Video-evoked fMRI BOLD responses are highly consistent across different data acquisition sites.

Naturalistic imaging paradigms, in which participants view complex videos in the scanner, are increasingly used in human cognitive neuroscience. Videos evoke temporally synchronized brain responses that are similar across subjects as well as within subjects, but the reproducibility of these brain responses across different data acquisition sites has not yet been quantified. Here, we characterize the consistency of brain responses across independent samples of participants viewing the same videos in functional magnetic resonance imaging (fMRI) scanners at different sites (Indiana University and Caltech). We compared brain responses collected at these different sites for two carefully matched datasets with identical scanner models, acquisition, and preprocessing details, along with a third unmatched dataset in which these details varied. Our overall conclusion is that for matched and unmatched datasets alike, video-evoked brain responses have high consistency across these different sites, both when compared across groups and across pairs of individuals. As one might expect, differences between sites were larger for unmatched datasets than matched datasets. Residual differences between datasets could in part reflect participant-level variability rather than scanner- or data- related effects. Altogether our results indicate promise for the development and, critically, generalization of video fMRI studies of individual differences in healthy and clinical populations alike.

The role of the amygdala in naturalistic mentalising in typical development and in autism spectrum disorder.

BACKGROUND: The substantial discrepancy between mentalising in experimental settings v. real-life social interactions hinders the understanding of the neural basis of real-life social cognition and of social impairments in psychiatric disorders. AIMS: To determine the neural mechanisms underlying naturalistic mentalising in individuals with and without autism spectrum disorder. METHOD: We investigated mentalising with a new video-based functional magnetic resonance imaging task in 20 individuals with autism spectrum disorder and 22 matched healthy controls. RESULTS: Naturalistic mentalising implicated regions of the traditional mentalising network (medial prefrontal cortex, temporoparietal junction), and additionally the insula and amygdala. Moreover, amygdala activity predicted implicit mentalising performance on an independent behavioural task. Compared with controls, the autism spectrum disorder group did not show differences in neural activity within classical mentalising regions. They did, however, show reduced amygdala activity and a reduced correlation between amygdala activity and mentalising accuracy on the behavioural task, compared with controls. CONCLUSIONS: These findings highlight the crucial role of the amygdala in making accurate implicit mental state inferences in typical development and in the social cognitive impairments of individuals with autism spectrum disorder.

Decoding task and stimulus representations in face-responsive cortex.

Observers can deliberately attend to some aspects of a face (e.g. emotional expression) while ignoring others. How do internal goals influence representational geometry in face-responsive cortex? Participants watched videos of naturalistic dynamic faces during MRI scanning. We measured multivariate neural response patterns while participants formed an intention to attend to a facial aspect (age, or emotional valence), and then attended to that aspect, and responses to the face's emotional valence, independent of attention. Distinct patterns of response to the two tasks were found while forming the intention, in left fronto-lateral but not face-responsive regions, and while attending to the face, in almost all face-responsive regions. Emotional valence was represented in right posterior superior temporal sulcus and medial prefrontal cortex, but could not be decoded when unattended. Shifting the focus of attention thus alters cortical representation of social information, probably reflecting neural flexibility to optimally integrate goals and perceptual input.

Training-induced plasticity of the social brain in autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is linked to social brain activity and facial affect recognition (FAR). AIMS: To examine social brain plasticity in ASD. METHOD: Using FAR tests and functional magnetic resonance imaging tasks for FAR, we compared 32 individuals with ASD and 25 controls. Subsequently, the participants with ASD were assigned to FAR computer-aided cognitive training or a control group. RESULTS: The ASD group performed more poorly than controls on explicit behavioural FAR tests. In the scanner, during implicit FAR, the amygdala, fusiform gyrus and other regions of the social brain were less activated bilaterally. The training group improved on behavioural FAR tests, and cerebral response to implicit affect processing tasks increased bilaterally post-training in the social brain. CONCLUSIONS: Individuals with ASD show FAR impairments associated with hypoactivation of the social brain. Computer-based training improves explicit FAR and neuronal responses during implicit FAR, indicating neuroplasticity in the social brain in ASD.

Resting-State Functional Connectivity of the Amygdala in Autism: A Preregistered Large-Scale Study.

OBJECTIVE: Three leading neurobiological hypotheses about autism spectrum disorder (ASD) propose underconnectivity between brain regions, atypical function of the amygdala, and generally higher variability between individuals with ASD than between neurotypical individuals. Past work has often failed to generalize, because of small sample sizes, unquantified data quality, and analytic flexibility. This study addressed these limitations while testing the above three hypotheses, applied to amygdala functional connectivity. METHODS: In a comprehensive preregistered study, the three hypotheses were tested in a subset (N=488 after exclusions; N=212 with ASD) of the Autism Brain Imaging Data Exchange data sets. The authors analyzed resting-state functional connectivity (FC) from functional MRI data from two anatomically defined amygdala subdivisions, in three hypotheses with respect to magnitude, pattern similarity, and variability, across different anatomical scales ranging from whole brain to specific regions and networks. RESULTS: A Bayesian approach to hypothesis evaluation produced inconsistent evidence in ASD for atypical amygdala FC magnitude, strong evidence that the multivariate pattern of FC was typical, and no consistent evidence of increased interindividual variability in FC. The results strongly depended on analytic choices, including preprocessing pipeline for the neuroimaging data, anatomical specificity, and subject exclusions. CONCLUSIONS: A preregistered set of analyses found no reliable evidence for atypical functional connectivity of the amygdala in autism, contrary to leading hypotheses. Future studies should test an expanded set of hypotheses across multiple processing pipelines, collect deeper data per individual, and include a greater diversity of participants to ensure robust generalizability of findings on amygdala FC in ASD.

A next-generation, histological atlas of the human brain and its application to automated brain MRI segmentation.

Magnetic resonance imaging (MRI) is the standard tool to image the human brain in vivo. In this domain, digital brain atlases are essential for subject-specific segmentation of anatomical regions of interest (ROIs) and spatial comparison of neuroanatomy from different subjects in a common coordinate frame. High-resolution, digital atlases derived from histology (e.g., Allen atlas [7], BigBrain [13], Julich [15]), are currently the state of the art and provide exquisite 3D cytoarchitectural maps, but lack probabilistic labels throughout the whole brain. Here we present NextBrain, a next-generation probabilistic atlas of human brain anatomy built from serial 3D histology and corresponding highly granular delineations of five whole brain hemispheres. We developed AI techniques to align and reconstruct ~10,000 histological sections into coherent 3D volumes with joint geometric constraints (no overlap or gaps between sections), as well as to semi-automatically trace the boundaries of 333 distinct anatomical ROIs on all these sections. Comprehensive delineation on multiple cases enabled us to build the first probabilistic histological atlas of the whole human brain. Further, we created a companion Bayesian tool for automated segmentation of the 333 ROIs in any in vivo or ex vivo brain MRI scan using the NextBrain atlas. We showcase two applications of the atlas: automated segmentation of ultra-high-resolution ex vivo MRI and volumetric analysis of Alzheimer's disease and healthy brain ageing based on ~4,000 publicly available in vivo MRI scans. We publicly release: the raw and aligned data (including an online visualisation tool); the probabilistic atlas; the segmentation tool; and ground truth delineations for a 100 µm isotropic ex vivo hemisphere (that we use for quantitative evaluation of our segmentation method in this paper). By enabling researchers worldwide to analyse brain MRI scans at a superior level of granularity without manual effort or highly specific neuroanatomical knowledge, NextBrain holds promise to increase the specificity of MRI findings and ultimately accelerate our quest to understand the human brain in health and disease.

The role of the amygdala in atypical gaze on emotional faces in autism spectrum disorders.

Reduced focus toward the eyes is a characteristic of atypical gaze on emotional faces in autism spectrum disorders (ASD). Along with the atypical gaze, aberrant amygdala activity during face processing compared with neurotypically developed (NT) participants has been repeatedly reported in ASD. It remains unclear whether the previously reported dysfunctional amygdalar response patterns in ASD support an active avoidance of direct eye contact or rather a lack of social attention. Using a recently introduced emotion classification task, we investigated eye movements and changes in blood oxygen level-dependent (BOLD) signal in the amygdala with a 3T MRI scanner in 16 autistic and 17 control adult human participants. By modulating the initial fixation position on faces, we investigated changes triggered by the eyes compared with the mouth. Between-group interaction effects revealed different patterns of gaze and amygdalar BOLD changes in ASD and NT: Individuals with ASD gazed more often away from than toward the eyes, compared with the NT group, which showed the reversed tendency. An interaction contrast of group and initial fixation position further yielded a significant cluster of amygdala activity. Extracted parameter estimates showed greater response to eyes fixation in ASD, whereas the NT group showed an increase for mouth fixation. The differing patterns of amygdala activity in combination with differing patterns of gaze behavior between groups triggered by direct eye contact and mouth fixation, suggest a dysfunctional profile of the amygdala in ASD involving an interplay of both eye-avoidance processing and reduced orientation.

Atypical gaze patterns in autistic adults are heterogeneous across but reliable within individuals.

BACKGROUND: Across behavioral studies, autistic individuals show greater variability than typically developing individuals. However, it remains unknown to what extent this variability arises from heterogeneity across individuals, or from unreliability within individuals. Here, we focus on eye tracking, which provides rich dependent measures that have been used extensively in studies of autism. Autistic individuals have an atypical gaze onto both static visual images and dynamic videos that could be leveraged for diagnostic purposes if the above open question could be addressed. METHODS: We tested three competing hypotheses: (1) that gaze patterns of autistic individuals are less reliable or noisier than those of controls, (2) that atypical gaze patterns are individually reliable but heterogeneous across autistic individuals, or (3) that atypical gaze patterns are individually reliable and also homogeneous among autistic individuals. We collected desktop-based eye tracking data from two different full-length television sitcom episodes, at two independent sites (Caltech and Indiana University), in a total of over 150 adult participants (N = 48 autistic individuals with IQ in the normal range, 105 controls) and quantified gaze onto features of the videos using automated computer vision-based feature extraction. RESULTS: We found support for the second of these hypotheses. Autistic people and controls showed equivalently reliable gaze onto specific features of videos, such as faces, so much so that individuals could be identified significantly above chance using a fingerprinting approach from video epochs as short as 2 min. However, classification of participants into diagnostic groups based on their eye tracking data failed to produce clear group classifications, due to heterogeneity in the autistic group. LIMITATIONS: Three limitations are the relatively small sample size, assessment across only two videos (from the same television series), and the absence of other dependent measures (e.g., neuroimaging or genetics) that might have revealed individual-level variability that was not evident with eye tracking. Future studies should expand to larger samples across longer longitudinal epochs, an aim that is now becoming feasible with Internet- and phone-based eye tracking. CONCLUSIONS: These findings pave the way for the investigation of autism subtypes, and for elucidating the specific visual features that best discriminate gaze patterns-directions that will also combine with and inform neuroimaging and genetic studies of this complex disorder.

Caltech Conte Center, a multimodal data resource for exploring social cognition and decision-making.

This data release of 117 healthy community-dwelling adults provides multimodal high-quality neuroimaging and behavioral data for the investigation of brain-behavior relationships. We provide structural MRI, resting-state functional MRI, movie functional MRI, together with questionnaire-based and task-based psychological variables; many of the participants have multiple datasets from retesting over the course of several years. Our dataset is distinguished by utilizing open-source data formats and processing tools (BIDS, FreeSurfer, fMRIPrep, MRIQC), providing data that is thoroughly quality checked, preprocessed to various extents and available in multiple anatomical spaces. A customizable denoising pipeline is provided as open-source code that includes tools for the generation of functional connectivity matrices and initialization of individual difference analyses. Behavioral data include a comprehensive set of psychological assessments on gold-standard instruments encompassing cognitive function, mood and personality, together with exploratory factor analyses. The dataset provides an in-depth, multimodal resource for investigating associations between individual differences, brain structure and function, with a focus on the domains of social cognition and decision-making.

Atypical reflexive gaze patterns on emotional faces in autism spectrum disorders.

Atypical scan paths on emotional faces and reduced eye contact represent a prominent feature of autism symptomatology, yet the reason for these abnormalities remains a puzzle. Do individuals with autism spectrum disorders (ASDs) fail to orient toward the eyes or do they actively avoid direct eye contact? Here, we used a new task to investigate reflexive eye movements on fearful, happy, and neutral faces. Participants (ASDs: 12; controls: 11) initially fixated either on the eyes or on the mouth. By analyzing the frequency of participants' eye movements away from the eyes and toward the eyes, respectively, we explored both avoidance and orientation reactions. The ASD group showed a reduced preference for the eyes relative to the control group, primarily characterized by more frequent eye movements away from the eyes. Eye-tracking data revealed a pronounced influence of active avoidance of direct eye contact on atypical gaze in ASDs. The combination of avoidance and reduced orientation into an individual index predicted emotional recognition performance. Crucially, this result provides evidence for a direct link between individual gaze patterns and associated social symptomatology. These findings thereby give important insights into the social pathology of ASD, with implications for future research and interventions.

Cooperation and heterogeneity of the autistic mind.

Individuals with autism spectrum conditions (ASCs) have a core difficulty in recursively inferring the intentions of others. The precise cognitive dysfunctions that determine the heterogeneity at the heart of this spectrum, however, remains unclear. Furthermore, it remains possible that impairment in social interaction is not a fundamental deficit but a reflection of deficits in distinct cognitive processes. To better understand heterogeneity within ASCs, we employed a game-theoretic approach to characterize unobservable computational processes implicit in social interactions. Using a social hunting game with autistic adults, we found that a selective difficulty representing the level of strategic sophistication of others, namely inferring others' mindreading strategy, specifically predicts symptom severity. In contrast, a reduced ability in iterative planning was predicted by overall intellectual level. Our findings provide the first quantitative approach that can reveal the underlying computational dysfunctions that generate the autistic "spectrum."

Reorganization of the Social Brain in Individuals with Only One Intact Cerebral Hemisphere.

Social cognition and emotion are ubiquitous human processes that recruit a reliable set of brain networks in healthy individuals. These brain networks typically comprise midline (e.g., medial prefrontal cortex) as well as lateral regions of the brain including homotopic regions in both hemispheres (e.g., left and right temporo-parietal junction). Yet the necessary roles of these networks, and the broader roles of the left and right cerebral hemispheres in socioemotional functioning, remains debated. Here, we investigated these questions in four rare adults whose right (three cases) or left (one case) cerebral hemisphere had been surgically removed (to a large extent) to treat epilepsy. We studied four closely matched healthy comparison participants, and also compared the patient findings to data from a previously published larger healthy comparison sample (n = 33). Participants completed standardized socioemotional and cognitive assessments to investigate social cognition. Functional magnetic resonance imaging (fMRI) data were obtained during passive viewing of a short, animated movie that distinctively recruits two social brain networks: one engaged when thinking about other agents' internal mental states (e.g., beliefs, desires, emotions; so-called Theory of Mind or ToM network), and the second engaged when thinking about bodily states (e.g., pain, hunger; so-called PAIN network). Behavioral assessments demonstrated remarkably intact general cognitive functioning in all individuals with hemispherectomy. Social-emotional functioning was somewhat variable in the hemispherectomy participants, but strikingly, none of these individuals had consistently impaired social-emotional processing and none of the assessment scores were consistent with a psychiatric disorder. Using inter-region correlation analyses, we also found surprisingly typical ToM and PAIN networks, as well as typical differentiation of the two networks (in the intact hemisphere of patients with either right or left hemispherectomy), based on idiosyncratic reorganization of cortical activation. The findings argue that compensatory brain networks can process social and emotional information following hemispherectomy across different age levels (from 3 months to 20 years old), and suggest that social brain networks typically distributed across midline and lateral brain regions in this domain can be reorganized, to a substantial degree.

Increased hippocampal shape asymmetry and volumetric ventricular asymmetry in autism spectrum disorder.

Autism spectrum disorder (ASD) is a prevalent and fast-growing pervasive neurodevelopmental disorder worldwide. Despite the increasing prevalence of ASD and the breadth of research conducted on the disorder, a conclusive etiology has yet to be established and controversy still exists surrounding the anatomical abnormalities in ASD. In particular, structural asymmetries have seldom been investigated in ASD, especially in subcortical regions. Additionally, the majority of studies for identifying structural biomarkers associated with ASD have focused on small sample sizes. Therefore, the present study utilizes a large-scale, multi-site database to investigate asymmetries in the amygdala, hippocampus, and lateral ventricles, given the potential involvement of these regions in ASD. Contrary to prior work, we are not only computing volumetric asymmetries, but also shape asymmetries, using a new measure of asymmetry based on spectral shape descriptors. This measure represents the magnitude of the asymmetry and therefore captures both directional and undirectional asymmetry. The asymmetry analysis is conducted on 437 individuals with ASD and 511 healthy controls using T1-weighted MRI scans from the Autism Brain Imaging Data Exchange (ABIDE) database. Results reveal significant asymmetries in the hippocampus and the ventricles, but not in the amygdala, in individuals with ASD. We observe a significant increase in shape asymmetry in the hippocampus, as well as increased volumetric asymmetry in the lateral ventricles in individuals with ASD. Asymmetries in these regions have not previously been reported, likely due to the different characterization of neuroanatomical asymmetry and smaller sample sizes used in previous studies. Given that these results were demonstrated in a large cohort, such asymmetries may be worthy of consideration in the development of neurodiagnostic classification tools for ASD.

Intrinsic Functional Connectivity of the Brain in Adults with a Single Cerebral Hemisphere.

A reliable set of functional brain networks is found in healthy people and thought to underlie our cognition, emotion, and behavior. Here, we investigated these networks by quantifying intrinsic functional connectivity in six individuals who had undergone surgical removal of one hemisphere. Hemispherectomy subjects and healthy controls were scanned with identical parameters on the same scanner and compared to a large normative sample (n = 1,482). Surprisingly, hemispherectomy subjects and controls all showed strong and equivalent intrahemispheric connectivity between brain regions typically assigned to the same functional network. Connectivity between parts of different networks, however, was markedly increased for almost all hemispherectomy participants and across all networks. These results support the hypothesis of a shared set of functional networks that underlie cognition and suggest that between-network interactions may characterize functional reorganization in hemispherectomy.

The influence of prior record on moral judgment.

Repeat offenders are commonly given more severe sentences than first-time offenders for the same violations. Though this practice makes intuitive sense, the theory behind escalating penalties is disputed in both legal and economic theories. Here we investigate folk intuitions concerning the moral and intentional status of actions performed by people with positive versus negative prior records. We hypothesized that prior record would modulate both moral judgment and mental state reasoning. Subjects first engaged in an economic game with fair (positive prior record) and unfair (negative prior record) competitors and then read descriptions of their competitors' actions that resulted in either positive or negative outcomes. The descriptions left the competitors' mental states unstated. We found that subjects judged actions producing negative outcomes as more "intentional" and more "blameworthy" when performed by unfair competitors. Although explicit mental state evaluation was not required, moral judgments in this case were accompanied by increased activation in brain regions associated with mental state reasoning, including predominantly the right temporo-parietal junction (RTPJ). The magnitude of RTPJ activation was correlated with individual subjects' behavioural responses to unfair play in the game. These results thus provide insight for both legal theory and moral psychology.

The social neuroscience of mentalizing: challenges and recommendations.

Our ability to understand and think about the mental states of other people is referred to as 'mentalizing' or 'theory of mind'. It features prominently in all social behavior, is essential for maintaining relationships, and shows pronounced individual differences. Here we review new approaches to study the underlying psychological mechanisms and discuss how they could best be investigated using modern tools from social neuroscience. We list key desiderata for the field, such as validity, specificity, and reproducibility, and link them to specific recommendations for the future. We also discuss new computational modeling approaches, and the application to psychopathology.

Cortical responses to dynamic emotional facial expressions generalize across stimuli, and are sensitive to task-relevance, in adults with and without Autism.

Individuals with Autism Spectrum Disorders (ASD) report difficulties extracting meaningful information from dynamic and complex social cues, like facial expressions. The nature and mechanisms of these difficulties remain unclear. Here we tested whether that difficulty can be traced to the pattern of activity in "social brain" regions, when viewing dynamic facial expressions. In two studies, adult participants (male and female) watched brief videos of a range of positive and negative facial expressions, while undergoing functional magnetic resonance imaging (Study 1: ASD n = 16, control n = 21; Study 2: ASD n = 22, control n = 30). Patterns of hemodynamic activity differentiated among facial emotional expressions in left and right superior temporal sulcus, fusiform gyrus, and parts of medial prefrontal cortex. In both control participants and high-functioning individuals with ASD, we observed (i) similar responses to emotional valence that generalized across facial expressions and animated social events; (ii) similar flexibility of responses to emotional valence, when manipulating the task-relevance of perceived emotions; and (iii) similar responses to a range of emotions within valence. Altogether, the data indicate that there was little or no group difference in cortical responses to isolated dynamic emotional facial expressions, as measured with fMRI. Difficulties with real-world social communication and social interaction in ASD may instead reflect differences in initiating and maintaining contingent interactions, or in integrating social information over time or context.

Directed network discovery with dynamic network modelling.

Cognitive tasks recruit multiple brain regions. Understanding how these regions influence each other (the network structure) is an important step to characterize the neural basis of cognitive processes. Often, limited evidence is available to restrict the range of hypotheses a priori, and techniques that sift efficiently through a large number of possible network structures are needed (network discovery). This article introduces a novel modelling technique for network discovery (Dynamic Network Modelling or DNM) that builds on ideas from Granger Causality and Dynamic Causal Modelling introducing three key changes: (1) efficient network discovery is implemented with statistical tests on the consistency of model parameters across participants, (2) the tests take into account the magnitude and sign of each influence, and (3) variance explained in independent data is used as an absolute (rather than relative) measure of the quality of the network model. In this article, we outline the functioning of DNM, we validate DNM in simulated data for which the ground truth is known, and we report an example of its application to the investigation of influences between regions during emotion recognition, revealing top-down influences from brain regions encoding abstract representations of emotions (medial prefrontal cortex and superior temporal sulcus) onto regions engaged in the perceptual analysis of facial expressions (occipital face area and fusiform face area) when participants are asked to switch between reporting the emotional valence and the age of a face.

Emotional prosody processing in autism spectrum disorder.

Individuals with Autism Spectrum Disorder (ASD) are characterized by severe deficits in social communication, whereby the nature of their impairments in emotional prosody processing have yet to be specified. Here, we investigated emotional prosody processing in individuals with ASD and controls with novel, lifelike behavioral and neuroimaging paradigms. Compared to controls, individuals with ASD showed reduced emotional prosody recognition accuracy on a behavioral task. On the neural level, individuals with ASD displayed reduced activity of the STS, insula and amygdala for complex vs basic emotions compared to controls. Moreover, the coupling between the STS and amygdala for complex vs basic emotions was reduced in the ASD group. Finally, groups differed with respect to the relationship between brain activity and behavioral performance. Brain activity during emotional prosody processing was more strongly related to prosody recognition accuracy in ASD participants. In contrast, the coupling between STS and anterior cingulate cortex (ACC) activity predicted behavioral task performance more strongly in the control group. These results provide evidence for aberrant emotional prosody processing of individuals with ASD. They suggest that the differences in the relationship between the neural and behavioral level of individuals with ASD may account for their observed deficits in social communication.

Approximating implicit and explicit mentalizing with two naturalistic video-based tasks in typical development and autism spectrum disorder.

Individuals with autism spectrum disorder (ASD) have been proposed to show greater impairments in implicit than explicit mentalizing. To test this proposition, we developed two comparable naturalistic tasks for a performance-based approximation of implicit and explicit mentalizing in 28 individuals with ASD and 23 matched typically developed (TD) participants. Although both tasks were sensitive to the social impairments of individuals with ASD, implicit mentalizing was not more dysfunctional than explicit mentalizing. In TD participants, performance on the tasks did not correlate with each other, whereas in individuals with ASD they were highly correlated. These findings suggest that implicit and explicit mentalizing processes are separable in typical development. In contrast, in individuals with ASD implicit and explicit mentalizing processes are similarly impaired and closely linked suggesting a lack of developmental specification of these processes in ASD.