Reduced Integration and Differentiation of the Imitation Network in Autism: A Combined Functional Connectivity Magnetic Resonance Imaging and Diffusion-Weighted Imaging Study

Objective: Converging evidence indicates that brain abnormalities in autism spectrum disorder (ASD) involve atypical network connectivity, but few studies have integrated functional with structural connectivity measures. This multimodal investigation examined functional and structural connectivity of the imitation network in children and adolescents with ASD, and its links with clinical symptoms.

Methods: Resting state functional magnetic resonance imaging and diffusion-weighted imaging were performed in 35 participants with ASD and 35 typically developing controls, aged 8 to 17 years, matched for age, gender, intelligence quotient, and head motion.

Results: Within-network analyses revealed overall reduced functional connectivity (FC) between distributed imitation regions in the ASD group. Whole brain analyses showed that underconnectivity in ASD occurred exclusively in regions belonging to the imitation network, whereas overconnectivity was observed between imitation nodes and extraneous regions. Structurally, reduced fractional anisotropy and increased mean diffusivity were found in white matter tracts directly connecting key imitation regions with atypical FC in ASD. These differences in microstructural organization of white matter correlated with weaker FC and greater ASD symptomatology.

Interpretation: Findings demonstrate atypical connectivity of the brain network supporting imitation in ASD, characterized by a highly specific pattern. This pattern of underconnectivity within, but overconnectivity outside the functional network is in contrast with typical development and suggests reduced network integration and differentiation in ASD. Our findings also indicate that atypical connectivity of the imitation network may contribute to ASD clinical symptoms, highlighting the role of this fundamental social cognition ability in the pathophysiology of ASD.

The intraparietal sulcus (IPS), a region in the dorsal attention network (DAN), has been implicated in multi-sensory attention and working memory. Working memory and attention develop across childhood; changes in functional connectivity within the DAN may relate to this maturation. Previous findings regarding fronto-parietal intrinsic functional connectivity age-effects were mixed. Our study aimed to circumvent limitations of previous work using a large cross-sectional sample, 183 typically developing participants 6.5-20 years, from the Autism Brain Imaging Data Exchange, and seed regions along the anterior-to-posterior axis of the IPS. These seeds, IPS0-4, were entered into functional connectivity models. Group-level models investigated differential connectivity along the IPS and relationships with age. Anterior IPS3/4 exhibited greater connectivity with sensorimotor/pre-motor regions. Posterior IPS0/1 demonstrated greater connectivity with dorsal and ventral visual regions. Positive age-effects were found between IPS3-4 and visual regions. Negative age-effects were found between IPS and superior parietal and medial orbitofrontal cortices. Follow-up region of interest analyses were used to estimate age-effects for DAN and anticorrelated default mode network regions. Results suggest age-effects on IPS functional connectivity are relatively modest, and may differ pre- and across-adolescence. Studying typical age-related connectivity variability within this network may help to understand neurodevelopmental disorders marked by impaired attention.

Keywords: Attention; Functional connectivity; IPS; Resting-state fMRI; Visual-spatial; Visuotopic.

Autism spectrum disorder (ASD) is a behaviorally defined and heterogeneous disorder. Biomarkers for ASD offer the opportunity to improve prediction, diagnosis, stratification by severity and subtype, monitoring over time and in response to interventions, and overall understanding of the underlying biology of this disorder. A variety of potential biomarkers, from the level of genes and proteins to network-level interactions, is currently being examined. Many of these biomarkers relate to inhibition, which is of particular interest because in many cases ASD is thought to be a disorder of imbalance between excitation and inhibition. Abnormalities in inhibition at the cellular level lead to emergent properties in networks of neurons. These properties take into account a more complete genetic and cellular background than findings at the level of individual genes or cells, and are able to be measured in live humans, offering additional potential as diagnostic biomarkers and predictors of behaviors. In this review we provide examples of how altered inhibition may inform the search for ASD biomarkers at multiple levels, from genes to cells to networks.

We sought to determine the potential effects of pooling on power, false positive rate (FPR), and bias of the estimated associations between hypothetical environmental exposures and dichotomous autism spectrum disorders (ASD) status. Simulated birth cohorts in which ASD outcome was assumed to have been ascertained with uncertainty were created. We investigated the impact on the power of the analysis (using logistic regression) to detect true associations with exposure (X₁) and the FPR for a non-causal correlate of exposure (X₂, r = 0.7) for a dichotomized ASD measure when the pool size, sample size, degree of measurement error variance in exposure, strength of the true association, and shape of the exposure-response curve varied. We found that there was minimal change (bias) in the measures of association for the main effect (X₁). There is some loss of power but there is less chance of detecting a false positive result for pooled compared to individual level models. The number of pools had more effect on the power and FPR than the overall sample size. This study supports the use of pooling to reduce laboratory costs while maintaining statistical efficiency in scenarios similar to the simulated prospective risk-enriched ASD cohort.

Keywords: autism spectrum disorders; measurement error; pooling.

Keywords: Cerebral morphometry; Cortical volume; Females; Gyrification; Neuroimaging; Sex differences.

SHANK3 (also known as PROSAP2) is a postsynaptic scaffolding protein at excitatory synapses in which mutations and deletions have been implicated in patients with idiopathic autism, Phelan-McDermid (aka 22q13 microdeletion) syndrome, and other neuropsychiatric disorders. In this study, we have created a novel mouse model of human autism caused by the insertion of a single guanine nucleotide into exon 21 (Shank3(G)). The resulting frameshift causes a premature STOP codon and loss of major higher molecular weight Shank3 isoforms at the synapse. Shank3(G/G) mice exhibit deficits in hippocampus-dependent spatial learning, impaired motor coordination, altered response to novelty, and sensory processing deficits. At the cellular level, Shank3(G/G) mice also exhibit impaired hippocampal excitatory transmission and plasticity as well as changes in baseline NMDA receptor-mediated synaptic responses. This work identifies clear alterations in synaptic function and behavior in a novel, genetically accurate mouse model of autism mimicking an autism-associated insertion mutation. Furthermore, these findings lay the foundation for future studies aimed to validate and study region-selective and temporally selective genetic reversal studies in the Shank3(G/G) mouse that was engineered with such future experiments in mind.

Keywords: Phelan–McDermid syndrome; Shank3; autism; behavior; postsynaptic density; synaptic plasticity.

Marijuana exerts profound effects on human social behavior, but the neural substrates underlying such effects are unknown. Here we report that social contact increases, whereas isolation decreases, the mobilization of the endogenous marijuana-like neurotransmitter, anandamide, in the mouse nucleus accumbens (NAc), a brain structure that regulates motivated behavior. Pharmacological and genetic experiments show that anandamide mobilization and consequent activation of CB1 cannabinoid receptors are necessary and sufficient to express the rewarding properties of social interactions, assessed using a socially conditioned place preference test. We further show that oxytocin, a neuropeptide that reinforces parental and social bonding, drives anandamide mobilization in the NAc. Pharmacological blockade of oxytocin receptors stops this response, whereas chemogenetic, site-selective activation of oxytocin neurons in the paraventricular nucleus of the hypothalamus stimulates it. Genetic or pharmacological interruption of anandamide degradation offsets the effects of oxytocin receptor blockade on both social place preference and cFos expression in the NAc. The results indicate that anandamide-mediated signaling at CB1 receptors, driven by oxytocin, controls social reward. Deficits in this signaling mechanism may contribute to social impairment in autism spectrum disorders and might offer an avenue to treat these conditions.

Keywords: anandamide; endocannabinoid; oxytocin; reward; social behavior.

The substantial progress in the last few years toward uncovering genetic causes and risk factors for autism spectrum disorders (ASDs) has opened new experimental avenues for identifying the underlying neurobiological mechanism of the condition. The bounty of genetic findings has led to a variety of data-driven exploratory analyses aimed at deriving new insights about the shared features of these genes. These approaches leverage data from a variety of different sources such as co-expression in transcriptomic studies, protein-protein interaction networks, gene ontologies (GOs) annotations, or multi-level combinations of all of these. Here, we review the recurrent themes emerging from these analyses and highlight some of the challenges going forward. Themes include findings that ASD associated genes discovered by a variety of methods have been shown to contain disproportionate amounts of neurite outgrowth/cytoskeletal, synaptic, and more recently Wnt-related and chromatin modifying genes. Expression studies have highlighted a disproportionate expression of ASD gene sets during mid fetal cortical development, particularly for rare variants, with multiple analyses highlighting the striatum and cortical projection and interneurons as well. While these explorations have highlighted potentially interesting relationships among these ASD-related genes, there are challenges in how to best transition these insights into empirically testable hypotheses. Nonetheless, defining shared molecular or cellular pathology downstream of the diverse genes associated with ASDs could provide the cornerstones needed to build toward broadly applicable therapeutic approaches.

Keywords: ASD; CSEA; WGCNA; autism; network analysis; review; systems biology.