The effects of esketamine and treatment expectation in acute major depressive disorder (Expect): study protocol for a pharmacological fMRI study using a balanced placebo design.

BACKGROUND: Major depressive disorder (MDD) is a highly prevalent (8-15%), severely disabling disorder and is associated with enormous socioeconomic impact. Antidepressant medication for the treatment of MDD has proven effective in RCTs; however, placebo response is also substantial. Given the potential benefits of modulating the placebo response in patient care and pharmacological research, understanding the mechanisms underlying placebo response is of high clinical relevance. The placebo response is mediated by treatment expectation, i.e. an individual's belief about whether and how much they will improve as a consequence of their treatment. The mechanisms and moderators of treatment expectation effects in MDD are poorly understood. Initial brain imaging studies on placebo responses in MDD point towards the relevance of the lateral prefrontal cortex and the rostral anterior cingulate cortex (rACC). In this project, we will investigate the neural mechanisms underlying the antidepressant effects of treatment expectation associated with the fast-acting antidepressant esketamine in patients with MDD. Esketamine is an NMDA receptor antagonist inducing antidepressant effects within hours. METHODS: We will employ a fully balanced placebo design with the factors "treatment" (i.v. esketamine / placebo) and verbally induced "expectation" (high / low) combined with fMRI (resting state, emotion and reward processing paradigms) to investigate the psychological and neural mechanisms underlying the antidepressant effects of expectation, and how these interact with the pharmacological effects of esketamine. DISCUSSION: The insights gained by this project promise fundamental implications for clinical treatment and future drug trials. Unraveling the mechanisms underlying expectation effects on antidepressant treatment may inform (1) strategies to modulate these effects and thus improve assay sensitivity in RCTs and (2) novel treatment regiments aiming to maximize the synergistic effects of expectation and pharmacological treatment in the clinical care of patients with MDD. TRIAL REGISTRATION: This trial has been prospectively registered with the EU Clinical Trials Register: EudraCT-No.: 2020-000784-23 (November 17, 2020).

Multimodal speech-gesture training in patients with schizophrenia spectrum disorder: Effects on quality of life and neural processing.

Dysfunctional social communication is one of the most stable characteristics in patients with schizophrenia spectrum disorder (SSD) that severely affects quality of life. Interpreting abstract speech and integrating nonverbal information is particularly affected. Considering the difficulty to treat communication dysfunctions with usual intervention, we investigated the possibility to apply a multimodal speech-gesture (MSG) training. In the MSG training, we offered 8 sessions (60 min each) including perceptive and expressive tasks as well as meta-learning elements and transfer exercises to 29 patients with SSD. In a within-group crossover design, patients were randomized to a TAU-first (treatment as usual first, then MSG training) group (N = 20) or a MSG-first (MSG training first, then TAU only) group (N = 9), and were compared to healthy controls (N = 17). Outcomes were quality of life and related changes in the neural processing of abstract speech-gesture information, which were measured pre-post training through standardized psychological questionnaires and functional Magnetic Resonance Imaging, respectively. Pre-training, patients showed reduced quality of life as compared to controls but improved significantly during the training. Strikingly, this improvement was correlated with neural activation changes in the middle temporal gyrus for the processing of abstract multimodal content. Improvement during training, self-report measures and ratings of relatives confirmed the MSG-related changes. Together, we provide first promising results of a novel multimodal speech-gesture training for patients with schizophrenia. We could link training induced changes in speech-gesture processing to changes in quality of life, demonstrating the relevance of intact communication skills and gesture processing for well-being.

Humor in Psychiatry: Lessons From Neuroscience, Psychopathology, and Treatment Research.

Humor is a ubiquitous human characteristic that is socially motivated at its core and has a broad range of significant positive effects on emotional well-being and interpersonal relationships. Simultaneously, however, impairments in humor abilities have often been described in close association with the occurrence and course of neuropsychiatric disorders, such as schizophrenia, social anxiety, or depression. In the past decade, research in the neuroimaging and psychiatric domain has substantially progressed to (i) characterize impaired humor as an element of psychopathology, and (ii) shed light on the neurobiological mechanisms underlying the role of humor in neuropsychiatric diseases. However, (iii) targeted interventions using concepts of positive psychology have revealed first evidence that a systematic training and/or a potential reactivation of humor-related skills can improve rehabilitative outcome in neuropsychiatric patient groups. Here, we sought to integrate evidence from neuroscience, as well as from psychopathology and treatment research to shed more light on the role of humor in psychiatry. Based on these considerations, we provide directions for future research and application in mental health services, focusing on the question of how our scientific understanding of humor can provide the basis for psychological interventions that foster positive attitudes and well-being.

Antagonism between brain regions relevant for cognitive control and emotional memory facilitates the generation of humorous ideas.

The ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the hypoactivation of frontal brain regions is associated with an hyperactivation in the amygdala and vice versa. This antagonistic connectivity is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

The Relationship Between Different Aspects of Theory of Mind and Symptom Clusters in Psychotic Disorders: Deconstructing Theory of Mind Into Cognitive, Affective, and Hyper Theory of Mind.

Background: Several meta-analyses highlight pronounced problems in general Theory of Mind (ToM), the ability to infer other persons' mental states, in patients with psychosis in comparison to non-clinical controls. In addition, first studies suggest associations between Hyper-ToM, an exaggerated inference of mental states to others, and delusions. Research on different ToM subtypes (Cognitive ToM, Affective ToM, and Hyper-ToM) and symptom clusters of psychosis (positive, negative, and disorganized symptoms) have gathered conflicting findings. Thus, the present study examined group differences between patients with psychosis and non-clinical controls concerning Cognitive ToM/Affective ToM and Hyper-ToM. Further, the association between ToM subtypes and symptom clusters (positive, negative, and disorganized symptoms) were examined. Methods: Patients with psychotic disorders (n = 64, 1/3 with present delusions indicated by a minimum score of four in the PANSS P1 item) and non-clinical controls (n = 21) were examined with assessments of Cognitive ToM and Affective ToM abilities and Hyper-ToM errors using the Frith-Happé animations. Psychopathology was assessed using the Positive and Negative Syndrome Scale. Results: Patients with psychosis presented more pronounced problems in Cognitive and Affective ToM in comparison to non-clinical controls, whereas there were no group differences with regard to Hyper-ToM errors. Furthermore, deficits in Cognitive ToM were associated with general delusions, whereas problems in Affective ToM were associated with negative and disorganized symptoms. In addition, there was no association between Hyper-ToM errors and any symptoms when controlling for years of education. Conclusions: Our findings suggest that deficits in ToM subtypes might not be directly related to delusions and positive symptoms and are in line with more recently developed cognitive models of delusions. In addition, our results support the well-established finding of associations between ToM alterations and negative or disorganized symptoms. Our results shed light on the role of different dimensions of ToM in specific symptoms of psychosis.

Characterizing the theory of mind network in schizophrenia reveals a sparser network structure.

Impaired social functioning is a hallmark of schizophrenia and altered functional integration between distant brain regions are expected to account for signs and symptoms of the disorder. The functional neuroarchitecture of a network relevant for social functioning, the mentalizing network, is however poorly understood. In this study we examined dysfunctions of the mentalizing network in patients with schizophrenia compared to healthy controls via dynamic causal modelling and an interactive social decision-making game. Network characteristics were analyzed on a single subject basis whereas graph theoretic metrics such as in-degree, out-degree and edge-connectivity per network node were compared between the groups. The results point to a sparser network structure in patients with schizophrenia and highlight the dorsomedial prefrontal cortex as a disconnected network hub receiving significantly less input from other brain regions in the network. Further analyses suggest that integrating pathways from the right and the left temporo-parietal junction into the dorsomedial prefrontal cortex were less frequently found in patients with schizophrenia. Brain and behavior analyses further suggest that the connectivity-intactness within the entire network is associated with functional interpersonal behavior during the task. Thus, the neurobiological alterations within the mentalizing network in patients with schizophrenia point to a specific integration deficit between core brain regions underlying the generation of higher-order representations and thereby provide a potential treatment target.

Cognitive and emotional empathy in patients with schizophrenia spectrum disorders: A replication and extension study.

Impairments of social cognition are defined as core features in the pathology of schizophrenia. In a study by Lehmann and colleagues (2014), patients with schizophrenia have been shown to demonstrate a diminished capacity to understand others' emotions (i.e. cognitive empathy), but a preserved ability to share or feel the emotional states of others (i.e. emotional empathy). Here, we report on an independent replication study investigating cognitive and emotional empathy in 35 patients with schizophrenia spectrum disorders and a matched control group, which 1) confirms that patients demonstrate preserved emotional empathy in self-report and behavioural measurements, and 2) reveals associations between emotional empathy and social anhedonia in patients.

Impaired Right Temporoparietal Junction-Hippocampus Connectivity in Schizophrenia and Its Relevance for Generating Representations of Other Minds.

Schizophrenia is associated with impaired and exaggerated Theory of Mind processes, pointing on alterations in generating a representation of another person's mind. Despite recent work on healthy subjects suggesting that a coupling between the right temporoparietal junction (rTPJ) and the hippocampus is relevant for building representations of others' intentions, the neural basis of related dysfunctions in patients with schizophrenia remains unclear. Therefore, we used structural and functional magnetic resonance imaging together with a modified prisoner's dilemma game to test the hypotheses, that patients show dysfunctional social updating on behavioral level accompanied by altered rTPJ-hippocampus coupling on a functional and a structural level. During the task, 31 patients with schizophrenia and 20 healthy controls interacted with 3 playing partners, who behaved according to stable strategies competitively, cooperatively, or randomly. Our data show that patients adapted their social behavior less flexibly to the playing partners than healthy controls, indicating differences in forming mental representations of the counterparts' intentions. Patients showed lower functional connectivity between the rTPJ and temporal lobe regions such as the hippocampus, the fusiform gyrus, and the middle temporal gyrus, indicating that in patients the rTPJ fails to integrate memory-informed processing streams during mental state inferences. Remarkably, the rTPJ-hippocampus coupling accounted for the participants' adaptive social behavior in the task, suggesting that a neural pathway relevant for updating social knowledge and forming forward predictions in social interactions is altered in schizophrenia.

Frontal hypoactivation and alterations in the reward-system during humor processing in patients with schizophrenia spectrum disorders.

Humor is a ubiquitous human ability with important implications for both social and emotional functioning. Patients with neuropsychiatric disorders, such as schizophrenia, experience difficulties in the comprehension and appreciation of humor. However, the specific neural mechanisms underlying these deficits are unknown. In the current study, we sought to elucidate the neural correlates of humor processing in patients with schizophrenia spectrum disorders (SSD). Functional Magnetic Resonance Imaging (fMRI) was used in thirty-one patients with SSD and a control group, performing a humor processing paradigm. Both regional brain activation and parametric modulation of brain responses via subjective funniness ratings were collected during the scanning procedure. On a neural level, large overlaps in fronto-temporal brain activation was found in both groups. However, patients compared to healthy control subjects showed attenuated responses in frontal brain regions, including the anterior cingulate cortex, medial prefrontal cortex (mPFC), superior frontal gyrus and middle frontal gyrus, as well as in the striatum (i.e. caudate nucleus, putamen). Furthermore, parametric modulation of subjective funniness ratings resulted in attenuated responses in the mPFC, bilateral insula, and left hippocampus. Analysis of functional connectivity revealed alterations in mPFC-caudate nucleus coupling in patients with SSD, which might reflect impairments in reward-related processing. Notably, alterations in mPFC-caudate nucleus coupling in patients were significantly associated to subjective funniness ratings. Our results extend previous findings demonstrating the relevance of frontal hypoactivation for humor processing impairments in patients with SSD and first point towards alterations in humor appreciation processes.

The role of the right temporo-parietal junction in social decision-making.

Identifying someone else's noncooperative intentions can prevent exploitation in social interactions. Hence, the inference of another person's mental state might be most pronounced in order to improve social decision-making. Here, we tested the hypothesis that brain regions associated with Theory of Mind (ToM), particularly the right temporo-parietal junction (rTPJ), show higher neural responses when interacting with a selfish person and that the rTPJ-activity as well as cooperative tendencies will change over time. We used functional magnetic resonance imaging (fMRI) and a modified prisoner's dilemma game in which 20 participants interacted with three fictive playing partners who behaved according to stable strategies either competitively, cooperatively or randomly during seven interaction blocks. The rTPJ and the posterior-medial prefrontal cortex showed higher activity during the interaction with a competitive compared with a cooperative playing partner. Only the rTPJ showed a high response during an early interaction phase, which preceded participants increase in defective decisions. Enhanced functional connectivity between the rTPJ and the left hippocampus suggests that social cognition and learning processes co-occur when behavioral adaptation seems beneficial.

Personality modulates amygdala and insula connectivity during humor appreciation: An event-related fMRI study.

Previous research and theory implicate that personality traits, such as extraversion and neuroticism, influence the processing of humor, as indicated by alterations in the activation of fronto-temporal and mesocorticolimbic brain regions during humor processing. In the current study, we sought to complement these findings by testing whether inter-individual differences in functional connectivity of humor-related brain regions are modulated by stable personality characteristics during humor processing. Using fMRI techniques, we studied 19 healthy subjects during the processing of standardized humorous and neutral cartoons. In order to isolate the specific effects of humor appreciation, subjective funniness ratings, collected during the scanning procedure, were implemented in the analysis as parametric modulation. Two distinct clusters in the right amygdala and the left insula were identified. Seed-to-voxel connectivity analysis investigating the effects of personality on inter-individual differences in functional connectivity revealed that amygdala and insula connectivity with brain areas previously related to humor comprehension (e.g. middle temporal gyrus) and appreciation (e.g. caudate nucleus) were significantly modulated by personality dimensions. These results underscore the sensitivity of humor processing to moderating influences, such as personality, and call attention to the importance of brain connectivity measures for the investigation of inter-individual differences in the processing of humor.