Idiosyncratic Brain Activation Patterns Are Associated with Poor Social Comprehension in Autism

Autism spectrum disorder (ASD) features profound social deficits but neuroimaging studies have failed to find any consistent neural signature. Here we connect these two facts by showing that idiosyncratic patterns of brain activation are associated with social comprehension deficits. Human participants with ASD (N = 17) and controls (N = 20) freely watched a television situation comedy (sitcom) depicting seminaturalistic social interactions (“The Office”, NBC Universal) in the scanner. Intersubject correlations in the pattern of evoked brain activation were reduced in the ASD group—but this effect was driven entirely by five ASD subjects whose idiosyncratic responses were also internally unreliable. The idiosyncrasy of these five ASD subjects was not explained by detailed neuropsychological profile, eye movements, or data quality; however, they were specifically impaired in understanding the social motivations of characters in the sitcom. Brain activation patterns in the remaining ASD subjects were indistinguishable from those of control subjects using multiple multivariate approaches. Our findings link neurofunctional abnormalities evoked by seminaturalistic stimuli with a specific impairment in social comprehension, and highlight the need to conceive of ASD as a heterogeneous classification

Sex differences in brain plasticity: a new hypothesis for sex ratio bias in autism.

Several observations support the hypothesis that differences in synaptic and regional cerebral plasticity between the sexes account for the high ratio of males to females in autism. First, males are more susceptible than females to perturbations in genes involved in synaptic plasticity. Second, sex-related differences in non-autistic brain structure and function are observed in highly variable regions, namely, the heteromodal associative cortices, and overlap with structural particularities and enhanced activity of perceptual associative regions in autistic individuals. Finally, functional cortical reallocations following brain lesions in non-autistic adults (for example, traumatic brain injury, multiple sclerosis) are sex-dependent. Interactions between genetic sex and hormones may therefore result in higher synaptic and consecutively regional plasticity in perceptual brain areas in males than in females. The onset of autism may largely involve mutations altering synaptic plasticity that create a plastic reaction affecting the most variable and sexually dimorphic brain regions. The sex ratio bias in autism may arise because males have a lower threshold than females for the development of this plastic reaction following a genetic or environmental event

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in adult male mice, here we show that loss of Shank3 (Shank3B-/-) results in disrupted local and long-range prefrontal and fronto-striatal functional connectivity. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity

Multivariate characterization of white matter heterogeneity in autism spectrum disorder

The complexity and heterogeneity of neuroimaging findings in individuals with autism spectrum disorder has suggested that many of the underlying alterations are subtle and involve many brain regions and networks. The ability to account for multivariate brain features and identify neuroimaging measures that can be used to characterize individual variation have thus become increasingly important for interpreting and understanding the neurobiological mechanisms of autism. In the present study, we utilize the Mahalanobis distance, a multidimensional counterpart of the Euclidean distance, as an informative index to characterize individual brain variation and deviation in autism. Longitudinal diffusion tensor imaging data from 149 participants (92 diagnosed with autism spectrum disorder and 57 typically developing controls) between 3.1 and 36.83 years of age were acquired over a roughly 10-year period and used to construct the Mahalanobis distance from regional measures of white matter microstructure. Mahalanobis distances were significantly greater and more variable in the autistic individuals as compared to control participants, demonstrating increased atypicalities and variation in the group of individuals diagnosed with autism spectrum disorder. Distributions of multivariate measures were also found to provide greater discrimination and more sensitive delineation between autistic and typically developing individuals than conventional univariate measures, while also being significantly associated with observed traits of the autism group. These results help substantiate autism as a truly heterogeneous neurodevelopmental disorder, while also suggesting that collectively considering neuroimaging measures from multiple brain regions provides improved insight into the diversity of brain measures in autism that is not observed when considering the same regions separately. Distinguishing multidimensional brain relationships may thus be informative for identifying neuroimaging-based phenotypes, as well as help elucidate underlying neural mechanisms of brain variation in autism spectrum disorders

Overt social interaction and resting state in young adult males with autism: core and contextual neural features

Conversation is an important and ubiquitous social behavior. Individuals with Autism Spectrum Disorder (autism) without intellectual disability often have normal structural language abilities but deficits in social aspects of communication like pragmatics, prosody, and eye contact. Previous studies of resting state activity suggest that intrinsic connections among neural circuits involved with social processing are disrupted in autism, but to date no neuroimaging study has examined neural activity during the most commonplace yet challenging social task: spontaneous conversation. Here we used functional MRI to scan autistic males (N=19) without intellectual disability and age- and IQ-matched typically developing controls (N=20) while they engaged in a total of 193 face-to-face interactions. Participants completed two kinds of tasks: Conversation, which had high social demand, and Repetition, which had low social demand. Autistic individuals showed abnormally increased task-driven inter-regional temporal correlation relative to controls, especially among social processing regions and during high social demand. Furthermore, these increased correlations were associated with parent ratings of participants’ social impairments. These results were then compared with previously-acquired resting-state data (56 Autism, 62 Control participants). While some inter-regional correlation levels varied by task or rest context, others were strikingly similar across both task and rest, namely increased correlation among the thalamus, dorsal and ventral striatum, somatomotor, temporal and prefrontal cortex in the autistic individuals, relative to the control groups. These results suggest a basic distinction. Autistic cortico-cortical interactions vary by context, tending to increase relative to controls during Task and decrease during Rest. In contrast, striato- and thalamocortical relationships with socially engaged brain regions are increased in both Task and Rest, and may be core to the condition of autism

Neuroimaging of Real-world Audio-visual Sensory Integration in High-functioning Autism

Sensory processing differences are a prevalent aspect of autism spectrum disorder (ASD) that may contribute to core deficits of ASD such as repetitive behaviors as well as comorbidities including anxiety disorders. The ability to integrate information among our senses is required to comprehend the world around us and is crucial for the development of language, motor skills, and social communication. Prior studies have shown that individuals with autism differ from individuals without autism when presented with simple, non-natural audio-visual stimuli such as basic shapes accompanied by pure tones. Because the human brain processes non-natural and natural stimuli differently, more recent studies have used real-world images paired with a sound. However, the stimuli used in many of these studies were static photos paired with a congruent sound and do not reflect the dynamic nature of a real-world environment. The bulk of studies using dynamic real-world stimuli have investigated language processing by pairing human vocalizations with a human face. However, because face and vocalization stimuli are processed in distinct areas of the brain, dynamic stimuli that contain faces and vocalizations confound investigations of multisensory integration. The remaining studies that used dynamic real-world videos to investigate multisensory integration, have primarily used very short video clips of only a few seconds in length. While these stimuli do represent the natural environment, the short length of these videos lacks the continuous nature of what we see and hear in our environment. Only two studies have used dynamic, real-world stimuli that are continuous to investigate multisensory integration in autism. Unfortunately, the stimuli used in both of these studies contained confounding facial and or language processing. Therefore, we currently do not have a good understanding of how individuals with autism integrate multiple real-world sensory inputs that reflect dynamic natural stimuli encountered in the environment outside of our understanding of language and face processing. Considering the gap in the current literature regarding processing of real-world, dynamic stimuli, the goal of this research was to use functional magnetic resonance imaging (fMRI) to investigate how individuals with autism integrate auditory and visual information of a real-world, dynamic scene. We hypothesized that individuals with high-functioning autism would show different levels of brain activation in regions known to process auditory and visual information as well as in brain areas known to integrate audio-visual information. While undergoing an MRI, participants (ASD n=20 and typically developed controls [TD] n=21) watched a video of a person bouncing a basketball. The person was filmed from the neck down to avoid engaging face processing brain regions while viewing the video. To ensure engagement, a simple attention task was used and was easily accomplished by both groups. Analysis of the fMRI data showed that the ASD group had significantly less brain activation in left-lateralized intraparietal sulcus and putamen/globus pallidus. These brain regions are known to be involved in processing human biological motion and regulating motor movements respectively. The hypoactivation seen in the ASD group may reflect underconnectivity between and within the hemispheres for processing this dynamic audio-visual stimulus. These data support the Underconnectivity Theory of Autism which posits long-distance networks are underconnected in individuals with autism contributing to global processing deficits

Audiovisual sensory processing in autism spectrum condition.

Autism spectrum condition (ASC) consists of a set of pervasive developmental problems marked by measurable deficits in social interaction and communication, often coupled with specific and repetitive patterns of behavior. Featured restrictions in the capability to communicate and remain attentive can directly relate to the individual’s ability to interact with others within societal norms. Evidence has suggested that the deficits commonly demonstrated by individuals with autism may arise from a disconnect between neural processes governing sensory inputs. Comparing ASC subjects to controls, previous investigations had shown that electroencephalogram (EEG) recordings and event-related potentials (ERPs) evoked via separate auditory and visual stimuli do not display aberrations in latency or amplitude in the ASC individuals. However, the findings reported here suggest decreased latencies in early-evoked potentials. Additionally, during the combined audiovisual task, electrophysiological recordings revealed significant cortical activity differences between ASC subjects and controls. To investigate the aforementioned phenomena this study employed EEG recording technology while subjects participated in an oddball-paradigm reaction time test. This project reports on the differences behavioral reactions as well as variances in amplitude and latency in twelve autistic individuals and twelve matched controls. Subjects were evaluated using the event related potentials, N100, N200, and P300, as well as dipole source coherence and power of EEG gamma oscillations recorded at fronto-central and parietal sites in both hemispheres. Findings of this study suggest that the irregularities arise from deficits in the integration and combinatorial processing of multiple sensory inputs. Previous research investigating the neuropathology of autism has identified abnormalities in the structure, number and activity of the cortical minicolumns, which are believed to influence excitatory and inhibitory impulses of sensory processing. The minicolumns of ASC individuals appear in greater number coupled with increased neuronal density due to a reduction in the volume of peripheral neuropil space and neuronal cell bodies. Such a cortical and cellular arrangement favors the formation of short intralobular connections between neurons at the expense of longer interlobular fibers. This study proposes that aberrations in sensory processing and functional cortical binding, as evidenced by EEG recordings related to the tasks, further reflect underlying abnormalities of minicolumns in ASC individuals. Thus, the results of this project intuitively suggest that dysfunction of sensory processing by way of minicolumn irregularity may in turn lead to symptoms commonly associated with autism spectrum condition

Neural Dynamics of Autistic Behaviors: Cognitive, Emotional, and Timing Substrates

What brain mechanisms underlie autism and how do they give rise to autistic behavioral symptoms? This article describes a neural model, called the iSTART model, which proposes how cognitive, emotional, timing, and motor processes may interact together to create and perpetuate autistic symptoms. These model processes were originally developed to explain data concerning how the brain controls normal behaviors. The iSTART model shows how autistic behavioral symptoms may arise from prescribed breakdowns in these brain processes.Air Force Office of Scientific Research (F49620-01-1-0397); Office of Naval Research (N00014-01-1-0624