Dan Kennedy

Autism spectrum disorders (ASDs) represent a formidable challenge for psychiatry and neuroscience because of their high prevalence, lifelong nature, complexity and substantial heterogeneity. Facing these obstacles requires large-scale multidisciplinary efforts. Although the field of genetics has pioneered data sharing for these reasons, neuroimaging had not kept pace. In response, we introduce the Autism Brain Imaging Data Exchange (ABIDE)—a grassroots consortium aggregating and openly sharing 1112 existing resting-state functional magnetic resonance imaging (R-fMRI) data sets with corresponding structural MRI and phenotypic information from 539 individuals with ASDs and 573 age-matched typical controls (TCs; 7–64 years)(http://fcon_1000. projects. nitrc. org/indi/abide/). Here, we present this resource and demonstrate its suitability for advancing knowledge of ASD neurobiology based on analyses …

Although the neurobiology of autism has been studied for more than two decades, the majority of these studies have examined brain structure 10, 20, or more years after the onset of clinical symptoms. The pathological biology that causes autism remains unknown, but its signature is likely to be most evident during the first years of life when clinical symptoms are emerging. This review highlights neurobiological findings during the first years of life and emphasizes early brain overgrowth as a key factor in the pathobiology of autism. We speculate that excess neuron numbers may be one possible cause of early brain overgrowth and produce defects in neural patterning and wiring, with exuberant local and short-distance cortical interactions impeding the function of large-scale, long-distance interactions between brain regions. Because large-scale networks underlie socio-emotional and communication functions, such …

Several regions of the brain (including medial prefrontal cortex, rostral anterior cingulate, posterior cingulate, and precuneus) are known to have high metabolic activity during rest, which is suppressed during cognitively demanding tasks. With functional magnetic resonance imaging (fMRI), this suppression of activity is observed as “deactivations,” which are thought to be indicative of an interruption of the mental activity that persists during rest. Thus, measuring deactivation provides a means by which rest-associated functional activity can be quantitatively examined. Applying this approach to autism, we found that the autism group failed to demonstrate this deactivation effect. Furthermore, there was a strong correlation between a clinical measure of social impairment and functional activity within the ventral medial prefrontal cortex. We speculate that the lack of deactivation in the autism group is indicative of abnormal …

In higher functioning individuals with autism, a striking disparity exists between impaired social and emotional abilities and relatively preserved sustained attention and goal-directed cognitive abilities. As these two functional domains appear to map onto two distinct large-scale brain networks, the Task-Negative Network and the Task-Positive Network, respectively, we examined their intrinsically defined functional organization in individuals with autism. Using resting functional connectivity MRI (fcMRI), we found that, in autism, there was altered functional organization of the network involved in social and emotional processing, but no group difference in the functional organization of the network involved in sustained attention and goal-directed cognition. We suggest that these findings might serve to relate the seemingly disparate strengths and weaknesses of the autistic behavioral, perceptual, and cognitive …

Psychiatric and neurological disorders have historically provided key insights into the structure-function relationships that subserve human social cognition and behavior, informing the concept of the ‘social brain’. In this review, we take stock of the current status of this concept, retaining a focus on disorders that impact social behavior. We discuss how the social brain, social cognition, and social behavior are interdependent, and emphasize the important role of development and compensation. We suggest that the social brain, and its dysfunction and recovery, must be understood not in terms of specific structures, but rather in terms of their interaction in large-scale networks.

The amygdala plays key roles in emotion and social cognition, but how this translates to face-to-face interactions involving real people remains unknown. We found that an individual with complete amygdala lesions lacked any sense of personal space. Furthermore, healthy individuals showed amygdala activation upon close personal proximity. The amygdala may be required to trigger the strong emotional reactions normally following personal space violations, thus regulating interpersonal distance in humans.

A new neurobiological phenomenon in autism has been described that precedes the onset of clinical behavioral symptoms, and is brief and age-delimited to the first two years of life. The neurobiological defects that precede, trigger, and underlie it may form part of the developmental precursors of some of the anatomical, functional, and behavioral manifestations of autism. Future studies of the first years of life may help elucidate the factors and processes that bring about the unfolding of autistic behavior.

Recent studies of autism have identified functional abnormalities of the default network during a passive resting state. Since the default network is also typically engaged during social, emotional and introspective processing, dysfunction of this network may underlie some of the difficulties individuals with autism exhibit in these broad domains. In the present experiment, we attempted to further delineate the nature of default network abnormality in autism using experimentally constrained social and introspective tasks. Thirteen autism and 12 control participants were scanned while making true/false judgments for various statements about themselves (SELF condition) or a close other person (OTHER), and pertaining to either psychological personality traits (INTERNAL) or observable characteristics and behaviors (EXTERNAL). In the ventral medial prefrontal cortex/ventral anterior cingulate cortex, activity was …

Autistic symptoms begin in the first years of life, and recent magnetic resonance imaging studies have discovered brain growth abnormalities that precede and overlap with the onset of these symptoms. Recent postmortem studies of the autistic brain provide evidence of cellular abnormalities and processes that may underlie the recently discovered early brain overgrowth and arrest of growth that marks the first years of life in autism. Alternative origins and time tables for these cellular defects and processes are discussed. These cellular and growth abnormalities are most pronounced in frontal, cerebellar, and temporal structures that normally mediate the development of those same higher order social, emotional, speech, language, speech, attention, and cognitive functions that characterize autism. Cellular and growth pathologies are milder and perhaps nonexistent in other …

The social difficulties that are a hallmark of autism spectrum disorder (ASD) are thought to arise, at least in part, from atypical attention toward stimuli and their features. To investigate this hypothesis comprehensively, we characterized 700 complex natural scene images with a novel three-layered saliency model that incorporated pixel-level (e.g., contrast), object-level (e.g., shape), and semantic-level attributes (e.g., faces) on 5,551 annotated objects. Compared with matched controls, people with ASD had a stronger image center bias regardless of object distribution, reduced saliency for faces and for locations indicated by social gaze, and yet a general increase in pixel-level saliency at the expense of semantic-level saliency. These results were further corroborated by direct analysis of fixation characteristics and investigation of feature interactions. Our results for the first time quantify atypical visual attention in ASD …

A leading hypothesis for the neural basis of autism postulates globally abnormal brain connectivity, yet the majority of studies report effects that are either very weak, inconsistent across studies, or explain results incompletely. Here we apply multiple analytical approaches to resting-state BOLD-fMRI data at the whole-brain level. Neurotypical and high-functioning adults with autism displayed very similar patterns and strengths of resting-state connectivity. We found only limited evidence in autism for abnormal resting-state connectivity at the regional level and no evidence for altered connectivity at the whole-brain level. Regional abnormalities in functional connectivity in autism spectrum disorder were primarily in the frontal and temporal cortices. Within these regions, functional connectivity with other brain regions was almost exclusively lower in the autism group. Further examination showed that even small …

Temporal correlations between different brain regions in the resting-state BOLD signal are thought to reflect intrinsic functional brain connectivity (Biswal et al., 1995; Greicius et al., 2003; Fox et al., 2007). The functional networks identified are typically bilaterally distributed across the cerebral hemispheres, show similarity to known white matter connections (Greicius et al., 2009), and are seen even in anesthetized monkeys (Vincent et al., 2007). Yet it remains unclear how they arise. Here we tested two distinct possibilities: (1) functional networks arise largely from structural connectivity constraints, and generally require direct interactions between functionally coupled regions mediated by white-matter tracts; and (2) functional networks emerge flexibly with the development of normal cognition and behavior and can be realized in multiple structural architectures. We conducted resting-state fMRI in eight adult humans …

The electrophysiological basis for higher brain activity during rest and internally directed cognition within the human default mode network (DMN) remains largely unknown. Here we use intracranial recordings in the human posteromedial cortex (PMC), a core node within the DMN, during conditions of cued rest, autobiographical judgments, and arithmetic processing. We found a heterogeneous profile of PMC responses in functional, spatial, and temporal domains. Although the majority of PMC sites showed increased broad gamma band activity (30–180 Hz) during rest, some PMC sites, proximal to the retrosplenial cortex, responded selectively to autobiographical stimuli. However, no site responded to both conditions, even though they were located within the boundaries of the DMN identified with resting-state functional imaging and similarly deactivated during arithmetic processing. These findings, which provide …

The second iteration of the Autism Brain Imaging Data Exchange (ABIDE II) aims to enhance the scope of brain connectomics research in Autism Spectrum Disorder (ASD). Consistent with the initial ABIDE effort (ABIDE I), that released 1112 datasets in 2012, this new multisite open-data resource is an aggregate of resting state functional magnetic resonance imaging (MRI) and corresponding structural MRI and phenotypic datasets. ABIDE II includes datasets from an additional 487 individuals with ASD and 557 controls previously collected across 16 international institutions. The combination of ABIDE I and ABIDE II provides investigators with 2156 unique cross-sectional datasets allowing selection of samples for discovery and/or replication. This sample size can also facilitate the identification of neurobiological subgroups, as well as preliminary examinations of sex differences in ASD. Additionally, ABIDE II …

SM is a patient with complete bilateral amygdala lesions who fails to fixate the eyes in faces and is consequently impaired in recognizing fear (Adolphs et al., 2005). Here we first replicated earlier findings in SM of reduced gaze to the eyes when seen in whole faces. Examination of the time course of fixations revealed that SM's reduced eye contact is particular pronounced in the first fixation to the face, and less abnormal in subsequent fixations. In a second set of experiments, we used a gaze-contingent presentation of faces with real time eye tracking, wherein only a small region of the face is made visible at the center of gaze. In essence, viewers explore the face by moving a small searchlight over the face with their gaze. Under such viewing conditions, SM's fixations to eye region of faces became entirely normalized. We suggest that this effect arises from the absence of bottom-up effects due to the facial features …