Autism spectrum disorders: Neuroimaging findings from systematic reviews

Autism Spectrum Disorders (ASD) are a cluster of neurodevelopmental conditions associated with core deficits in social communication, social interaction, and restricted and repetitive behaviours. Current evidence suggests a complex interaction between genetic and environmental factors that underlie the heterogeneity of neuroanatomy and clinical symptomatology of ASD across a spectrum. Although abnormalities in brain structure and function have been implicated in the neurodevelopmental trajectory of ASD, the search for definitive neuroimaging markers remains obscured by inconsistent or incompatible findings. Specifically, discrepancies between independent studies impede reliable identification of the nature and form of atypical alterations in grey-matter structural morphometry and intrinsic functional networks in ASD. This review aims to illustrate the heterogeneity in ASD neuroimaging literature by comparing systematic reviews and meta-analyses of neuroimaging investigations in ASD over the last several decades, with particular emphasis on structural morphometry, structural connectivity and resting-state intrinsic connectivity techniques. Given the unique challenges in ASD research, standardized methodologies to validate potential neuroimaging markers will be an important step towards advancing clinical and research methods to investigate complex aetiological mechanisms and risk factors underlying ASD.     

Identifying electrophysiological markers of autism spectrum disorder and schizophrenia against a backdrop of normal brain development

An examination of electroencephalographic and magnetoencephalographic studies demonstrates how age‐related changes in brain neural function temporally constrain their use as diagnostic markers. A first example shows that, given maturational changes in the resting‐state peak alpha frequency in typically developing children but not in children who have autism spectrum disorder (ASD), group differences in alpha‐band activity characterize only a subset of children who have ASD. A second example, auditory encoding processes in schizophrenia, shows that the complication of normal age‐related brain changes on detecting and interpreting group differences in neural activity is not specific to children. MRI studies reporting group differences in the rate of brain maturation demonstrate that a group difference in brain maturation may be a concern for all diagnostic brain markers. Attention to brain maturation is needed whether one takes a DSM‐5 or a Research Domain Criteria approach to research. For example, although there is interest in cross‐diagnostic studies comparing brain measures in ASD and schizophrenia, such studies are difficult given that measures are obtained in one group well after and in the other much closer to the onset of symptoms. In addition, given differences in brain activity among infants, toddlers, children, adolescents, and younger and older adults, creating tasks and research designs that produce interpretable findings across the life span and yet allow for development is difficult at best. To conclude, brain imaging findings show an effect of brain maturation on diagnostic markers separate from (and potentially difficult to distinguish from) effects of disease processes. Available research with large samples already provides direction about the age range(s) when diagnostic markers are most robust and informative.     

Differential amygdala response to lower face in patients with autistic spectrum disorders: An fMRI study

Much functional neuroimaging evidence indicates that autistic spectrum disorders (ASD) demonstrate marked brain abnormalities in face processing. Most of these findings were obtained from studies using tasks related to whole faces. However, individuals with ASD tend to rely more on individual parts of the face for identification than on the overall configuration. Therefore, this neuroimaging evidence might reflect differential visual attention systems in face recognition. It was hypothesized that differential brain function is shown between ASD and control participants with face recognition tasks presenting parts of faces separately. Nine adults with high-functioning ASD and 24 age-matched normal comparison participants were studied using a 3T-MR scanner. We investigated brain activation when processing whole faces and parts of faces displaying positive or negative expressions. The control group showed bilateral amygdalae activation to the whole face, but not to parts of the face. The ASD group showed bilateral amygdalae activation to the lower face (mainly mouth region), but not to the whole face and upper face (mainly eye region). These findings suggest that differential amygdala function for face processing exists in ASD. This aberrant amygdala function might cause abnormalities in gaze processing or recognition of emotional expressions, shown clinically in ASD.     

Imaging evidence for disturbances in multiple learning and memory systems in persons with autism spectrum disorders

Aim The aim of this article is to review neuroimaging studies of autism spectrum disorders (ASD) that examine declarative, socio‐emotional, and procedural learning and memory systems. Method We conducted a search of PubMed from 1996 to 2010 using the terms ‘autism,’‘learning,’‘memory,’ and ‘neuroimaging.’ We limited our review to studies correlating learning and memory function with neuroimaging features of the brain. Results The early literature supports the following preliminary hypotheses: (1) abnormalities of hippocampal subregions may contribute to autistic deficits in episodic and relational memory; (2) disturbances to an amygdala‐based network (which may include the fusiform gyrus, superior temporal cortex, and mirror neuron system) may contribute to autistic deficits in socio‐emotional learning and memory; and (3) abnormalities of the striatum may contribute to developmental dyspraxia in individuals with ASD. Interpretation Characterizing the disturbances to learning and memory systems in ASD can inform our understanding of the neural bases of autistic behaviors and the phenotypic heterogeneity of ASD.     

Depression and Anxiety Symptoms in Children and Adolescents with Autism Spectrum Disorders without Intellectual Disability

Recent studies have shown that rates of depression and anxiety symptoms are elevated among individuals with autism spectrum disorders (ASDs) of various ages and IQs and that depression/anxiety symptoms are associated with higher IQ and fewer ASD symptoms. In this study which examined correlates of depression and anxiety symptoms in the full school-age range of children and adolescents (age 6-18) with ASDs and IQs ≥ 70 (n = 95), we also observed elevated rates of depression/anxiety symptoms, but we did not find higher IQ or fewer ASD symptoms among individuals with ASDs and depression or anxiety symptoms. These findings indicate an increased risk for depression/anxiety symptoms in children and adolescents with ASDs without intellectual disability, regardless of age, IQ, or ASD symptoms.     

Developmental pathways to autism: A review of prospective studies of infants at risk

Autism Spectrum Disorders (ASDs) are neurodevelopmental disorders characterized by impairments in social interaction and communication, and the presence of restrictive and repetitive behaviors. Symptoms of ASD likely emerge from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the child's environment, modified by compensatory skills and protective factors. Prospective studies of infants at high familial risk for ASD (who have an older sibling with a diagnosis) are beginning to characterize these developmental pathways to the emergence of clinical symptoms. Here, we review the range of behavioral and neurocognitive markers for later ASD that have been identified in high-risk infants in the first years of life. We discuss theoretical implications of emerging patterns, and identify key directions for future work, including potential resolutions to several methodological challenges for the field. Mapping how ASD unfolds from birth is critical to our understanding of the developmental mechanisms underlying this disorder. A more nuanced understanding of developmental pathways to ASD will help us not only to identify children who need early intervention, but also to improve the range of interventions available to them.     

Magnetoencephalography in the study of children with autism spectrum disorder

Magnetoencephalography (MEG) is a non‐invasive neuroimaging technique that provides a measure of cortical neural activity on a millisecond timescale with high spatial resolution. MEG has been clinically applied to various neurological diseases, including epilepsy and cognitive dysfunction. In the past decade, MEG has also emerged as an important investigatory tool in neurodevelopmental studies. It is therefore an opportune time to review how MEG is able to contribute to the study of atypical brain development. We limit this review to autism spectrum disorder (ASD). The relevant published work for children was accessed using PubMed on 5 January 2015. Case reports, case series, and papers on epilepsy were excluded. Owing to their accurate separation of brain activity in the right and left hemispheres and the higher accuracy of source localization, MEG studies have added new information related to auditory‐evoked brain responses to findings from previous electroencephalography studies of children with ASD. In addition, evidence of atypical brain connectivity in children with ASD has accumulated over the past decade. MEG is well suited for the study of neural activity with high time resolution even in young children. Although further studies are still necessary, the detailed findings provided by neuroimaging methods may aid clinical diagnosis and even contribute to the refinement of diagnostic categories for neurodevelopmental disorders in the future.     

Of mice and monkeys: using non-human primate models to bridge mouse- and human-based investigations of autism spectrum disorders

The autism spectrum disorders (ASDs) arise from a diverse array of genetic and environmental origins that disrupt the typical developmental trajectory of neural connectivity and synaptogenesis. ASDs are marked by dysfunctional social behavior and cognition, among other deficits. Greater understanding of the biological substrates of typical social behavior in animal models will further our understanding of the etiology of ASDs. Despite the precision and tractability of molecular genetics models of ASDs in rodents, these organisms lack the complexity of human social behavior, thus limiting their impact on understanding ASDs to basic mechanisms. Non-human primates (NHPs) provide an attractive, complementary model for ASDs, due in part to the complexity and dynamics of social structures, reliance on vision for social signaling, and deep homology in brain circuitry mediating social behavior and reward. This knowledge is based on a rich literature, compiled over 50 years of observing primate behavior in the wild, which, in the case of rhesus macaques, is complemented by a large body of research characterizing neuronal activity during cognitive behavior. Several recent developments in this field are directly relevant to ASDs, including how the brain represents the perceptual features of social stimuli, how social information influences attention processes in the brain, and how the value of social interaction is computed. Because the symptoms of ASDs may represent extreme manifestations of traits that vary in intensity within the general population, we will additionally discuss ways in which nonhuman primates also show variation in social behavior and reward sensitivity. In cases where variation in species-typical behavior is analogous to similar variations in human behavior, we believe that study of the neural circuitry underlying this variation will provide important insights into the systems-level mechanisms contributing to ASD pathology.     

A feature-based network analysis and fMRI meta-analysis reveal three distinct types of prosocial decisions

Tasks that measure correlates of prosocial decision-making share one common feature: agents can make choices that increase the welfare of a beneficiary. However, prosocial decisions vary widely as a function of other task features. The diverse ways that prosociality is defined and the heterogeneity of prosocial decisions have created challenges for interpreting findings across studies and identifying their neural correlates. To overcome these challenges, we aimed to organize the prosocial decision-making task space of neuroimaging studies. We conducted a systematic search for studies in which participants made decisions to increase the welfare of others during functional magnetic resonance imaging. We identified shared and distinct features of these tasks and employed an unsupervised graph-based approach to assess how various forms of prosocial decision-making are related in terms of their low-level components (e.g. task features like potential cost to the agent or potential for reciprocity). Analyses uncovered three clusters of prosocial decisions, which we labeled as cooperation, equity and altruism. This feature-based representation of the task structure was supported by results of a neuroimaging meta-analysis that each type of prosocial decisions recruited diverging neural systems. Results clarify some of the existing heterogeneity in how prosociality is conceptualized and generate insight for future research and task paradigm development.     

Attention and Working Memory in Adolescents with Autism Spectrum Disorder: A Functional MRI Study

The present study examined attention and memory load-dependent differences in the brain activation and deactivation patterns between adolescents with autism spectrum disorders (ASDs) and typically developing (TD) controls using functional magnetic resonance imaging. Attentional (0-back) and working memory (WM; 2-back) processing and load differences (0 vs. 2-back) were analysed. WM-related areas activated and default mode network deactivated normally in ASDs as a function of task load. ASDs performed the attentional 0-back task similarly to TD controls but showed increased deactivation in cerebellum and right temporal cortical areas and weaker activation in other cerebellar areas. Increasing task load resulted in multiple responses in ASDs compared to TD and in inadequate modulation of brain activity in right insula, primary somatosensory, motor and auditory cortices. The changes during attentional task may reflect compensatory mechanisms enabling normal behavioral performance. The inadequate memory load-dependent modulation of activity suggests diminished compensatory potential in ASD.     

Absence of age-related prefrontal NAA change in adults with autism spectrum disorders

Atypical trajectory of brain growth in autism spectrum disorders (ASDs) has been recognized as a potential etiology of an atypical course of behavioral development. Numerous neuroimaging studies have focused on childhood to investigate atypical age-related change of brain structure and function, because it is a period of neuron and synapse maturation. Recent studies, however, have shown that the atypical age-related structural change of autistic brain expands beyond childhood and constitutes neural underpinnings for lifelong difficulty to behavioral adaptation. Thus, we examined effects of aging on neurochemical aspects of brain maturation using 3-T proton magnetic resonance spectroscopy (¹H-MRS) with single voxel in the medial prefrontal cortex (PFC) in 24 adult men with non-medicated high-functioning ASDs and 25 age-, IQ- and parental-socioeconomic-background-matched men with typical development (TD). Multivariate analyses of covariance demonstrated significantly high N-acetylaspartate (NAA) level in the ASD subjects compared with the TD subjects (F=4.83, P=0.033). The low NAA level showed a significant positive correlation with advanced age in the TD group (r=−0.618, P=0.001), but was not evident among the ASD individuals (r=0.258, P=0.223). Fisher''s r-to-z transformation showed a significant difference in the correlations between the ASD and TD groups (Z=−3.23, P=0.001), which indicated that the age–NAA relationship was significantly specific to people with TD. The current ¹H-MRS study provided new evidence that atypical age-related change of neurochemical aspects of brain maturation in ASD individuals expands beyond childhood and persists during adulthood.     

Neuroanatomical and neurofunctional markers of social cognition in autism spectrum disorder

Social impairments in autism spectrum disorder (ASD), a hallmark feature of its diagnosis, may underlie specific neural signatures that can aid in differentiating between those with and without ASD. To assess common and consistent patterns of differences in brain responses underlying social cognition in ASD, this study applied an activation likelihood estimation (ALE) meta‐analysis to results from 50 neuroimaging studies of social cognition in children and adults with ASD. In addition, the group ALE clusters of activation obtained from this was used as a social brain mask to perform surface‐based cortical morphometry (SBM) in an empirical structural MRI dataset collected from 55 ASD and 60 typically developing (TD) control participants. Overall, the ALE meta‐analysis revealed consistent differences in activation in the posterior superior temporal sulcus at the temporoparietal junction, middle frontal gyrus, fusiform face area (FFA), inferior frontal gyrus (IFG), amygdala, insula, and cingulate cortex between ASD and TD individuals. SBM analysis showed alterations in the thickness, volume, and surface area in individuals with ASD in STS, insula, and FFA. Increased cortical thickness was found in individuals with ASD, the IFG. The results of this study provide functional and anatomical bases of social cognition abnormalities in ASD by identifying common signatures from a large pool of neuroimaging studies. These findings provide new insights into the quest for a neuroimaging‐based marker for ASD. Hum Brain Mapp 37:3957–3978, 2016. © 2016 Wiley Periodicals, Inc.     

The neurobiology of autism: Theoretical applications

Autism spectrum disorders (ASD) are complex neurological disorders characterized by heterogeneity in skills and impairments. A variety of models have been developed to describe the disorders and a wide range of brain processes have been implicated. This review attempts to integrate some of the consistent neurological findings in the research with three of the dominant models of core deficits of ASDs: the weak central coherence model, the theory of mind model, and the mirror neuron system model. A review of the literature suggests that the cerebellum and the frontal lobes may be implicated in all three of the models, while the temporal lobe is associated with the theory of mind model and the mirror neuron model. In particular, the theory of mind model and the mirror neuron system model both implicate the inferior frontal gyrus and the superior temporal sulcus. This review indicates that each model appears to be heavily substantiated by neurological research, suggesting that each may capture important aspects of ASDs.     

Imagery and spatial processes in blindness and visual impairment

The objective of this review is to examine and evaluate recent findings on cognitive functioning (in particular imagery processes) in individuals with congenital visual impairments, including total blindness, low-vision and monocular vision. As one might expect, the performance of blind individuals in many behaviours and tasks requiring imagery can be inferior to that of sighted subjects; however, surprisingly often this is not the case. Interestingly, there is evidence that the blind often employ different cognitive mechanisms than sighted subjects, suggesting that compensatory mechanisms can overcome the limitations of sight loss. Taken together, these studies suggest that the nature of perceptual input on which we commonly rely strongly affects the organization of our mental processes. We also review recent neuroimaging studies on the neural correlates of sensory perception and mental imagery in visually impaired individuals that have cast light on the plastic functional reorganization mechanisms associated with visual deprivation.     

Relationship between symptom dimensions and brain morphology in obsessive-compulsive disorder

Obsessive-compulsive disorder (OCD) is known as a clinically heterogeneous disorder characterized by symptom dimensions. Although substantial numbers of neuroimaging studies have demonstrated the presence of brain abnormalities in OCD, their results are controversial. The clinical heterogeneity of OCD could be one of the reasons for this. It has been hypothesized that certain brain regions contributed to the respective obsessive-compulsive dimensions. In this study, we investigated the relationship between symptom dimensions of OCD and brain morphology using voxel-based morphometry to discover the specific regions showing alterations in the respective dimensions of obsessive-compulsive symptoms. The severities of symptom dimensions in thirty-three patients with OCD were assessed using Obsessive-Compulsive Inventory-Revised (OCI-R). Along with numerous MRI studies pointing out brain abnormalities in autistic spectrum disorder (ASD) patients, a previous study reported a positive correlation between ASD traits and regional gray matter volume in the left dorsolateral prefrontal cortex and amygdala in OCD patients. We investigated the correlation between gray and white matter volumes at the whole brain level and each symptom dimension score, treating all remaining dimension scores, age, gender, and ASD traits as confounding covariates. Our results revealed a significant negative correlation between washing symptom dimension score and gray matter volume in the right thalamus and a significant negative correlation between hoarding symptom dimension score and white matter volume in the left angular gyrus. Although our result was preliminary, our findings indicated that there were specific brain regions in gray and white matter that contributed to symptom dimensions in OCD patients.     

Functional magnetic resonance imaging of autism spectrum disorders

This review presents an overview of functional magnetic resonance imaging findings in autism spectrum disorders (ASDs), Although there is considerable heterogeneity with respect to results across studies, common themes have emerged, including: (i) hypoactivation in nodes of the “social brain” during social processing tasks, including regions within the prefrontal cortex, the posterior superior temporal sulcus, the amygdala, and the fusiform gyrus; (ii) aberrant frontostriatal activation during cognitive control tasks relevant to restricted and repetitive behaviors and interests, including regions within the dorsal prefrontal cortex and the basal ganglia; (iii) differential lateralization and activation of language processing and production regions during communication tasks; (iv) anomalous mesolimbic responses to social and nonsocial rewards; (v) task-based long-range functional hypoconnectivity and short-range hyper-connectivity; and (vi) decreased anterior-posterior functional connectivity during resting states. These findings provide mechanistic accounts of ASD pathophysiology and suggest directions for future research aimed at elucidating etiologic models and developing rationally derived and targeted treatments.     

Face-brain asymmetry in autism spectrum disorders

The heterogeneity of autism spectrum disorders (ASDs) confounds attempts to identify causes and pathogenesis. Identifiable endophenotypes and reliable biomarkers within ASDs would help to focus molecular research and uncover genetic causes and developmental mechanisms. We used dense surface-modelling techniques to compare the facial morphology of 72 boys with ASD and 128 first-degree relatives to that of 254 unrelated controls. Pattern-matching algorithms were able to discriminate between the faces of ASD boys and those of matched controls (AUC=0.82) and also discriminate between the faces of unaffected mothers of ASD children and matched female controls (AUC=0.76). We detected significant facial asymmetry in boys with ASD (P<0.01), notably depth-wise in the supra- and periorbital regions anterior to the frontal pole of the right hemisphere of the brain. Unaffected mothers of children with ASD display similar significant facial asymmetry, more exaggerated than that in matched controls (P<0.03) and, in particular, show vertical asymmetry of the periorbital region. Unaffected fathers of children with ASD did not show facial asymmetry to a significant degree compared to controls. Two thirds of unaffected male siblings tested were classified unseen as more facially similar to unrelated boys with ASD than to unrelated controls. These unaffected male siblings and two small groups of girls with ASD and female siblings, all show overall directional asymmetry, but without achieving statistical significance in two-tailed t-tests of individual asymmetry of ASD family and matched control groups. We conclude that previously identified right dominant asymmetry of the frontal poles of boys with ASD could explain their facial asymmetry through the direct effect of brain growth. The atypical facial asymmetry of unaffected mothers of children with ASD requires further brain studies before the same explanation can be proposed. An alternative explanation, not mutually exclusive, is a simultaneous and parallel action on face and brain growth by genetic factors. Both possibilities suggest the need for coordinated face and brain studies on ASD probands and their first-degree relatives, especially on unaffected mothers, given that their unusual facial asymmetry suggests an ASD susceptibility arising from maternal genes.     

Systematic review of intervention research with adolescents with autism spectrum disorders

A growing body of research provides effective interventions to address the core symptoms of autism spectrum disorders (ASD). However, adolescents with ASDs may face age-specific challenges necessitating the need for contextually relevant and effective interventions. This systematic review examined peer-reviewed intervention research for adolescents (ages 12–21) with ASD. Electronic database searches and ancestral searches were used to identify studies published between 1980 and 2011. 102 studies were identified. A variety of interventions were implemented in these studies to address a wide range of targeted skills and behaviors. Reviewed studies were categorized into seven domains based on the skills and behaviors targeted: (a) social skills; (b) communication skills; (c) challenging behavior; (d) academic skills; (e) vocational skills; (f) independence and self-care; and (g) physical development. Results indicate that effective interventions exist in each category. These results are discussed in relation to participant characteristics, intervention effectiveness, social validity, generalization and maintenance. Generalization, maintenance, and social validity data were gathered in only 34%, 43%, and 31% of the articles, respectively. Additionally, few studies investigated interventions addressing communication, vocational or academic skills. Recommendations for future research are provided.     

The NeuroDevNet Autism Spectrum Disorders Demonstration Project

The NeuroDevNet Autism Spectrum Disorder Demonstration Project interfaces at many levels with the network's research themes and priorities. Our interdisciplinary team aims to improve understanding of genetic factors underlying vulnerability to autism spectrum disorders (ASDs) to develop better diagnostic strategies and, ultimately, to pinpoint molecular pathways relevant to developing biologically based treatments. Linking our existing longitudinal ASD cohorts with both genetics and neuroimaging studies will provide, for the first time, integrated data on how the genetic variation influences brain and behavioral development in ASD. Importantly, as our science progresses and we translate this information to the health care system, we will also educate policy makers, media, and business, so an informed society is prepared to capitalize on new genomic advances and effectively integrate these into health services for the broader community. We believe that this research has the potential to transform assessment and care for individuals with ASD.     

Consortium neuroscience of attention deficit/hyperactivity disorder and autism spectrum disorder: The ENIGMA adventure

Neuroimaging has been extensively used to study brain structure and function in individuals with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) over the past decades. Two of the main shortcomings of the neuroimaging literature of these disorders are the small sample sizes employed and the heterogeneity of methods used. In 2013 and 2014, the ENIGMA‐ADHD and ENIGMA‐ASD working groups were respectively, founded with a common goal to address these limitations. Here, we provide a narrative review of the thus far completed and still ongoing projects of these working groups. Due to an implicitly hierarchical psychiatric diagnostic classification system, the fields of ADHD and ASD have developed largely in isolation, despite the considerable overlap in the occurrence of the disorders. The collaboration between the ENIGMA‐ADHD and ‐ASD working groups seeks to bring the neuroimaging efforts of the two disorders closer together. The outcomes of case–control studies of subcortical and cortical structures showed that subcortical volumes are similarly affected in ASD and ADHD, albeit with small effect sizes. Cortical analyses identified unique differences in each disorder, but also considerable overlap between the two, specifically in cortical thickness. Ongoing work is examining alternative research questions, such as brain laterality, prediction of case–control status, and anatomical heterogeneity. In brief, great strides have been made toward fulfilling the aims of the ENIGMA collaborations, while new ideas and follow‐up analyses continue that include more imaging modalities (diffusion MRI and resting‐state functional MRI), collaborations with other large databases, and samples with dual diagnoses.