rewarding nature of social stimuli. Previous neuroimaging studies have indicated that autistic males do indeed display reduced neural activity to social rewards, but it is unknown whether this finding extends to autistic females, particularly as behavioral evidence suggests that affected females may not exhibit the same reduction in social motivation as their male peers. We therefore used functional magnetic resonance imaging to examine social reward processing during an instrumental implicit learning task in 154 children and adolescents (ages 8-17): 39 autistic girls, 43 autistic boys, 33 typically developing girls, and 39 typically developing boys. We found that autistic girls displayed increased activity to socially rewarding stimuli, including greater activity in the nucleus accumbens relative to autistic boys, as well as greater activity in lateral frontal cortices and the anterior insula compared with typically developing girls. These results demonstrate for the first time that autistic girls do not exhibit the same reduction in activity within social reward systems as autistic boys. Instead, autistic girls display increased neural activation to such stimuli in areas related to reward processing and salience detection. Our findings indicate that a reduced sensitivity to social rewards, as assessed with a rewarded instrumental implicit learning task, does not generalize to affected female youth and highlight the importance of studying potential sex differences in autism to improve our understanding of the condition and its heterogeneity.
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http://dx.doi.org/10.1038/s41398-020-0824-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7266816PMC
June 2020

Day-to-Day Test-Retest Reliability of EEG Profiles in Children With Autism Spectrum Disorder and Typical Development.

Front Integr Neurosci 2020 30;14:21. Epub 2020 Apr 30.

Department of Biostatistics, University of California, Los Angeles, Los Angeles, CA, United States.

Biomarker development is currently a high priority in neurodevelopmental disorder research. For many types of biomarkers (particularly biomarkers of diagnosis), reliability over short periods is critically important. In the field of autism spectrum disorder (ASD), resting electroencephalography (EEG) power spectral densities (PSD) are well-studied for their potential as biomarkers. Classically, such data have been decomposed into pre-specified frequency bands (e.g., delta, theta, alpha, beta, and gamma). Recent technical advances, such as the Fitting Oscillations and One-Over-F (FOOOF) algorithm, allow for targeted characterization of the features that naturally emerge within an EEG PSD, permitting a more detailed characterization of the frequency band-agnostic shape of each individual's EEG PSD. Here, using two resting EEGs collected a median of 6 days apart from 22 children with ASD and 25 typically developing (TD) controls during the Feasibility Visit of the Autism Biomarkers Consortium for Clinical Trials, we estimate test-retest reliability based on the characterization of the PSD shape in two ways: (1) Using the FOOOF algorithm we estimate six parameters (offset, slope, number of peaks, and amplitude, center frequency and bandwidth of the largest alpha peak) that characterize the shape of the EEG PSD; and (2) using nonparametric functional data analyses, we decompose the shape of the EEG PSD into a reduced set of basis functions that characterize individual power spectrum shapes. We show that individuals exhibit idiosyncratic PSD signatures that are stable over recording sessions using both characterizations. Our data show that EEG activity from a brief 2-min recording provides an efficient window into characterizing brain activity at the single-subject level with desirable psychometric characteristics that persist across different analytical decomposition methods. This is a necessary step towards analytical validation of biomarkers based on the EEG PSD and provides insights into parameters of the PSD that offer short-term reliability (and thus promise as potential biomarkers of trait or diagnosis) vs. those that are more variable over the short term (and thus may index state or other rapidly dynamic measures of brain function). Future research should address the longer-term stability of the PSD, for purposes such as monitoring development or response to treatment.
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http://dx.doi.org/10.3389/fnint.2020.00021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204836PMC
April 2020

The Presence of Another Person Influences Oscillatory Cortical Dynamics During Dual Brain EEG Recording.

Front Psychiatry 2020 17;11:246. Epub 2020 Apr 17.

Child Study Center, Yale School of Medicine, New Haven, CT, United States.

Humans are innately social creatures and the social environment strongly influences brain development. As such, the human brain is primed for and sensitive to social information even in the absence of explicit task or instruction. In this study, we examined the influence of different levels of interpersonal proximity on resting state brain activity and its association with social cognition. We measured EEG in pairs of 13 typically developing (TD) adults seated in separate rooms, in the same room back-to-back, and in the same room facing each other. Interpersonal proximity modulated broadband EEG power from 4-55 Hz and individual differences in self-reported social cognition modulated these effects in the beta and gamma frequency bands. These findings provide novel insight into the influence of social environment on brain activity and its association with social cognition through dual-brain EEG recording and demonstrate the importance of using interactive methods to study the human brain.
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http://dx.doi.org/10.3389/fpsyt.2020.00246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7180176PMC
April 2020

Sex Differences in Functional Connectivity of the Salience, Default Mode, and Central Executive Networks in Youth with ASD.

Cereb Cortex 2020 07;30(9):5107-5120

Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.

Autism spectrum disorder (ASD) is associated with the altered functional connectivity of 3 neurocognitive networks that are hypothesized to be central to the symptomatology of ASD: the salience network (SN), default mode network (DMN), and central executive network (CEN). Due to the considerably higher prevalence of ASD in males, however, previous studies examining these networks in ASD have used primarily male samples. It is thus unknown how these networks may be differentially impacted among females with ASD compared to males with ASD, and how such differences may compare to those observed in neurotypical individuals. Here, we investigated the functional connectivity of the SN, DMN, and CEN in a large, well-matched sample of girls and boys with and without ASD (169 youth, ages 8-17). Girls with ASD displayed greater functional connectivity between the DMN and CEN than boys with ASD, whereas typically developing girls and boys differed in SN functional connectivity only. Together, these results demonstrate that youth with ASD exhibit altered sex differences in these networks relative to what is observed in typical development, and highlight the importance of considering sex-related biological factors and participant sex when characterizing the neural mechanisms underlying ASD.
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http://dx.doi.org/10.1093/cercor/bhaa105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391269PMC
July 2020

Higher Depressive Symptoms Predict Lower Social Adaptive Functioning in Children and Adolescents with ASD.

J Clin Child Adolesc Psychol 2020 Apr 29:1-8. Epub 2020 Apr 29.

Yale Child Study Center, School of Medicine, Yale University.

: Despite the frequent occurrence of depressive symptoms in children and adolescents with autism spectrum disorder (ASD), few studies have investigated the relationship between depressive symptoms and adaptive functioning. The present study explored the impact of depressive symptoms on different domains of adaptive functioning in children and adolescents with ASD.: Depressive symptoms and adaptive functioning were analyzed in 62 children and adolescents with ASD (20 females) and 36 children and adolescents (15 females) with typical development between 5 and 18 years of age.: After controlling for IQ, age and sex, higher depressive symptoms predicted lower functioning in the social domain among children and adolescents with ASD. Depressive symptoms did not significantly predict communication or daily living skills.: These findings highlight the relevance of depression in social adaptive function in ASD and emphasize the importance of assessing depressive symptomatology when evaluating social skills and planning treatment for children and adolescents with ASD.
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http://dx.doi.org/10.1080/15374416.2020.1750020DOI Listing
April 2020

The Autism Biomarkers Consortium for Clinical Trials (ABC-CT): Scientific Context, Study Design, and Progress Toward Biomarker Qualification.

Front Integr Neurosci 2020 9;14:16. Epub 2020 Apr 9.

Center for Child Health, Behavior and Development, Seattle Children's Research Institute, Seattle Children's Hospital, Seattle, WA, United States.

Clinical research in neurodevelopmental disorders remains reliant upon clinician and caregiver measures. Limitations of these approaches indicate a need for objective, quantitative, and reliable biomarkers to advance clinical research. Extant research suggests the potential utility of multiple candidate biomarkers; however, effective application of these markers in trials requires additional understanding of replicability, individual differences, and intra-individual stability over time. The Autism Biomarkers Consortium for Clinical Trials (ABC-CT) is a multi-site study designed to investigate a battery of electrophysiological (EEG) and eye-tracking (ET) indices as candidate biomarkers for autism spectrum disorder (ASD). The study complements published biomarker research through: inclusion of large, deeply phenotyped cohorts of children with ASD and typical development; a longitudinal design; a focus on well-evidenced candidate biomarkers harmonized with an independent sample; high levels of clinical, regulatory, technical, and statistical rigor; adoption of a governance structure incorporating diverse expertise in the ASD biomarker discovery and qualification process; prioritization of open science, including creation of a repository containing biomarker, clinical, and genetic data; and use of economical and scalable technologies that are applicable in developmental populations and those with special needs. The ABC-CT approach has yielded encouraging results, with one measure accepted into the FDA's Biomarker Qualification Program to date. Through these advances, the ABC-CT and other biomarker studies in progress hold promise to deliver novel tools to improve clinical trials research in ASD.
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http://dx.doi.org/10.3389/fnint.2020.00016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7173348PMC
April 2020
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