Differences in the Late Positive Potential and P300 to Emotional Faces in Individuals with Autism Spectrum Disorder

Despite evidence suggesting differences in early event-related potential (ERP) responses to social emotional stimuli, little is known about later stage ERP contributions to social emotional processing in individuals with autism spectrum disorder (ASD). Adults with and without ASD completed a facial emotion recognition task involving stimuli that varied by emotional intensity while electroencephalograms were recorded. Principal components analysis was used to examine P300 and late positive potential (LPP) modulation by emotional intensity. Results indicated that greater ASD symptomatology evinced heightened P300 to high relative to low intensity faces, then heightened LPP to low relative to high intensity faces. Findings suggest that adults with greater ASD symptomatology may demonstrate a lag in engagement in elaborative processing of low intensity faces.

Keywords: Autism spectrum disorder; ERP; Emotion processing; LPP; P300; Social cognition

Altered gamma-band electrophysiological activity in individuals with autism spectrum disorder (ASD) is well documented, and analogous gamma-band alterations are recapitulated in several preclinical murine models relevant to ASD. Such gamma-band activity is hypothesized to underlie local circuit processes. Gamma-band cross-frequency coupling (CFC), a related though distinct metric, interrogates local neural circuit signal integration. Several recent studies have observed perturbed gamma-band CFC in individuals with ASD, although the direction of change remains unresolved. It also remains unclear whether murine models relevant to ASD recapitulate this altered gamma-band CFC. As such, this study examined whether mice with parvalbumin (PV) cell-specific ablation of NMDA-R1 (PVcre/NR1fl/fl) demonstrated altered gamma-band CFC as compared with their control littermates (PVcre/NR1+/+-mice that do not have the PV cell-specific ablation of NMDA-R1). Ten mice of each genotype had 4 min of “resting” electroencephalography recorded and analyzed. First, resting electrophysiological power was parsed into the canonical frequency bands and genotype-related differences were subsequently explored so as to provide context for the subsequent CFC analyses. PVcre/NR1fl/fl mice exhibited an increase in resting power specific to the high gamma-band, but not other frequency bands, as compared with PVcre/NR1+/+. CFC analyses then examined both the standard magnitude (strength) of CFC and the novel metric PhaseMax-which denotes the phase of the lower frequency signal at which the peak higher frequency signal power occurred. PVcre/NR1fl/fl mice exhibited altered PhaseMax, but not strength, of gamma-band CFC as compared with PVcre/NR1+/+ mice. As such, this study suggests a potential novel metric to explore when studying neuropsychiatric disorders.

Keywords: ASD; cross-frequency coupling; gamma; phase; phase-amplitude coupling.

While genes with an excess of de novo mutations (DNMs) have been identified in children with neurodevelopmental disorders (NDDs), few studies focus on DNM patterns where the sex of affected children is examined separately. We considered ∼8,825 sequenced parent-child trios (n ∼26,475 individuals) and identify 54 genes with a DNM enrichment in males (n = 18), females (n = 17), or overlapping in both the male and female subsets (n = 19). A replication cohort of 18,778 sequenced parent-child trios (n = 56,334 individuals) confirms 25 genes (n = 3 in males, n = 7 in females, n = 15 in both male and female subsets). As expected, we observe significant enrichment on the X chromosome for females but also find autosomal genes with potential sex bias (females, CDK13, ITPR1; males, CHD8, MBD5, SYNGAP1); 6.5% of females harbor a DNM in a female-enriched gene, whereas 2.7% of males have a DNM in a male-enriched gene. Sex-biased genes are enriched in transcriptional processes and chromatin binding, primarily reside in the nucleus of cells, and have brain expression. By downsampling, we find that DNM gene discovery is greatest when studying affected females. Finally, directly comparing de novo allele counts in NDD-affected males and females identifies one replicated genome-wide significant gene (DDX3X) with locus-specific enrichment in females. Our sex-based DNM enrichment analysis identifies candidate NDD genes differentially affecting males and females and indicates that the study of females with NDDs leads to greater gene discovery consistent with the female-protective effect.

Keywords: X chromosome; autism; female protective effect; intellectual disability; neurodevelopmental disorder; sex bias

Autism spectrum disorders (ASDs) are increasingly prevalent neurodevelopmental disorders characterized by sociocommunicative impairments. Growing consensus indicates that neurobehavioral abnormalities require explanation in terms of interconnected networks. Despite theoretical speculations about increased local and reduced distal connectivity, links between local and distal functional connectivity have not been systematically investigated in ASDs. Specifically, it remains open whether hypothesized local overconnectivity may reflect isolated versus overly integrative processing. Resting state functional MRI data from 57 children and adolescents with ASDs and 51 typically developing (TD) participants were included. In regional homogeneity (ReHo) analyses, pericalcarine visual cortex was found be locally overconnected (ASD > TD). Using this region as seed in whole-brain analyses, we observed overconnectivity in distal regions, specifically middle frontal gyri, for an ASD subgroup identified through k-means clustering. While in this subgroup local occipital to distal frontal overconnectivity was associated with greater symptom severity, a second subgroup showed the opposite pattern of connectivity and symptom severity correlations. Our findings suggest that increased local connectivity in ASDs is region-specific and may be partially associated with more integrative long-distance connectivity. Results also highlight the need to test for subtypes, as differential patterns of brain-behavior links were observed in two distinct subgroups of our ASD cohort.

Keywords: autism; frontal cortex; functional connectivity MRI; local connectivity; visual cortex.

There are two established electroencephalogram (EEG) indices that putatively relate to anxiety symptoms: a) the error-related negativity (ERN), which reflects endogenous threat sensitivity, and b) resting-state EEG relative right frontal activity (rRFA), which relates to approach/withdrawal motivation. We examined these indices conjointly to better elucidate differential mechanisms underlying the common anxiety phenotype in youth with autism spectrum disorder (ASD), in relation to subjective reports of symptomatology and treatment response. EEG was recorded from 53 youth with ASD who participated in a 10-week social skills intervention (SSI). More negative ERN related to higher self-reported social anxiety symptoms at baseline, and predicted improvements in self-reported social anxiety symptoms following SSI. Although rRFA did not relate to anxiety symptoms at baseline, more rRFA predicted improvement in parent-reported anxiety domains but worsening in self-reported anxiety symptoms. This study provides evidence for unique neural mechanisms of anxiety symptoms and changes in anxiety after SSI in youth with ASD.

Keywords: Anxiety; Autism spectrum disorder; Electroencephalogram (EEG); Error-related negativity (ERN); Hemispheric asymmetry.

Language development in children with autism spectrum disorder (ASD) varies greatly among affected individuals and is a strong predictor of later outcomes. Younger siblings of children with ASD have increased risk of ASD, but also language delay. Identifying neural markers of language outcomes in infant siblings could facilitate earlier intervention and improved outcomes. This study aimed to determine whether EEG measures from the first 2-years of life can explain heterogeneity in language development in children at low- and high-risk for ASD, and to determine whether associations between EEG measures and language development are different depending on ASD risk status or later ASD diagnosis. In this prospective longitudinal study EEG measures collected between 3-24 months were used in a multivariate linear regression model to estimate participants’ 24-month language development. Individual baseline longitudinal EEG measures included (1) the slope of EEG power across 3-12 months or 3-24 months of life for 6 canonical frequency bands, (2) estimated EEG power at age 6-months for the same frequency bands, and (3) terms representing the interaction between ASD risk status and EEG power measures. Modeled 24-month language scores using EEG data from either the first 2-years (Pearson R = 0.70, 95% CI 0.595-0.783, P=1×10-18) or the first year of life (Pearson R=0.66, 95% CI 0.540-0.761, P=2.5×10-14) were highly correlated with observed scores. All models included significant interaction effects of risk on EEG measures, suggesting that EEG-language associations are different depending on risk status, and that different brain mechanisms effect language development in low-versus high-risk infants.

2020Alycia Halladay

2020Alycia Halladay

Cerebellar dysfunction has been demonstrated in autism spectrum disorders (ASDs); however, the circuits underlying cerebellar contributions to ASD-relevant behaviors remain unknown. In this study, we demonstrated functional connectivity between the cerebellum and the medial prefrontal cortex (mPFC) in mice; showed that the mPFC mediates cerebellum-regulated social and repetitive/inflexible behaviors; and showed disruptions in connectivity between these regions in multiple mouse models of ASD-linked genes and in individuals with ASD. We delineated a circuit from cerebellar cortical areas Right crus 1 (Rcrus1) and posterior vermis through the cerebellar nuclei and ventromedial thalamus and culminating in the mPFC. Modulation of this circuit induced social deficits and repetitive behaviors, whereas activation of Purkinje cells (PCs) in Rcrus1 and posterior vermis improved social preference impairments and repetitive/inflexible behaviors, respectively, in male PC-Tsc1 mutant mice. These data raise the possibility that these circuits might provide neuromodulatory targets for the treatment of ASD.

22q11.2 deletion syndrome (22q11DS) is a highly penetrant and common genetic cause of neuropsychiatric disease. Here we generated induced pluripotent stem cells from 15 individuals with 22q11DS and 15 control individuals and differentiated them into three-dimensional (3D) cerebral cortical organoids. Transcriptional profiling across 100 days showed high reliability of differentiation and revealed changes in neuronal excitability-related genes. Using electrophysiology and live imaging, we identified defects in spontaneous neuronal activity and calcium signaling in both organoid- and 2D-derived cortical neurons. The calcium deficit was related to resting membrane potential changes that led to abnormal inactivation of voltage-gated calcium channels. Heterozygous loss of DGCR8 recapitulated the excitability and calcium phenotypes and its overexpression rescued these defects. Moreover, the 22q11DS calcium abnormality could also be restored by application of antipsychotics. Taken together, our study illustrates how stem cell derived models can be used to uncover and rescue cellular phenotypes associated with genetic forms of neuropsychiatric disease.