Noninvasive brain stimulation in autism: review and outlook for personalized interventions in adult patients.

Noninvasive brain stimulation (NIBS) has been increasingly investigated during the last decade as a treatment option for persons with autism spectrum disorder (ASD). Yet, previous studies did not reach a consensus on a superior treatment protocol or stimulation target. Persons with ASD often suffer from social isolation and high rates of unemployment, arising from difficulties in social interaction. ASD involves multiple neural systems involved in perception, language, and cognition, and the underlying brain networks of these functional domains have been well documented. Aiming to provide an overview of NIBS effects when targeting these neural systems in late adolescent and adult ASD, we conducted a systematic search of the literature starting at 631 non-duplicate publications, leading to six studies corresponding with inclusion and exclusion criteria. We discuss these studies regarding their treatment rationale and the accordingly chosen methodological setup. The results of these studies vary, while methodological advances may allow to explain some of the variability. Based on these insights, we discuss strategies for future clinical trials to personalize the selection of brain stimulation targets taking into account intersubject variability of brain anatomy as well as function.

Using second-person neuroscience to elucidate the mechanisms of social interaction.

Although a large proportion of our lives are spent participating in social interactions, the investigation of the neural mechanisms supporting these interactions has largely been restricted to situations of social observation - that is, situations in which an individual observes a social stimulus without opportunity for interaction. In recent years, efforts have been made to develop a truly social, or 'second-person', neuroscientific approach to these investigations in which neural processes are examined within the context of a real-time reciprocal social interaction. These developments have helped to elucidate the behavioural and neural mechanisms of social interactions; however, further theoretical and methodological innovations are still needed. Findings to date suggest that the neural mechanisms supporting social interaction differ from those involved in social observation and highlight a role of the so-called 'mentalizing network' as important in this distinction. Taking social interaction seriously may also be particularly important for the advancement of the neuroscientific study of different psychiatric conditions.

Social belonging: brain structure and function is linked to membership in sports teams, religious groups, and social clubs.

Human behavior across the life span is driven by the psychological need to belong, right from kindergarten to bingo nights. Being part of social groups constitutes a backbone for communal life and confers many benefits for the physical and mental health. Capitalizing on the neuroimaging and behavioral data from ∼40,000 participants from the UK Biobank population cohort, we used structural and functional analyses to explore how social participation is reflected in the human brain. Across 3 different types of social groups, structural analyses point toward the variance in ventromedial prefrontal cortex, fusiform gyrus, and anterior cingulate cortex as structural substrates tightly linked to social participation. Functional connectivity analyses not only emphasized the importance of default mode and limbic network but also showed differences for sports teams and religious groups as compared to social clubs. Taken together, our findings establish the structural and functional integrity of the default mode network as a neural signature of social belonging.

Spatio-temporal dynamics of oscillatory brain activity during the observation of actions and interactions between point-light agents.

Predicting actions from non-verbal cues and using them to optimise one's response behaviour (i.e. interpersonal predictive coding) is essential in everyday social interactions. We aimed to investigate the neural correlates of different cognitive processes evolving over time during interpersonal predictive coding. Thirty-nine participants watched two agents depicted by moving point-light stimuli while an electroencephalogram (EEG) was recorded. One well-recognizable agent performed either a 'communicative' or an 'individual' action. The second agent either was blended into a cluster of noise dots (i.e. present) or was entirely replaced by noise dots (i.e. absent), which participants had to differentiate. EEG amplitude and coherence analyses for theta, alpha and beta frequency bands revealed a dynamic pattern unfolding over time: Watching communicative actions was associated with enhanced coupling within medial anterior regions involved in social and mentalising processes and with dorsolateral prefrontal activation indicating a higher deployment of cognitive resources. Trying to detect the agent in the cluster of noise dots without having seen communicative cues was related to enhanced coupling in posterior regions for social perception and visual processing. Observing an expected outcome was modulated by motor system activation. Finally, when the agent was detected correctly, activation in posterior areas for visual processing of socially relevant features was increased. Taken together, our results demonstrate that it is crucial to consider the temporal dynamics of social interactions and of their neural correlates to better understand interpersonal predictive coding. This could lead to optimised treatment approaches for individuals with problems in social interactions.

[Antipsychotic Treatment of Alcohol Withdrawal Syndrome with Focus on Delirium Tremens: a Systematic Review]. / Systematische Übersichtsarbeit Antipsychotische Behandlung des Alkoholentzugssyndroms: Fokus Delirium Tremens.

BACKGROUND: Delirium tremens (DT) is a common complication of alcohol withdrawal. Pharmacological treatment of hospitalized patients with DT is important in addiction medicine but also in other medical disciplines where DT can occur as a complication of hospitalization. Patients suffering from DT require treatment with benzodiazepines (short-acting benzodiazepines for elderly patients to reduce accumulation), and in cases of psychotic symptoms, treatment with antipsychotics. Benzodiazepines are a first-line treatment for DT. A specific guideline for the use of antipsychotics has yet to be developed. This review discusses the current guidelines and literature on the antipsychotic treatment options in DT. AIM: Systematic presentation of relevant antipsychotics for the treatment of DT. METHODS: A systematic literature search was conducted using Scopus and PubMed. The last search was conducted on May 22nd 2022. Original articles and reviews on antipsychotic treatment in alcohol withdrawal and DT were included in this review. Further, international guidelines were also considered. The review was registered using the PROSPERO database (https://www.crd.york.ac.uk/prospero/); CRD42021264611. RESULTS: Haloperidol is mainly recommended for use in the intensive care unit. There is little literature on the use of atypical antipsychotics to treat DT. Treatment with antipsychotics always should be combined with benzodiazepines, and physicians should watch out for complications like neuroleptic malignant syndrome, QTc interval prolongation, extrapyramidal symptoms and withdrawal seizures resulting from lowering the threshold for seizures. CONCLUSION: Antipsychotic treatment should depend on the experience of the physician. Beside haloperidol, no other clear recommendations are available.

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.

Sleep Deprivation Selectively Upregulates an Amygdala-Hypothalamic Circuit Involved in Food Reward.

Sleep loss is associated with increased obesity risk, as demonstrated by correlations between sleep duration and change in body mass index or body fat percentage. Whereas previous studies linked this weight gain to disturbed endocrine parameters after sleep deprivation or restriction, neuroimaging studies revealed upregulated neural processing of food rewards after sleep loss in reward-processing areas such as the anterior cingulate cortex, ventral striatum, and insula. To address this ongoing debate between hormonal versus hedonic factors underlying sleep-loss-associated weight gain, we rigorously tested the association between sleep deprivation and food cue processing using high-resolution fMRI and assessment of hormones. After taking blood samples from 32 lean, healthy, human male participants, they underwent fMRI while performing a neuroeconomic, value-based decision-making task with snack food and trinket rewards following a full night of habitual sleep and a night of sleep deprivation in a repeated-measures crossover design. We found that des-acyl ghrelin concentrations were increased after sleep deprivation compared with habitual sleep. Despite similar hunger ratings due to fasting in both conditions, participants were willing to spend more money on food items only after sleep deprivation. Furthermore, fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. Behavioral and fMRI results were not significantly correlated with changes in acyl, des-acyl, or total ghrelin concentrations. Our results suggest that increased food valuation after sleep loss might be due to hedonic rather than hormonal mechanisms.SIGNIFICANCE STATEMENT Epidemiological studies suggest an association between overweight and reduced nocturnal sleep, but the relative contributions of hedonic and hormonal factors to overeating after sleep loss are a matter of ongoing controversy. Here, we tested the association between sleep deprivation and food cue processing in a repeated-measures crossover design using fMRI. We found that willingness to pay increased for food items only after sleep deprivation. fMRI data paralleled this behavioral finding, revealing a food-reward-specific upregulation of hypothalamic valuation signals and amygdala-hypothalamic coupling after a single night of sleep deprivation. However, there was no evidence for hormonal modulations of behavioral or fMRI findings. Our results suggest that increased food valuation after sleep loss is due to hedonic rather than hormonal mechanisms.

Schema therapy versus cognitive behavioral therapy versus individual supportive therapy for depression in an inpatient and day clinic setting: study protocol of the OPTIMA-RCT.

BACKGROUND: Major depressive disorder represents (MDD) a major cause of disability and disease burden. Beside antidepressant medication, psychotherapy is a key approach of treatment. Schema therapy has been shown to be effective in the treatment of psychiatric disorders, especially personality disorders, in a variety of settings and patient groups. Nevertheless, there is no evidence on its effectiveness for MDD in an inpatient nor day clinic setting and little is known about the factors that drive treatment response in such a target group. METHODS: In the current protocol, we outline OPTIMA (OPtimized Treatment Identification at the MAx Planck Institute): a single-center randomized controlled trial of schema therapy as a treatment approach for MDD in an inpatient and day clinic setting. Over the course of 7 weeks, we compare schema therapy with cognitive behavioral therapy and individual supportive therapy, conducted in individual and group sessions and with no restrictions regarding concurrent antidepressant medication, thus approximating real-life treatment conditions. N = 300 depressed patients are included. All study therapists undergo a specific training and supervision and therapy adherence is assessed. Primary outcome is depressive symptom severity as self-assessment (Beck Depression Inventory-II) and secondary outcomes are clinical ratings of MDD (Montgomery-Asberg Depression Rating Scale), recovery rates after 7 weeks according to the Munich-Composite International Diagnostic Interview, general psychopathology (Brief Symptom Inventory), global functioning (World Health Organization Disability Assessment Schedule), and clinical parameters such as dropout rates. Further parameters on a behavioral, cognitive, psychophysiological, and biological level are measured before, during and after treatment and in 2 follow-up assessments after 6 and 24 months after end of treatment. DISCUSSION: To our knowledge, the OPTIMA-Trial is the first to investigate the effectiveness of schema therapy as a treatment approach of MDD, to investigate mechanisms of change, and explore predictors of treatment response in an inpatient and day clinic setting by using such a wide range of parameters. Insights from OPTIMA will allow more integrative approaches of psychotherapy of MDD. Especially, the identification of intervention-specific markers of treatment response can improve evidence-based clinical decision for individualizing treatment. TRIAL REGISTRATION: Identifier on clinicaltrials.gov : NCT03287362 ; September, 12, 2017.

The biological classification of mental disorders (BeCOME) study: a protocol for an observational deep-phenotyping study for the identification of biological subtypes.

BACKGROUND: A major research finding in the field of Biological Psychiatry is that symptom-based categories of mental disorders map poorly onto dysfunctions in brain circuits or neurobiological pathways. Many of the identified (neuro) biological dysfunctions are "transdiagnostic", meaning that they do not reflect diagnostic boundaries but are shared by different ICD/DSM diagnoses. The compromised biological validity of the current classification system for mental disorders impedes rather than supports the development of treatments that not only target symptoms but also the underlying pathophysiological mechanisms. The Biological Classification of Mental Disorders (BeCOME) study aims to identify biology-based classes of mental disorders that improve the translation of novel biomedical findings into tailored clinical applications. METHODS: BeCOME intends to include at least 1000 individuals with a broad spectrum of affective, anxiety and stress-related mental disorders as well as 500 individuals unaffected by mental disorders. After a screening visit, all participants undergo in-depth phenotyping procedures and omics assessments on two consecutive days. Several validated paradigms (e.g., fear conditioning, reward anticipation, imaging stress test, social reward learning task) are applied to stimulate a response in a basic system of human functioning (e.g., acute threat response, reward processing, stress response or social reward learning) that plays a key role in the development of affective, anxiety and stress-related mental disorders. The response to this stimulation is then read out across multiple levels. Assessments comprise genetic, molecular, cellular, physiological, neuroimaging, neurocognitive, psychophysiological and psychometric measurements. The multilevel information collected in BeCOME will be used to identify data-driven biologically-informed categories of mental disorders using cluster analytical techniques. DISCUSSION: The novelty of BeCOME lies in the dynamic in-depth phenotyping and omics characterization of individuals with mental disorders from the depression and anxiety spectrum of varying severity. We believe that such biology-based subclasses of mental disorders will serve as better treatment targets than purely symptom-based disease entities, and help in tailoring the right treatment to the individual patient suffering from a mental disorder. BeCOME has the potential to contribute to a novel taxonomy of mental disorders that integrates the underlying pathomechanisms into diagnoses. TRIAL REGISTRATION: Retrospectively registered on June 12, 2019 on ClinicalTrials.gov (TRN: NCT03984084).

"Through others we become ourselves": The dialectics of predictive coding and active inference.

Thinking through other minds creatively situates the free-energy principle within real-life cultural processes, thereby enriching both sociocultural theories and Bayesian accounts of cognition. Here, shifting the attention from thinking-through to becoming-with, we suggest complementing such an account by focusing on the empirical, computational, and conceptual investigation of the multiscale dynamics of social interaction.

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.

Role of the 5-HT2A Receptor in Self- and Other-Initiated Social Interaction in Lysergic Acid Diethylamide-Induced States: A Pharmacological fMRI Study.

Distortions of self-experience are critical symptoms of psychiatric disorders and have detrimental effects on social interactions. In light of the immense need for improved and targeted interventions for social impairments, it is important to better understand the neurochemical substrates of social interaction abilities. We therefore investigated the pharmacological and neural correlates of self- and other-initiated social interaction. In a double-blind, randomized, counterbalanced, crossover study 24 healthy human participants (18 males and 6 females) received either (1) placebo + placebo, (2) placebo + lysergic acid diethylamide (LSD; 100 µg, p.o.), or (3) ketanserin (40 mg, p.o.) + LSD (100 µg, p.o.) on three different occasions. Participants took part in an interactive task using eye-tracking and functional magnetic resonance imaging completing trials of self- and other-initiated joint and non-joint attention. Results demonstrate first, that LSD reduced activity in brain areas important for self-processing, but also social cognition; second, that change in brain activity was linked to subjective experience; and third, that LSD decreased the efficiency of establishing joint attention. Furthermore, LSD-induced effects were blocked by the serotonin 2A receptor (5-HT2AR) antagonist ketanserin, indicating that effects of LSD are attributable to 5-HT2AR stimulation. The current results demonstrate that activity in areas of the "social brain" can be modulated via the 5-HT2AR thereby pointing toward this system as a potential target for the treatment of social impairments associated with psychiatric disorders.SIGNIFICANCE STATEMENT Distortions of self-representation and, potentially related to this, dysfunctional social cognition are central hallmarks of various psychiatric disorders and critically impact disease development, progression, treatment, as well as real-world functioning. However, these deficits are insufficiently targeted by current treatment approaches. The administration of lysergic acid diethylamide (LSD) in combination with functional magnetic resonance imaging and real-time eye-tracking offers the unique opportunity to study alterations in self-experience, their relation to social cognition, and the underlying neuropharmacology. Results demonstrate that LSD alters self-experience as well as basic social cognition processing in areas of the "social brain". Furthermore, these alterations are attributable to 5-HT2A receptor stimulation, thereby pinpointing toward this receptor system in the development of pharmacotherapies for sociocognitive deficits in psychiatric disorders.

The promise of two-person neuroscience for developmental psychiatry: using interaction-based sociometrics to identify disorders of social interaction.

Social interactions are fundamental for human development, and disordered social interactions are pervasive in many psychiatric disorders. Recent advances in 'two-person neuroscience' have provided new tools for characterising social interactions. Accordingly, interaction-based 'sociometrics' hold great promise for developmental psychology and psychiatry, particularly in the early identification of social disorders. DECLARATION OF INTEREST: None.

Cognitive emotion regulation modulates the balance of competing influences on ventral striatal aversive prediction error signals.

Cognitive emotion regulation (CER) is a critical human ability to face aversive emotional stimuli in a flexible way, via recruitment of specific prefrontal brain circuits. Animal research reveals a central role of ventral striatum in emotional behavior, for both aversive conditioning, with striatum signaling aversive prediction errors (aPE), and for integrating competing influences of distinct striatal inputs from regions such as the prefrontal cortex (PFC), amygdala, hippocampus and ventral tegmental area (VTA). Translating these ventral striatal findings from animal research to human CER, we hypothesized that successful CER would affect the balance of competing influences of striatal afferents on striatal aPE signals, in a way favoring PFC as opposed to 'subcortical' (i.e., non-isocortical) striatal inputs. Using aversive Pavlovian conditioning with and without CER during fMRI, we found that during CER, superior regulators indeed reduced the modulatory impact of 'subcortical' striatal afferents (hippocampus, amygdala and VTA) on ventral striatal aPE signals, while keeping the PFC impact intact. In contrast, inferior regulators showed an opposite pattern. Our results demonstrate that ventral striatal aPE signals and associated competing modulatory inputs are critical mechanisms underlying successful cognitive regulation of aversive emotions in humans.

Functional changes of the reward system underlie blunted response to social gaze in cocaine users.

Social interaction deficits in drug users likely impede treatment, increase the burden of the affected families, and consequently contribute to the high costs for society associated with addiction. Despite its significance, the neural basis of altered social interaction in drug users is currently unknown. Therefore, we investigated basal social gaze behavior in cocaine users by applying behavioral, psychophysiological, and functional brain-imaging methods. In study I, 80 regular cocaine users and 63 healthy controls completed an interactive paradigm in which the participants' gaze was recorded by an eye-tracking device that controlled the gaze of an anthropomorphic virtual character. Valence ratings of different eye-contact conditions revealed that cocaine users show diminished emotional engagement in social interaction, which was also supported by reduced pupil responses. Study II investigated the neural underpinnings of changes in social reward processing observed in study I. Sixteen cocaine users and 16 controls completed a similar interaction paradigm as used in study I while undergoing functional magnetic resonance imaging. In response to social interaction, cocaine users displayed decreased activation of the medial orbitofrontal cortex, a key region of reward processing. Moreover, blunted activation of the medial orbitofrontal cortex was significantly correlated with a decreased social network size, reflecting problems in real-life social behavior because of reduced social reward. In conclusion, basic social interaction deficits in cocaine users as observed here may arise from altered social reward processing. Consequently, these results point to the importance of reinstatement of social reward in the treatment of stimulant addiction.

Beyond Autism: Introducing the Dialectical Misattunement Hypothesis and a Bayesian Account of Intersubjectivity.

Drawing on sociocultural theories and Bayesian accounts of brain function, in this article we construe psychiatric conditions as disorders of social interaction to fully account for their complexity and dynamicity across levels of description and temporal scales. After an introduction of the theoretical underpinnings of our integrative approach, we take autism spectrum conditions (ASC) as a paradigm example and discuss how neurocognitive hypotheses can be translated into a Bayesian formulation, i.e., in terms of predictive processing and active inference. We then argue that consideration of individuals (even within a Bayesian framework) will not be enough for a comprehensive understanding of psychiatric conditions and consequently put forward the dialectical misattunement hypothesis, which views psychopathology not merely as disordered function within single brains but also as a dynamic interpersonal mismatch that encompasses various levels of description. Moving from a mere comparison of groups, i.e., "healthy" persons versus "patients," to a fine-grained analysis of social interactions within dyads and groups of individuals will open new avenues and may allow to avoid an overly neurocentric scope in psychiatric research as well as help to reduce social exclusion.

Contempt - Where the modularity of the mind meets the modularity of the brain?

"Contempt" is proposed to be a unique aspect of human nature, yet a non-natural kind. Its psychological construct is framed as a sentiment emerging from a stratification of diverse basic emotions and dispositional attitudes. Accordingly, "contempt" might transcend traditional conceptual levels in social psychology, including experience and recognition of emotion, dyadic and group dynamics, context-conditioned attitudes, time-enduring personality structure, and morality. This strikes us as a modern psychological account of a high-level, social-affective cognitive facet that joins forces with recent developments in the social neuroscience by drawing psychological conclusions from brain biology.