A machine-learning approach for differentiating borderline personality disorder from community participants with brain-wide functional connectivity.

BACKGROUND: Functional connectivity has garnered interest as a potential biomarker of psychiatric disorders including borderline personality disorder (BPD). However, small sample sizes and lack of within-study replications have led to divergent findings with no clear spatial foci. AIMS: Evaluate discriminative performance and generalizability of functional connectivity markers for BPD. METHOD: Whole-brain fMRI resting state functional connectivity in matched subsamples of 116 BPD and 72 control individuals defined by three grouping strategies. We predicted BPD status using classifiers with repeated cross-validation based on multiscale functional connectivity within and between regions of interest (ROIs) covering the whole brain-global ROI-based network, seed-based ROI-connectivity, functional consistency, and voxel-to-voxel connectivity-and evaluated the generalizability of the classification in the left-out portion of non-matched data. RESULTS: Full-brain connectivity allowed classification (∼70 %) of BPD patients vs. controls in matched inner cross-validation. The classification remained significant when applied to unmatched out-of-sample data (∼61-70 %). Highest seed-based accuracies were in a similar range to global accuracies (∼70-75 %), but spatially more specific. The most discriminative seed regions included midline, temporal and somatomotor regions. Univariate connectivity values were not predictive of BPD after multiple comparison corrections, but weak local effects coincided with the most discriminative seed-ROIs. Highest accuracies were achieved with a full clinical interview while self-report results remained at chance level. LIMITATIONS: The accuracies vary considerably between random sub-samples of the population, global signal and covariates limiting the practical applicability. CONCLUSIONS: Spatially distributed functional connectivity patterns are moderately predictive of BPD despite heterogeneity of the patient population.

Peripheral oxytocin levels are linked to hypothalamic gray matter volume in autistic adults: a cross-sectional secondary data analysis.

Oxytocin (OXT) is known to modulate social behavior and cognition and has been discussed as pathophysiological and therapeutic factor for autism spectrum disorder (ASD). An accumulating body of evidence indicates the hypothalamus to be of particular importance with regard to the underlying neurobiology. Here we used a region of interest voxel-based morphometry (VBM) approach to investigate hypothalamic gray matter volume (GMV) in autistic (n = 29, age 36.03 ± 11.0) and non-autistic adults (n = 27, age 30.96 ± 11.2). Peripheral plasma OXT levels and the autism spectrum quotient (AQ) were used for correlation analyses. Results showed no differences in hypothalamic GMV in autistic compared to non-autistic adults but suggested a differential association between hypothalamic GMV and OXT levels, such that a positive association was found for the ASD group. In addition, hypothalamic GMV showed a positive association with autistic traits in the ASD group. Bearing in mind the limitations such as a relatively small sample size, a wide age range and a high rate of psychopharmacological treatment in the ASD sample, these results provide new preliminary evidence for a potentially important role of the HTH in ASD and its relationship to the OXT system, but also point towards the importance of interindividual differences.

Hippocampus-Centered Network Is Associated With Positive Symptom Alleviation in Patients With First-Episode Psychosis.

BACKGROUND: Previous functional magnetic resonance imaging studies have reported widespread brain functional connectivity alterations in patients with psychosis. These studies have mostly used either resting-state or simple-task paradigms, thereby compromising experimental control or ecological validity, respectively. Additionally, in a conventional functional magnetic resonance imaging intrasubject functional connectivity analysis, it is difficult to identify which connections relate to extrinsic (stimulus-induced) and which connections relate to intrinsic (non-stimulus-related) neural processes. METHODS: To mitigate these limitations, we used intersubject functional connectivity (ISFC) to analyze longitudinal functional magnetic resonance imaging data collected while 36 individuals with first-episode psychosis (FEP) and 29 age- and sex-matched population control participants watched scenes from the fantasy movie Alice in Wonderland at baseline and again at 1-year follow-up. Furthermore, to allow unconfounded comparison and to overcome possible circularity of ISFC, we introduced a novel approach wherein ISFC in both the FEP and population control groups was calculated with respect to an independent group of participants (not included in the analyses). RESULTS: Using this independent-reference ISFC approach, we found an interaction effect wherein the independent-reference ISFC in individuals with FEP, but not in the control group participants, was significantly stronger at baseline than at follow-up in a network centered in the hippocampus and involving thalamic, striatal, and cortical regions, such as the orbitofrontal cortex. Alleviation of positive symptoms, particularly delusions, from baseline to follow-up was correlated with decreased network connectivity in patients with FEP. CONCLUSIONS: These findings link deviation of naturalistic information processing in the hippocampus-centered network to positive symptoms.

Lipreading a naturalistic narrative in a female population: Neural characteristics shared with listening and reading.

INTRODUCTION: Few of us are skilled lipreaders while most struggle with the task. Neural substrates that enable comprehension of connected natural speech via lipreading are not yet well understood. METHODS: We used a data-driven approach to identify brain areas underlying the lipreading of an 8-min narrative with participants whose lipreading skills varied extensively (range 6-100%, mean = 50.7%). The participants also listened to and read the same narrative. The similarity between individual participants' brain activity during the whole narrative, within and between conditions, was estimated by a voxel-wise comparison of the Blood Oxygenation Level Dependent (BOLD) signal time courses. RESULTS: Inter-subject correlation (ISC) of the time courses revealed that lipreading, listening to, and reading the narrative were largely supported by the same brain areas in the temporal, parietal and frontal cortices, precuneus, and cerebellum. Additionally, listening to and reading connected naturalistic speech particularly activated higher-level linguistic processing in the parietal and frontal cortices more consistently than lipreading, probably paralleling the limited understanding obtained via lip-reading. Importantly, higher lipreading test score and subjective estimate of comprehension of the lipread narrative was associated with activity in the superior and middle temporal cortex. CONCLUSIONS: Our new data illustrates that findings from prior studies using well-controlled repetitive speech stimuli and stimulus-driven data analyses are also valid for naturalistic connected speech. Our results might suggest an efficient use of brain areas dealing with phonological processing in skilled lipreaders.

Imagery of negative interpersonal experiences influence the neural mechanisms of social interaction.

Negative interpersonal experiences are a key contributor to psychiatric disorders. While previous research has shown that negative interpersonal experiences influence social cognition, less is known about the effects on participation in social interactions and the underlying neurobiology. To address this, we developed a new naturalistic version of a gaze-contingent paradigm using real video sequences of gaze behaviour that respond to the participants' gaze in real-time in order to create a believable and continuous interactive social situation. Additionally, participants listened to two autobiographical audio-scripts that guided them to imagine a recent stressful and a relaxing situation and performed the gaze-based social interaction task before and after the presentation of either the stressful or the relaxing audio-script. Our results demonstrate that the social interaction task robustly recruits brain areas with known involvement in social cognition, namely the medial prefrontal cortex, bilateral temporoparietal junction, superior temporal sulcus as well as the precuneus. Imagery of negative interpersonal experiences compared to relaxing imagery led to a prolonged change in affective state and to increased brain responses during the subsequent social interaction paradigm in the temporoparietal junction, medial prefrontal cortex, anterior cingulate cortex, precuneus and inferior frontal gyrus. Taken together this study presents a new naturalistic social interaction paradigm suitable to study the neural mechanisms of social interaction and the results demonstrate that the imagery of negative interpersonal experiences affects social interaction on neural levels.

Interpersonal similarity of autistic traits predicts friendship quality.

Autistic traits are known to be associated with social interaction difficulties. Yet, somewhat paradoxically, relevant research has been typically restricted to studying individuals. In line with the 'dialectical misattunement hypothesis' and clinical insights of intact social interactions among autistic individuals, we hypothesized that friendship quality varies as a function of interpersonal similarity and more concretely the difference value of autistic traits in a dyad, above and beyond autistic traits per se. Therefore, in this study, we used self-report questionnaires to investigate these measures in a sample of 67 neurotypical dyads across a broad range of autistic traits. Our results demonstrate that the more similar two persons are in autistic traits, the higher is the perceived quality of their friendship, irrespective of friendship duration, age, sex and, importantly, the (average of) autistic traits in a given dyad. More specifically, higher interpersonal similarity of autistic traits was associated with higher measures of closeness, acceptance and help. These results, therefore, lend support to the idea of an interactive turn in the study of social abilities across the autism spectrum and pave the way for future studies on the multiscale dynamics of social interactions.

Aberrant computational mechanisms of social learning and decision-making in schizophrenia and borderline personality disorder.

Psychiatric disorders are ubiquitously characterized by debilitating social impairments. These difficulties are thought to emerge from aberrant social inference. In order to elucidate the underlying computational mechanisms, patients diagnosed with major depressive disorder (N = 29), schizophrenia (N = 31), and borderline personality disorder (N = 31) as well as healthy controls (N = 34) performed a probabilistic reward learning task in which participants could learn from social and non-social information. Patients with schizophrenia and borderline personality disorder performed more poorly on the task than healthy controls and patients with major depressive disorder. Broken down by domain, borderline personality disorder patients performed better in the social compared to the non-social domain. In contrast, controls and major depressive disorder patients showed the opposite pattern and schizophrenia patients showed no difference between domains. In effect, borderline personality disorder patients gave up a possible overall performance advantage by concentrating their learning in the social at the expense of the non-social domain. We used computational modeling to assess learning and decision-making parameters estimated for each participant from their behavior. This enabled additional insights into the underlying learning and decision-making mechanisms. Patients with borderline personality disorder showed slower learning from social and non-social information and an exaggerated sensitivity to changes in environmental volatility, both in the non-social and the social domain, but more so in the latter. Regarding decision-making the modeling revealed that compared to controls and major depression patients, patients with borderline personality disorder and schizophrenia showed a stronger reliance on social relative to non-social information when making choices. Depressed patients did not differ significantly from controls in this respect. Overall, our results are consistent with the notion of a general interpersonal hypersensitivity in borderline personality disorder and schizophrenia based on a shared computational mechanism characterized by an over-reliance on beliefs about others in making decisions and by an exaggerated need to make sense of others during learning specifically in borderline personality disorder.

Unobtrusive tracking of interpersonal orienting and distance predicts the subjective quality of social interactions.

Interpersonal coordination of behaviour is essential for smooth social interactions. Measures of interpersonal behaviour, however, often rely on subjective evaluations, invasive measurement techniques or gross measures of motion. Here, we constructed an unobtrusive motion tracking system that enables detailed analysis of behaviour at the individual and interpersonal levels, which we validated using wearable sensors. We evaluate dyadic measures of joint orienting and distancing, synchrony and gaze behaviours to summarize data collected during natural conversation and joint action tasks. Our results demonstrate that patterns of proxemic behaviours, rather than more widely used measures of interpersonal synchrony, best predicted the subjective quality of the interactions. Increased distance between participants predicted lower enjoyment, while increased joint orienting towards each other during cooperation correlated with increased effort reported by the participants. Importantly, the interpersonal distance was most informative of the quality of interaction when task demands and experimental control were minimal. These results suggest that interpersonal measures of behaviour gathered during minimally constrained social interactions are particularly sensitive for the subjective quality of social interactions and may be useful for interaction-based phenotyping for further studies.

Bayesian modelling captures inter-individual differences in social belief computations in the putamen and insula.

Computational models of social learning and decision-making provide mechanistic tools to investigate the neural mechanisms that are involved in understanding other people. While most studies employ explicit instructions to learn from social cues, everyday life is characterized by the spontaneous use of such signals (e.g., the gaze of others) to infer on internal states such as intentions. To investigate the neural mechanisms of the impact of gaze cues on learning and decision-making, we acquired behavioural and fMRI data from 50 participants performing a probabilistic task, in which cards with varying winning probabilities had to be chosen. In addition, the task included a computer-generated face that gazed towards one of these cards providing implicit advice. Participants' individual belief trajectories were inferred using a hierarchical Gaussian filter (HGF) and used as predictors in a linear model of neuronal activation. During learning, social prediction errors were correlated with activity in inferior frontal gyrus and insula. During decision-making, the belief about the accuracy of the social cue was correlated with activity in inferior temporal gyrus, putamen and pallidum while the putamen and insula showed activity as a function of individual differences in weighting the social cue during decision-making. Our findings demonstrate that model-based fMRI can give insight into the behavioural and neural aspects of spontaneous social cue integration in learning and decision-making. They provide evidence for a mechanistic involvement of specific components of the basal ganglia in subserving these processes.

A naturalistic paradigm simulating gaze-based social interactions for the investigation of social agency.

Sense of agency describes the experience of being the cause of one's own actions and the resulting effects. In a social interaction, one's actions may also have a perceivable effect on the actions of others. In this article, we refer to the experience of being responsible for the behavior of others as social agency, which has important implications for the success or failure of social interactions. Gaze-contingent eyetracking paradigms provide a useful tool to analyze social agency in an experimentally controlled manner, but the current methods are lacking in terms of their ecological validity. We applied this technique in a novel task using video stimuli of real gaze behavior to simulate a gaze-based social interaction. This enabled us to create the impression of a live interaction with another person while being able to manipulate the gaze contingency and congruency shown by the simulated interaction partner in a continuous manner. Behavioral data demonstrated that participants believed they were interacting with a real person and that systematic changes in the responsiveness of the simulated partner modulated the experience of social agency. More specifically, gaze contingency (temporal relatedness) and gaze congruency (gaze direction relative to the participant's gaze) influenced the explicit sense of being responsible for the behavior of the other. In general, our study introduces a new naturalistic task to simulate gaze-based social interactions and demonstrates that it is suitable to studying the explicit experience of social agency.

Increased functional coupling of the left amygdala and medial prefrontal cortex during the perception of communicative point-light stimuli.

Interpersonal predictive coding (IPPC) describes the behavioral phenomenon whereby seeing a communicative rather than an individual action helps to discern a masked second agent. As little is known, yet, about the neural correlates of IPPC, we conducted a functional magnetic resonance imaging study in a group of 27 healthy participants using point-light displays of moving agents embedded in distractors. We discovered that seeing communicative compared to individual actions was associated with higher activation of right superior frontal gyrus, whereas the reversed contrast elicited increased neural activation in an action observation network that was activated during all trials. Our findings, therefore, potentially indicate the formation of action predictions and a reduced demand for executive control in response to communicative actions. Further, in a regression analysis, we revealed that increased perceptual sensitivity was associated with a deactivation of the left amygdala during the perceptual task. A consecutive psychophysiological interaction analysis showed increased connectivity of the amygdala with medial prefrontal cortex in the context of communicative compared to individual actions. Thus, whereas increased amygdala signaling might interfere with task-relevant processes, increased co-activation of the amygdala and the medial prefrontal cortex in a communicative context might represent the integration of mentalizing computations.

Opioidergic Regulation of Emotional Arousal: A Combined PET-fMRI Study.

Emotions can be characterized by dimensions of arousal and valence (pleasantness). While the functional brain bases of emotional arousal and valence have been actively investigated, the neuromolecular underpinnings remain poorly understood. We tested whether the opioid and dopamine systems involved in reward and motivational processes would be associated with emotional arousal and valence. We used in vivo positron emission tomography to quantify µ-opioid receptor and type 2 dopamine receptor (MOR and D2R, respectively) availability in brains of 35 healthy adult females. During subsequent functional magnetic resonance imaging carried out to monitor hemodynamic activity, the subjects viewed movie scenes of varying emotional content. Arousal and valence were associated with hemodynamic activity in brain regions involved in emotional processing, including amygdala, thalamus, and superior temporal sulcus. Cerebral MOR availability correlated negatively with the hemodynamic responses to arousing scenes in amygdala, hippocampus, thalamus, and hypothalamus, whereas no positive correlations were observed in any brain region. D2R availability-here reliably quantified only in striatum-was not associated with either arousal or valence. These results suggest that emotional arousal is regulated by the MOR system, and that cerebral MOR availability influences brain activity elicited by arousing stimuli.

Sharing the social world via intersubject neural synchronisation.

Sociability and capability of shared mental states are hallmarks of the human species, and pursuing shared goals oftentimes requires coordinating both behaviour and mental states. Here we review recent work using indices of intersubject neural synchronisation for measuring similarity of mental states across individuals. We discuss the methodological advances and limitations in the analyses based on intersubject synchrony, and discuss how these kinds of model-free analysis techniques enable the investigation of the brain basis of complex social processes. We argue that similarity of brain activity across individuals can be used, under certain conditions, to index the similarity of their subjective states of consciousness, and thus be used for investigating brain basis of mutual understanding and cooperation.

Brain-to-brain hyperclassification reveals action-specific motor mapping of observed actions in humans.

Seeing an action may activate the corresponding action motor code in the observer. It remains unresolved whether seeing and performing an action activates similar action-specific motor codes in the observer and the actor. We used novel hyperclassification approach to reveal shared brain activation signatures of action execution and observation in interacting human subjects. In the first experiment, two "actors" performed four types of hand actions while their haemodynamic brain activations were measured with 3-T functional magnetic resonance imaging (fMRI). The actions were videotaped and shown to 15 "observers" during a second fMRI experiment. Eleven observers saw the videos of one actor, and the remaining four observers saw the videos of the other actor. In a control fMRI experiment, one of the actors performed actions with closed eyes, and five new observers viewed these actions. Bayesian canonical correlation analysis was applied to functionally realign observers' and actors' fMRI data. Hyperclassification of the seen actions was performed with Bayesian logistic regression trained on actors' data and tested with observers' data. Without the functional realignment, between-subjects accuracy was at chance level. With the realignment, the accuracy increased on average by 15 percentage points, exceeding both the chance level and the accuracy without functional realignment. The highest accuracies were observed in occipital, parietal and premotor cortices. Hyperclassification exceeded chance level also when the actor did not see her own actions. We conclude that the functional brain activation signatures underlying action execution and observation are partly shared, yet these activation signatures may be anatomically misaligned across individuals.

Differential inter-subject correlation of brain activity when kinship is a variable in moral dilemma.

Previous behavioural studies have shown that humans act more altruistically towards kin. Whether and how knowledge of genetic relatedness translates into differential neurocognitive evaluation of observed social interactions has remained an open question. Here, we investigated how the human brain is engaged when viewing a moral dilemma between genetic vs. non-genetic sisters. During functional magnetic resonance imaging, a movie was shown, depicting refusal of organ donation between two sisters, with subjects guided to believe the sisters were related either genetically or by adoption. Although 90% of the subjects self-reported that genetic relationship was not relevant, their brain activity told a different story. Comparing correlations of brain activity across all subject pairs between the two viewing conditions, we found significantly stronger inter-subject correlations in insula, cingulate, medial and lateral prefrontal, superior temporal, and superior parietal cortices, when the subjects believed that the sisters were genetically related. Cognitive functions previously associated with these areas include moral and emotional conflict regulation, decision making, and mentalizing, suggesting more similar engagement of such functions when observing refusal of altruism from a genetic sister. Our results show that mere knowledge of a genetic relationship between interacting persons robustly modulates social cognition of the perceiver.

Dissociable Roles of Cerebral µ-Opioid and Type 2 Dopamine Receptors in Vicarious Pain: A Combined PET-fMRI Study.

Neuroimaging studies have shown that seeing others in pain activates brain regions that are involved in first-hand pain, suggesting that shared neuromolecular pathways support processing of first-hand and vicarious pain. We tested whether the dopamine and opioid neurotransmitter systems involved in nociceptive processing also contribute to vicarious pain experience. We used in vivo positron emission tomography to quantify type 2 dopamine and µ-opioid receptor (D2R and MOR, respectively) availabilities in brains of 35 subjects. During functional magnetic resonance imaging, the subjects watched short movie clips depicting persons in painful and painless situations. Painful scenes activated pain-responsive brain regions including anterior insulae, thalamus and secondary somatosensory cortices, as well as posterior superior temporal sulci. MOR availability correlated negatively with the haemodynamic responses during painful scenes in anterior and posterior insulae, thalamus, secondary and primary somatosensory cortices, primary motor cortex, and superior temporal sulci. MOR availability correlated positively with orbitofrontal haemodynamic responses during painful scenes. D2R availability was not correlated with the haemodynamic responses in any brain region. These results suggest that the opioid system contributes to neural processing of vicarious pain, and that interindividual differences in opioidergic system could explain why some individuals react more strongly than others to seeing pain.

Neural mechanisms for integrating consecutive and interleaved natural events.

To understand temporally extended events, the human brain needs to accumulate information continuously across time. Interruptions that require switching of attention to other event sequences disrupt this process. To reveal neural mechanisms supporting integration of event information, we measured brain activity with functional magnetic resonance imaging (fMRI) from 18 participants while they viewed 6.5-minute excerpts from three movies (i) consecutively and (ii) as interleaved segments of approximately 50-s in duration. We measured inter-subject reliability of brain activity by calculating inter-subject correlations (ISC) of fMRI signals and analyzed activation timecourses with a general linear model (GLM). Interleaving decreased the ISC in posterior temporal lobes, medial prefrontal cortex, superior precuneus, medial occipital cortex, and cerebellum. In the GLM analyses, posterior temporal lobes were activated more consistently by instances of speech when the movies were viewed consecutively than as interleaved segments. By contrast, low-level auditory and visual stimulus features and editing boundaries caused similar activity patterns in both conditions. In the medial occipital cortex, decreases in ISC were seen in short bursts throughout the movie clips. By contrast, the other areas showed longer-lasting differences in ISC during isolated scenes depicting socially-relevant and suspenseful content, such as deception or inter-subject conflict. The areas in the posterior temporal lobes also showed sustained activity during continuous actions and were deactivated when actions ended at scene boundaries. Our results suggest that the posterior temporal and dorsomedial prefrontal cortices, as well as the cerebellum and dorsal precuneus, support integration of events into coherent event sequences. Hum Brain Mapp 38:3360-3376, 2017. © 2017 Wiley Periodicals, Inc.

Neural mechanisms supporting evaluation of others' errors in real-life like conditions.

The ability to evaluate others' errors makes it possible to learn from their mistakes without the need for first-hand trial-and-error experiences. Here, we compared functional magnetic resonance imaging activation to self-committed errors during a computer game to a variety of errors committed by others during movie clips (e.g., figure skaters falling down and persons behaving inappropriately). While viewing errors by others there was activation in lateral and medial temporal lobe structures, posterior cingulate cortex, precuneus, and medial prefrontal cortex possibly reflecting simulation and storing for future use alternative action sequences that could have led to successful behaviors. During both self- and other-committed errors activation was seen in the striatum, temporoparietal junction, and inferior frontal gyrus. These areas may be components of a generic error processing mechanism. The ecological validity of the stimuli seemed to matter, since we largely failed to see activations when subjects observed errors by another player in the computer game, as opposed to observing errors in the rich real-life like human behaviors depicted in the movie clips.

Reorganization of functionally connected brain subnetworks in high-functioning autism.

Previous functional connectivity studies have found both hypo- and hyper-connectivity in brains of individuals having autism spectrum disorder (ASD). Here we studied abnormalities in functional brain subnetworks in high-functioning individuals with ASD during free viewing of a movie containing social cues and interactions. Twenty-six subjects (13 with ASD) watched a 68-min movie during functional magnetic resonance imaging. For each subject, we computed Pearson's correlation between haemodynamic time-courses of each pair of 6-mm isotropic voxels. From the whole-brain functional networks, we derived individual and group-level subnetworks using graph theory. Scaled inclusivity was then calculated between all subject pairs to estimate intersubject similarity of connectivity structure of each subnetwork. Additional 54 individuals (27 with ASD) from the ABIDE resting-state database were included to test the reproducibility of the results. Between-group differences were observed in the composition of default-mode and ventro-temporal-limbic (VTL) subnetworks. The VTL subnetwork included amygdala, striatum, thalamus, parahippocampal, fusiform, and inferior temporal gyri. Further, VTL subnetwork similarity between subject pairs correlated significantly with similarity of symptom gravity measured with autism quotient. This correlation was observed also within the controls, and in the reproducibility dataset with ADI-R and ADOS scores. Our results highlight how the reorganization of functional subnetworks in individuals with ASD clarifies the mixture of hypo- and hyper-connectivity findings. Importantly, only the functional organization of the VTL subnetwork emerges as a marker of inter-individual similarities that co-vary with behavioral measures across all participants. These findings suggest a pivotal role of ventro-temporal and limbic systems in autism.