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Abstract Deviations in syntax production have been well documented in schizophrenia spectrum disorders (SSD). Recently, we have shown evidence for transdiagnostic subtypes of syntactic complexity and diversity. However, there is a lack of studies exploring brain structural correlates of syntax across diagnoses. We assessed syntactic complexity and diversity of oral language production using four Thematic Apperception Test pictures in a sample of N = 87 subjects (n = 24 major depressive disorder (MDD), n = 30 SSD patients both diagnosed according to DSM-IV-TR, and n = 33 healthy controls (HC)). General linear models were used to investigate the association of syntax with gray matter volume (GMV), fractional anisotropy (FA), axial (AD), radial (RD), and mean diffusivity (MD). Age, sex, total intracranial volume, group, interaction of group and syntax were covariates of no interest. Syntactic diversity was positively correlated with the GMV of the right medial pre- and postcentral gyri and with the FA of the left superior-longitudinal fasciculus (temporal part). Conversely, the AD of the left cingulum bundle and the forceps minor were negatively correlated with syntactic diversity. The AD of the right inferior-longitudinal fasciculus was positively correlated with syntactic complexity. Negative associations were observed between syntactic complexity and the FA of the left cingulum bundle, the right superior-longitudinal fasciculus, and the AD of the forceps minor and the left uncinate fasciculus. Our study showed brain structural correlates of syntactic complexity and diversity across diagnoses and HC. This contributes to a comprehensive understanding of the interplay between linguistic and neural substrates in syntax production in psychiatric disorders and HC.

Abstract Background Emotional disorders such as depression and anxiety disorders share substantial similarities in their etiology and treatment. In recent decades, these commonalities have been increasingly recognized in classification systems and treatment programs crossing diagnostic boundaries. Methods To examine the prospective effects of different transdiagnostic markers on relevant treatment outcomes, we plan to track a minimum of N = 200 patients with emotional disorders during their routine course of cognitive behavioral therapy at two German outpatient clinics. We will collect a wide range of transdiagnostic markers, ranging from basic perceptual processes and self-report measures to complex behavioral and neurobiological indicators, before entering therapy. Symptoms and psychopathological processes will be recorded before entering therapy, between the 20th and 24th therapy session, and at the end of therapy. Discussion Our results could help to identify transdiagnostic markers with high predictive power, but also provide deeper insights into which patient groups with which symptom clusters are less likely to benefit from therapy, and for what reasons. Trial Registration The trial was preregistered at the German Clinical Trial Register (DRKS-ID: DRKS00031206; 2023–05-09).

IntroductionTo interact with the environment, it is crucial to distinguish between sensory information that is externally generated and inputs that are self-generated. The sensory consequences of one's own movements tend to induce attenuated behavioral- and neural responses compared to externally generated inputs. We propose a computational model of sensory attenuation (SA) based on Bayesian Causal Inference, where SA occurs when an internal cause for sensory information is inferred.MethodsExperiment 1investigates sensory attenuation during a stroking movement. Tactile stimuli on the stroking finger were suppressed, especially when they were predictable. Experiment 2 showed impaired delay detection between an arm movement and a video of the movement when participants were moving vs. when their arm was moved passively. We reconsider these results from the perspective of Bayesian Causal Inference (BCI). Using a hierarchical Markov Model (HMM) and variational message passing, we first qualitatively capture patterns of task behavior and sensory attenuation in simulations. Next, we identify participant-specific model parameters for both experiments using optimization.ResultsA sequential BCI model is well equipped to capture empirical patterns of SA across both datasets. Using participant-specific optimized model parameters, we find a good agreement between data and model predictions, with the model capturing both tactile detections in Experiment 1 and delay detections in Experiment 2.DiscussionBCI is an appropriate framework to model sensory attenuation in humans. Computational models of sensory attenuation may help to bridge the gap across different sensory modalities and experimental paradigms and may contribute towards an improved description and understanding of deficits in specific patient groups (e.g. schizophrenia).

Summary: Tactile sensitivity on a limb is reduced during movement. This tactile suppression results presumably from central predictive mechanisms that downregulate sensations caused during voluntary action. Suppression also occurs during passive movements, indicating a role for peripheral mechanisms, questioning the predictive nature of suppression. Yet, predictions existing beyond the motor domain (non-motor predictions) can also modulate tactile suppression. This study aimed to disentangle central motor predictive and peripheral feedback mechanisms while accounting for non-motor predictions. Participants detected tactile stimuli on their limb shortly before it moved in an active or passive manner. Passive movements were either fully (100%) or partially (50%) predictable. We found tactile suppression during both active and passive movements irrespective of whether the passive movements were predictable. Importantly, tactile suppression was stronger in active than passive movements highlighting the specific role of central predictive mechanisms.

Data-based predictions of individual Cognitive Behavioral Therapy (CBT) treatment response are a fundamental step towards precision medicine. Past studies demonstrated only moderate prediction accuracy (i.e. ability to discriminate between responders and non-responders of a given treatment) when using clinical routine data such as demographic and questionnaire data, while neuroimaging data achieved superior prediction accuracy. However, these studies may be considerably biased due to very limited sample sizes and bias-prone methodology. Adequately powered and cross-validated samples are a prerequisite to evaluate predictive performance and to identify the most promising predictors. We therefore analyzed resting state functional magnet resonance imaging (rs-fMRI) data from two large clinical trials to test whether functional neuroimaging data continues to provide good prediction accuracy in much larger samples. Data came from two distinct German multicenter studies on exposure-based CBT for anxiety disorders, the Protect-AD and SpiderVR studies. We separately and independently preprocessed baseline rs-fMRI data from n = 220 patients (Protect-AD) and n = 190 patients (SpiderVR) and extracted a variety of features, including ROI-to-ROI and edge-functional connectivity, sliding-windows, and graph measures. Including these features in sophisticated machine learning pipelines, we found that predictions of individual outcomes never significantly differed from chance level, even when conducting a range of exploratory post-hoc analyses. Moreover, resting state data never provided prediction accuracy beyond the sociodemographic and clinical data. The analyses were independent of each other in terms of selecting methods to process resting state data for prediction input as well as in the used parameters of the machine learning pipelines, corroborating the external validity of the results. These similar findings in two independent studies, analyzed separately, urge caution regarding the interpretation of promising prediction results based on neuroimaging data from small samples and emphasizes that some of the prediction accuracies from previous studies may result from overestimation due to homogeneous data and weak cross-validation schemes. The promise of resting-state neuroimaging data to play an important role in the prediction of CBT treatment outcomes in patients with anxiety disorders remains yet to be delivered.

Abstract Core symptoms in patients with schizophrenia spectrum disorders (SSD), like hallucinations or ego-disturbances, have been associated with a failure of internal forward models to predict the sensory outcomes of self-generated actions. Importantly, forward model predictions must also be able to flexibly recalibrate to changing environmental conditions, for example to account for additional delays between action and outcome. We investigated whether transcranial direct current stimulation (tDCS) can be used to improve these sensorimotor temporal recalibration mechanisms in patients and healthy individuals. While receiving tDCS on the cerebellum, temporo-parietal junction, supplementary motor area, or sham stimulation, patients with SSD and healthy control participants were repeatedly exposed to delays between actively or passively elicited button presses and auditory outcomes. Effects of this procedure on temporal perception were assessed with a delay detection task. Similar recalibration outcomes and faciliatory effects of cerebellar tDCS on recalibration were observed in SSD and healthy individuals. Our findings indicate that sensorimotor recalibration mechanisms may be preserved in SSD and highlight the importance of the cerebellum in both patients and healthy individuals for this process. They further suggest that cerebellar tDCS could be a promising tool for addressing deficits in action-outcome monitoring and related adaptive sensorimotor processes in SSD.

Abstract The brain can adapt its expectations about the relative timing of actions and their sensory outcomes in a process known as temporal recalibration. This might occur as the recalibration of timing between the sensory (e.g. visual) outcome and (1) the motor act (sensorimotor) or (2) tactile/proprioceptive information (inter-sensory). This fMRI recalibration study investigated sensorimotor contributions to temporal recalibration by comparing active and passive conditions. Subjects were repeatedly exposed to delayed (150 ms) or undelayed visual stimuli, triggered by active or passive button presses. Recalibration effects were tested in delay detection tasks, including visual and auditory outcomes. We showed that both modalities were affected by visual recalibration. However, an active advantage was observed only in visual conditions. Recalibration was generally associated with the left cerebellum (lobules IV, V and vermis) while action related activation (active > passive) occurred in the right middle/superior frontal gyri during adaptation and test phases. Recalibration transfer from vision to audition was related to action specific activations in the cingulate cortex, the angular gyrus and left inferior frontal gyrus. Our data provide new insights in sensorimotor contributions to temporal recalibration via the middle/superior frontal gyri and inter-sensory contributions mediated by the cerebellum.

BackgroundIndividuals with anxiety disorders (ADs) often display hypervigilance to threat information, although this response may be less pronounced following psychotherapy. This study aims to investigate the unconscious recognition performance of facial expressions in patients with panic disorder (PD) post-treatment, shedding light on alterations in their emotional processing biases.MethodsPatients with PD (n=34) after (exposure-based) cognitive behavior therapy and healthy controls (n=43) performed a subliminal affective recognition task. Emotional facial expressions (fearful, happy, or mirrored) were displayed for 33 ms and backwardly masked by a neutral face. Participants completed a forced choice task to discriminate the briefly presented facial stimulus and an uncovered condition where only the neutral mask was shown. We conducted a secondary analysis to compare groups based on their four possible response types under the four stimulus conditions and examined the correlation of the false alarm rate for fear responses to non-fearful (happy, mirrored, and uncovered) stimuli with clinical anxiety symptoms.ResultsThe patient group showed a unique selection pattern in response to happy expressions, with significantly more correct “happy” responses compared to controls. Additionally, lower severity of anxiety symptoms after psychotherapy was associated with a decreased false fear response rate with non-threat presentations.ConclusionThese data suggest that patients with PD exhibited a “happy-face recognition advantage” after psychotherapy. Less symptoms after treatment were related to a reduced fear bias. Thus, a differential facial emotion detection task could be a suitable tool to monitor response patterns and biases in individuals with ADs in the context of psychotherapy.

BackgroundIn schizophrenia patients, spontaneous speech production has been hypothesized as correlating with right hemispheric activation, including the inferior frontal and superior temporal gyri as speech-relevant areas. However, robust evidence for this association is still missing. The aim of the present fMRI study is to examine BOLD signal changes during natural, fluent speech production in patients with schizophrenia in the chronic phase of their disease.MethodsUsing a case–control design, the study included 15 right-handed patients with schizophrenia spectrum disorders as well as 15 healthy controls. The participants described eight pictures from the Thematic Apperception Test for 1 min each, while BOLD signal changes were measured with 3T fMRI. The occurrence of positive and negative formal thought disorders was determined using standardized psychopathological assessments.ResultsWe found significant BOLD signal changes during spontaneous speech production in schizophrenia patients compared to healthy controls, particularly in the right hemispheric network. A post-hoc analysis showed that this right-hemispheric lateralization was mainly driven by activation during experimental rests. Furthermore, the TLI sum value in patients correlated negatively with BOLD signal changes in the right Rolandic operculum.ConclusionsPossible underlying factors for this inverse right-hemispheric lateralization of speech-associated areas are structural changes and transmitter system alterations, as well as a lack of neural downregulation in schizophrenia patients during rest periods due to dysfunctional executive functions. When examining spontaneous speech as the most natural form of language, other influencing factors, such as social cognition or emotional processing, should be considered. Our results indicate that future studies should consider group differences during rest, which might provide additional information typically covered in differential contrasts.

Abstract Temporal neural synchrony disruption can be linked to a variety of symptoms of major depressive disorder (MDD), including mood rigidity and the inability to break the cycle of negative emotion or attention biases. This might imply that altered dynamic neural synchrony may play a role in the persistence and exacerbation of MDD symptoms. Our study aimed to investigate the changes in whole-brain dynamic patterns of the brain functional connectivity and activity related to depression using the hidden Markov model (HMM) on resting-state functional magnetic resonance imaging (rs-fMRI) data. We compared the patterns of brain functional dynamics in a large sample of 314 patients with MDD (65.9% female; age (mean ± standard deviation): 35.9 ± 13.4) and 498 healthy controls (59.4% female; age: 34.0 ± 12.8). The HMM model was used to explain variations in rs-fMRI functional connectivity and averaged functional activity across the whole-brain by using a set of six unique recurring states. This study compared the proportion of time spent in each state and the average duration of visits to each state to assess stability between different groups. Compared to healthy controls, patients with MDD showed significantly higher proportional time spent and temporal stability in a state characterized by weak functional connectivity within and between all brain networks and relatively strong averaged functional activity of regions located in the somatosensory motor (SMN), salience (SN), and dorsal attention (DAN) networks. Both proportional time spent and temporal stability of this brain state was significantly associated with depression severity. Healthy controls, in contrast to the MDD group, showed proportional time spent and temporal stability in a state with relatively strong functional connectivity within and between all brain networks but weak averaged functional activity across the whole brain. These findings suggest that disrupted brain functional synchrony across time is present in MDD and associated with current depression severity.

Abstract Self-motion induces sensory signals that allow to determine travel distance (path integration). For veridical path integration, one must distinguish self-generated from externally induced sensory signals. Predictive coding has been suggested to attenuate self-induced sensory responses, while task relevance can reverse the attenuating effect of prediction. But how is self-motion processing affected by prediction and task demands, and do effects generalize across senses? In this fMRI study, we investigated visual and tactile self-motion processing and its modulation by task demands. Visual stimuli simulated forward self-motion across a ground plane. Tactile self-motion stimuli were delivered by airflow across the subjects’ forehead. In one task, subjects replicated a previously observed distance (Reproduction/Active; high behavioral demand) of passive self-displacement (Reproduction/Passive). In a second task, subjects travelled a self-chosen distance (Self/Active; low behavioral demand) which was recorded and played back to them (Self/Passive). For both tasks and sensory modalities, Active as compared to Passive trials showed enhancement in early visual areas and suppression in higher order areas of the inferior parietal lobule (IPL). Contrasting high and low demanding active trials yielded supramodal enhancement in the anterior insula. Suppression in the IPL suggests this area to be a comparator of sensory self-motion signals and predictions thereof.

Deficits in memory performance have been linked to a wide range of neurological and neuropsychiatric conditions. While many studies have assessed the memory impacts of individual conditions, this study considers a broader perspective by evaluating how memory recall is differentially associated with nine common neuropsychiatric conditions using data drawn from 55 international studies, aggregating 15,883 unique participants aged 15–90. The effects of dementia, mild cognitive impairment, Parkinson’s disease, traumatic brain injury, stroke, depression, attention-deficit/hyperactivity disorder (ADHD), schizophrenia, and bipolar disorder on immediate, short-, and long-delay verbal learning and memory (VLM) scores were estimated relative to matched healthy individuals. Random forest models identified age, years of education, and site as important VLM covariates. A Bayesian harmonization approach was used to isolate and remove site effects. Regression estimated the adjusted association of each clinical group with VLM scores. Memory deficits were strongly associated with dementia and schizophrenia (p < 0.001), while neither depression nor ADHD showed consistent associations with VLM scores (p > 0.05). Differences associated with clinical conditions were larger for longer delayed recall duration items. By comparing VLM across clinical conditions, this study provides a foundation for enhanced diagnostic precision and offers new insights into disease management of comorbid disorders.

Abstract Adaptation to delays between actions and sensory feedback is important for efficiently interacting with our environment. Adaptation may rely on predictions of action-feedback pairing (motor-sensory component), or predictions of tactile-proprioceptive sensation from the action and sensory feedback of the action (inter-sensory component). Reliability of temporal information might differ across sensory feedback modalities (e.g. auditory or visual), which in turn influences adaptation. Here, we investigated the role of motor-sensory and inter-sensory components on sensorimotor temporal recalibration for motor-auditory (button press-tone) and motor-visual (button press-Gabor patch) events. In the adaptation phase of the experiment, action-feedback pairs were presented with systematic temporal delays (0 ms or 150 ms). In the subsequent test phase, audio/visual feedback of the action were presented with variable delays. The participants were then asked whether they detected a delay. To disentangle motor-sensory from inter-sensory component, we varied movements (active button press or passive depression of button) at adaptation and test. Our results suggest that motor-auditory recalibration is mainly driven by the motor-sensory component, whereas motor-visual recalibration is mainly driven by the inter-sensory component. Recalibration transferred from vision to audition, but not from audition to vision. These results indicate that motor-sensory and inter-sensory components contribute to recalibration in a modality-dependent manner.

Abstract Background Bacteria associated with plants can enhance the plants’ growth and resistance against phytopathogens. Today, growers aim to reduce the use of mineral fertilizers and pesticides. Since phytopathogens cause severe yield losses in crop production systems, biological alternatives gain more attention. Plant and also seed endophytes have the potential to influence the plant, especially seed-borne bacteria may express their beneficiary impact at initial plant developmental stages. In the current study, we assessed the endophytic seed microbiome of seven genetically diverse barley accessions by 16S rRNA gene amplicon sequencing and verified the in vitro plant beneficial potential of isolated seed endophytes. Furthermore, we investigated the impact of the barley genotype and its seed microbiome on the rhizosphere microbiome at an early growth stage by 16S rRNA gene amplicon sequencing. Results The plant genotype displayed a significant impact on the microbiota in both barley seed and rhizosphere. Consequently, the microbial alpha- and beta-diversity of the endophytic seed microbiome was highly influenced by the genotype. Interestingly, no correlation was observed between the endophytic seed microbiome and the single nucleotide polymorphisms of the seven genotypes. Unclassified members of Enterobacteriaceae were by far most dominant. Other abundant genera in the seed microbiome belonged to Curtobacterium, Paenibacillus, Pantoea, Sanguibacter and Saccharibacillus. Endophytes isolated from barley seeds were affiliated to dominant genera of the core seed microbiome, based on their 16S rRNA gene sequence. Most of these endophytic isolates produced in vitro plant beneficial secondary metabolites known to induce plant resistance. Conclusion Although barley accessions representing high genetic diversity displayed a genotype-dependent endophytic seed microbiome, a core seed microbiome with high relative abundances was identified. Endophytic isolates were affiliated to members of the core seed microbiome and many of them showed plant beneficial properties. We propose therefore that new breeding strategies should consider genotypes with high abundance of beneficial microbes.

Sensory consequences of one's own action are often perceived as less intense, and lead to reduced neural responses, compared to externally generated stimuli. Presumably, such sensory attenuation is due to predictive mechanisms based on the motor command (efference copy). However, sensory attenuation has also been observed outside the context of voluntary action, namely when stimuli are temporally predictable. Here, we aimed at disentangling the effects of motor and temporal predictability-based mechanisms on the attenuation of sensory action consequences. During fMRI data acquisition, participants (N = 25) judged which of two visual stimuli was brighter. In predictable blocks, the stimuli appeared temporally aligned with their button press (active) or aligned with an automatically generated cue (passive). In unpredictable blocks, stimuli were presented with a variable delay after button press/cue, respectively. Eye tracking was performed to investigate pupil-size changes and to ensure proper fixation. Self-generated stimuli were perceived as darker and led to less neural activation in visual areas than their passive counterparts, indicating sensory attenuation for self-generated stimuli independent of temporal predictability. Pupil size was larger during self-generated stimuli, which correlated negatively with the blood oxygenation level dependent (BOLD) response: the larger the pupil, the smaller the BOLD amplitude in visual areas. Our results suggest that sensory attenuation in visual cortex is driven by action-based predictive mechanisms rather than by temporal predictability. This effect may be related to changes in pupil diameter. Altogether, these results emphasize the role of the efference copy in the processing of sensory action consequences.

Abstract 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 characteristic temporal relationship between actions and their sensory outcomes allows us to distinguish self- from externally generated sensory events. However, the complex sensory environment can cause transient delays between action and outcome calling for flexible recalibration of predicted sensorimotor timing. Since the neural underpinnings of this process are largely unknown this study investigated the involvement of the cerebellum by means of cerebellar transcranial direct current stimulation (ctDCS). While receiving anodal, cathodal, dual-hemisphere or sham ctDCS, in an adaptation phase, participants were exposed to constant delays of 150 ms between actively or passively generated button presses and visual sensory outcomes. Recalibration in the same (visual outcome) and in another sensory modality (auditory outcome) was assessed in a subsequent test phase during which variable delays between button press and visual or auditory outcome had to be detected. Results indicated that temporal recalibration occurred in audition after anodal ctDCS while it was absent in vision. As the adaptation modality was visual, effects in audition suggest that recalibration occurred on a supra-modal level. In active conditions, anodal ctDCS improved sensorimotor recalibration at the delay level closest to the adaptation delay, suggesting a precise cerebellar-dependent temporal recalibration mechanism. In passive conditions, the facilitation of inter-sensory recalibration by anodal ctDCS was overall stronger and tuned to larger delays. These findings point to a role of the cerebellum in supra-modal temporal recalibration across sensorimotor and perceptual domains, but the differential manifestation of the effect across delay levels in active and passive conditions points to differences in the underlying mechanisms depending on the availability of action-based predictions. Furthermore, these results suggest that anodal ctDCS can be a promising tool for facilitating effects of temporal recalibration in sensorimotor and inter-sensory contexts.

Adapting threat-related memories towards changing environments is a fundamental ability of organisms. One central process of fear reduction is suggested to be extinction learning, experimentally modeled by extinction training that is repeated exposure to a previously conditioned stimulus (CS) without providing the expected negative consequence (unconditioned stimulus, US). Although extinction training is well investigated, evidence regarding process-related changes in neural activation over time is still missing. Using optimized delayed extinction training in a multicentric trial we tested whether: 1) extinction training elicited decreasing CS-specific neural activation and subjective ratings, 2) extinguished conditioned fear would return after presentation of the US (reinstatement), and 3) results are comparable across different assessment sites and repeated measures. We included 100 healthy subjects (measured twice, 13-week-interval) from six sites. 24 h after fear acquisition training, extinction training, including a reinstatement test, was applied during fMRI. Alongside, participants had to rate subjective US-expectancy, arousal and valence. In the course of the extinction training, we found decreasing neural activation in the insula and cingulate cortex as well as decreasing US-expectancy, arousal and negative valence towards CS+. Re-exposure to the US after extinction training was associated with a temporary increase in neural activation in the anterior cingulate cortex (exploratory analysis) and changes in US-expectancy and arousal ratings. While ICCs-values were low, findings from small groups suggest highly consistent effects across time-points and sites. Therefore, this delayed extinction fMRI-paradigm provides a solid basis for the investigation of differences in neural fear-related mechanisms as a function of anxiety-pathology and exposure-based treatment.

Gestures are an integral part of in-person conversations and complement the meaning of the speech they accompany. The neural processing of co-speech gestures is supported by a mostly left-lateralized network of fronto-temporal regions. However, in contrast to iconic gestures, metaphoric as well as unrelated gestures have been found to more strongly engage the left and right inferior frontal gyrus (IFG), respectively. With this study, we conducted the first systematic comparison of all three types of gestures and resulting potential laterality effects.During collection of functional imaging data, 74 subjects were presented with 5 s videos of abstract speech with related metaphoric gestures, concrete speech with related iconic gestures and concrete speech with unrelated gestures. They were asked to judge whether the content of the speech and gesture matched or not.Differential contrasts revealed that both abstract related and concrete unrelated compared to concrete related stimuli elicited stronger activation of the bilateral IFG. Analyses of lateralization indices for IFG activation further showed a left hemispheric dominance for metaphoric gestures and a right hemispheric dominance for unrelated gestures.Our results give support to the hypothesis that the bilateral IFG is activated specifically when processing load for speech-gesture combinations is high. In addition, laterality effects indicate a stronger involvement of the right IFG in mismatch detection and conflict processing, whereas the left IFG performs the actual integration of information from speech and gesture.

Sensory action consequences are highly predictable and thus engage less neural resources compared to externally generated sensory events. While this has frequently been observed to lead to attenuated perceptual sensitivity and suppression of activity in sensory cortices, some studies conversely reported enhanced perceptual sensitivity for action consequences. These divergent findings might be explained by the type of action feedback, i.e., discrete outcomes vs. continuous feedback. Therefore, in the present study we investigated the impact of discrete and continuous action feedback on perceptual and neural processing during action feedback monitoring.During fMRI data acquisition, participants detected temporal delays (0–417 ms) between actively or passively generated wrist movements and visual feedback that was either continuously provided during the movement or that appeared as a discrete outcome.Both feedback types resulted in (1) a neural suppression effect (active

Electrophysiological studies in rodents allow recording neural activity during threats with high temporal and spatial precision. Although fMRI has helped translate insights about the anatomy of underlying brain circuits to humans, the temporal dynamics of neural fear processes remain opaque and require EEG. To date, studies on electrophysiological brain signals in humans have helped to elucidate underlying perceptual and attentional processes, but have widely ignored how fear memory traces evolve over time. The low signal-to-noise ratio of EEG demands aggregations across high numbers of trials, which will wash out transient neurobiological processes that are induced by learning and prone to habituation. Here, our goal was to unravel the plasticity and temporal emergence of EEG responses during fear conditioning. To this end, we developed a new sequential-set fear conditioning paradigm that comprises three successive acquisition and extinction phases, each with a novel CS+/CS- set. Each set consists of two different neutral faces on different background colors which serve as CS+ and CS-, respectively. Thereby, this design provides sufficient trials for EEG analyses while tripling the relative amount of trials that tap into more transient neurobiological processes. Consistent with prior studies on ERP components, data-driven topographic EEG analyses revealed that ERP amplitudes were potentiated during time periods from 33–60 ms, 108–200 ms, and 468–820 ms indicating that fear conditioning prioritizes early sensory processing in the brain, but also facilitates neural responding during later attentional and evaluative stages. Importantly, averaging across the three CS+/CS- sets allowed us to probe the temporal evolution of neural processes: Responses during each of the three time windows gradually increased from early to late fear conditioning, while long-latency (460–730 ms) electrocortical responses diminished throughout fear extinction. Our novel paradigm demonstrates how short-, mid-, and long-latency EEG responses change during fear conditioning and extinction, findings that enlighten the learning curve of neurophysiological responses to threat in humans.

Schizophrenia is characterized by marked communication dysfunctions encompassing potential impairments in the processing of social-abstract and non-social-concrete information, especially in everyday situations where multiple modalities are present in the form of speech and gesture. To date, the neurobiological basis of these deficits remains elusive. In a functional magnetic resonance imaging (fMRI) study, 17 patients with schizophrenia or schizoaffective disorder, and 18 matched controls watched videos of an actor speaking, gesturing (unimodal), and both speaking and gesturing (bimodal) about social or non-social events in a naturalistic way. Participants were asked to judge whether each video contains person-related (social) or object-related (non-social) information. When processing social-abstract content, patients showed reduced activation in the medial prefrontal cortex (mPFC) only in the gesture but not in the speech condition. For non-social-concrete content, remarkably, reduced neural activation for patients in the left postcentral gyrus and the right insula was observed only in the speech condition. Moreover, in the bimodal conditions, patients displayed improved task performance and comparable activation to controls in both social and non-social content. To conclude, patients with schizophrenia displayed modality-specific aberrant neural processing of social and non-social information, which is not present for the bimodal conditions. This finding provides novel insights into dysfunctional multimodal communication in schizophrenia, and may have potential therapeutic implications.

Dysfunctional social communication is one of the most stable characteristics in patients with schizophrenia that also affects quality of life. Interpreting abstract speech and integrating nonverbal modalities is particularly affected. Considering the impact of communication on social life but failure to treat communication dysfunctions with usual treatment, we will investigate the possibility to improve verbal and non-verbal communication in schizophrenia by applying a multimodal speech-gesture training (MSG training). Here we describe the newly developed MSG training program and the study design for the first clinical investigation. The intervention contains perceptive rating (match/mismatch of sentence and gesture) and memory tasks (n-back tasks), imitation and productive tasks (e.g., SG fluency—similar to verbal fluency where words are accompanied by gesture). In addition, we offer information about gesture as meta-learning element as well as homework for reasons of transfer to everyday life as part of every session. In the MSG training intervention, we offer eight sessions (60 min each) of training. The first pilot study is currently conducted as a single-center, randomized controlled trial of speech-gesture intervention versus wait-list control with a follow-up. Outcomes are measured through pre-post-fMRI and standardized psychological questionnaires comparing two subject groups (30 patients with schizophrenia and 30 healthy controls). Patients and healthy controls are randomized in two intervention groups (with 20 being in the wait-training group and 10 in the training-follow-up group). With our study design we will be able to demonstrate the beneficial effect of the MSG training intervention on behavioral and neural levels.Clinical Trial RegistrationDRKS.de, identifier DRKS00015118.

Tool use is one of the most remarkable skills of the human species, enabling complex interactions with the environment. To establish such interactions, we predict the sensory consequences of our actions based on a copy of the motor command (efference copy), leading to an attenuated perception and neural suppression of the sensory input. Here, we investigated whether and how tools can be incorporated into these predictions. We hypothesized that similar predictive mechanisms are used for both hand and tool use actions, but that additional resources are needed to integrate the tool.During fMRI data acquisition, 19 healthy participants used either their right hand or a tool to hold the handle of a movement device. To manipulate the effect of the efference copy, the handle was moved either actively by participants or passively by the movement device. The sensory outcome, consisting of a real-time video of the hand or tool movement shown on a screen, was presented with varying delays (0–417 ms). Participants reported their perception of such delays.The processing of hand and tool movements yielded largely similar results when comparing active against passive conditions: Active movements were in both cases associated with worse delay detection performances. Moreover, during both hand and tool use actions, active movements led to a downregulation of sensory (somatosensory, visual) areas as well as the right cerebellum and right posterior parietal cortex, as assessed by a conjunction analysis. By contrast, an interaction analysis indicated differential processing of active vs. passive movements in hand vs. tool conditions in the left postcentral gyrus, right middle temporal gyrus (MTG), and bilateral caudate nuclei.Our findings provide behavioral and neural support that hand and tool actions share similar mechanisms for sensory predictions. We propose that the MTG and (sensori)motor areas (postcentral gyrus, caudate nuclei) contribute to these predictions by optimizing them to the physics of the end effector (hand or tool). Collectively, these results suggest that the brain dynamically adjusts sensorimotor predictive models to anticipate the dynamics of the end effector, be it a hand or a tool.

Neuronal nitric oxide synthase (NOS-I) impacts on fear/anxiety-like behavior in animals. In humans, the short (S) allele of a functional promotor polymorphism of NOS1 (NOS1 ex1f-VNTR) has been shown to be associated with higher anxiety and altered fear conditioning in healthy subjects in the amygdala and hippocampus (AMY/HIPP). Here, we explore the role of NOS1 ex1f-VNTR as a pathophysiological correlate of panic disorder and agoraphobia (PD/AG). In a sub-sample of a multicenter cognitive behavioral therapy (CBT) randomized controlled trial in patients with PD/AG (n = 48: S/S-genotype n=15, S/L-genotype n=21, L/L-genotype n=12) and healthy control subjects, HS (n = 34: S/S-genotype n=7, S/L-genotype n=17, L/L-genotype=10), a differential fear conditioning and extinction fMRI-paradigm was used to investigate how NOS1 ex1f-VNTR genotypes are associated with differential neural activation in AMY/HIPP. Prior to CBT, L/L-allele carriers showed higher activation than S/S-allele carriers in AMY/HIPP. A genotype × diagnosis interaction revealed that the S-allele in HS was associated with a pronounced deactivation in AMY/HIPP, while patients showed contrary effects. The interaction of genotype × stimulus type (CS+, conditioned stimulus associated with an aversive stimulus vs. CS-, unassociated) showed effects on differential learning in AMY/HIPP. All effects were predominately found during extinction. Genotype associated effects in patients were not altered after CBT. Low statistical power due to small sample size in each subgroup is a major limitation. However, our findings provide first preliminary evidence for dysfunctional neural fear conditioning/extinction associated with NOS1 ex1f-VNTR genotype in the context of PD/AG, shedding new light on the complex interaction between genetic risk, current psychopathology and treatment-related effects.

Introduction: The neurobiological mechanisms behind panic disorder with agoraphobia (PD/AG) are not completely explored. The functional A/T single nucleotide polymorphism (SNP) rs324981 in the neuropeptide S receptor gene (NPSR1) has repeatedly been associated with panic disorder and might partly drive function respectively dysfunction of the neural “fear network”. We aimed to investigate whether the NPSR1 T risk allele was associated with malfunctioning in a fronto-limbic network during the anticipation and perception of agoraphobia-specific stimuli. Method: 121 patients with PD/AG and 77 healthy controls (HC) underwent functional magnetic resonance imaging (fMRI) using the disorder specific “Westphal-Paradigm”. It consists of neutral and agoraphobia-specific pictures, half of the pictures were cued to induce anticipatory anxiety. Results: Risk allele carriers showed significantly higher amygdala activation during the perception of agoraphobia-specific stimuli than A/A homozygotes. A linear group x genotype interaction during the perception of agoraphobia-specific stimuli showed a strong trend towards significance. Patients with the one or two T alleles displayed the highest and HC with the A/A genotype the lowest activation in the inferior orbitofrontal cortex (iOFC). Discussion: The study demonstrates an association of the NPSR1rs324981 genotype and the perception of agoraphobia-specific stimuli. These results support the assumption of a fronto-limbic dysfunction as an intermediate phenotype of PD/AG. Keywords: Panic disorder, Agoraphobia, NPSR1, Imaging genetics, fMRI, Westphal-Paradigm

Metaphoric (MP) co-speech gestures are commonly used during daily communication. They communicate about abstract information by referring to gestures that are clearly concrete (e.g., raising a hand for “the level of the football game is high”). To understand MP co-speech gestures, a multisensory integration at semantic level is necessary between abstract speech and concrete gestures. While semantic gesture-speech integration has been extensively investigated using functional magnetic resonance imaging, evidence from electroencephalography (EEG) is rare. In the current study, we set out an EEG experiment, investigating the processing of MP vs. iconic (IC) co-speech gestures in different contexts, to reveal the oscillatory signature of MP gesture integration. German participants (n = 20) viewed video clips with an actor performing both types of gestures, accompanied by either comprehensible German or incomprehensible Russian (R) speech, or speaking German sentences without any gestures. Time-frequency analysis of the EEG data showed that, when gestures were accompanied by comprehensible German speech, MP gestures elicited decreased gamma band power (50–70 Hz) between 500 and 700 ms in the parietal electrodes when compared to IC gestures, and the source of this effect was localized to the right middle temporal gyrus. This difference is likely to reflect integration processes, as it was reduced in the R language and no-gesture conditions. Our findings provide the first empirical evidence suggesting the functional relationship between gamma band oscillations and higher-level semantic processes in a multisensory setting.

Speech-associated gestures represent an important communication modality. However, individual differences in the production and perception of gestures are not well understood so far. We hypothesized that the perception of multisensory action consequences might play a crucial role. Verbal communication involves continuous calibration of audio–visual information produced by the speakers. The effective production and perception of gestures supporting this process could depend on the given capacities to perceive multisensory information accurately. We explored the association between the production and perception of gestures and the monitoring of multisensory action consequences in a sample of 31 participants. We applied a recently introduced gesture scale to assess self-reported gesture production and perception in everyday life situations. In the perceptual experiment, we presented unimodal (visual) and bimodal (visual and auditory) sensory outcomes with various delays after a self-initiated (active) or externally generated (passive) button press. Participants had to report whether they detected a delay between the button press and the visual stimulus. We derived psychometric functions for each condition and determined points of subjective equality, reflecting detection thresholds for delays. Results support a robust link between gesture scores and detection thresholds. Individuals with higher detection thresholds (lower performance) reported more frequent gesture production and perception and furthermore profited more from multisensory information in the experimental task. We propose that our findings indicate a compensational function of multisensory processing as a basis for individual differences in both action outcome monitoring and gesture production and perception in everyday life situations.

Forming a coherent percept of an event requires different sensory inputs originating from the event to be bound. Perceiving synchrony aids in binding of these inputs. In two experiments, we investigated how voluntary movements influence the perception of simultaneity, by measuring simultaneity judgments (SJs) for an audiovisual (AV) stimulus pair triggered by a voluntary button press. In Experiment 1, we manipulated contiguity between the action and its consequences by introducing delays between the button press and the AV stimulus pair. We found a widened window of subjective simultaneity (WSS) when the action-feedback relationship was time contiguous. Introducing a delay narrowed the WSS, suggesting that the wider WSS around the time of an action might facilitate perception of simultaneity. In Experiment 2, we introduced an involuntary condition using an externally controlled button to assess the influence of action-related predictive processes on SJs. We found a widened WSS around the action time, regardless of movement type, supporting the influence of causal relations in the perception of synchrony. Interestingly, the slopes of the psychometric functions in the voluntary condition were significantly steeper than the slopes in the involuntary condition, suggesting a role of action-related predictive mechanisms in making SJs more precise.

BackgroundThe approach to apply multivariate pattern analyses based on neuro imaging data for outcome prediction holds out the prospect to improve therapeutic decisions in mental disorders. Patients suffering from panic disorder with agoraphobia (PD/AG) often exhibit an increased perception of bodily sensations. The purpose of this investigation was to assess whether multivariate classification applied to a functional magnetic resonance imaging (fMRI) interoception paradigm can predict individual responses to cognitive behavioral therapy (CBT) in PD/AG.MethodsThis analysis is based on pretreatment fMRI data during an interoceptive challenge from a multicenter trial of the German PANIC-NET. Patients with DSM-IV PD/AG were dichotomized as responders (n = 30) or non-responders (n = 29) based on the primary outcome (Hamilton Anxiety Scale Reduction ≥50%) after 6 weeks of CBT (2 h/week). fMRI parametric maps were used as features for response classification with linear support vector machines (SVM) with or without automated feature selection. Predictive accuracies were assessed using cross validation and permutation testing. The influence of methodological parameters and the predictive ability for specific interoception-related symptom reduction were further evaluated.ResultsSVM did not reach sufficient overall predictive accuracies (38.0–54.2%) for anxiety reduction in the primary outcome. In the exploratory analyses, better accuracies (66.7%) were achieved for predicting interoception-specific symptom relief as an alternative outcome domain. Subtle information regarding this alternative response criterion but not the primary outcome was revealed by post hoc univariate comparisons.ConclusionIn contrast to reports on other neurofunctional probes, SVM based on an interoception paradigm was not able to reliably predict individual response to CBT. Results speak against the clinical applicability of this technique.

Predictive mechanisms are essential to successfully interact with the environment and to compensate for delays in the transmission of neural signals. However, whether and how we predict multisensory action outcomes remains largely unknown. Here we investigated the existence of multisensory predictive mechanisms in a context where actions have outcomes in different modalities. During fMRI data acquisition auditory, visual and auditory-visual stimuli were presented in active and passive conditions. In the active condition, a self-initiated button press elicited the stimuli with variable short delays (0-417ms) between action and outcome, and participants had to detect the presence of a delay for auditory or visual outcome (task modality). In the passive condition, stimuli appeared automatically, and participants had to detect the number of stimulus modalities (unimodal/bimodal). For action consequences compared to identical but unpredictable control stimuli we observed suppression of the blood oxygen level depended (BOLD) response in a broad network including bilateral auditory and visual cortices. This effect was independent of task modality or stimulus modality and strongest for trials where no delay was detected (undetected

In a natural setting, speech is often accompanied by gestures. As language, speech-accompanying iconic gestures to some extent convey semantic information. However, if comprehension of the information contained in both the auditory and visual modality depends on same or different brain-networks is quite unknown. In this fMRI study, we aimed at identifying the cortical areas engaged in supramodal processing of semantic information. BOLD changes were recorded in 18 healthy right-handed male subjects watching video clips showing an actor who either performed speech (S, acoustic) or gestures (G, visual) in more (+) or less (-) meaningful varieties. In the experimental conditions familiar speech or isolated iconic gestures were presented; during the visual control condition the volunteers watched meaningless gestures (G-), while during the acoustic control condition a foreign language was presented (S-). The conjunction of the visual and acoustic semantic processing revealed activations extending from the left inferior frontal gyrus to the precentral gyrus, and included bilateral posterior temporal regions. We conclude that proclaiming this frontotemporal network the brain's core language system is to take too narrow a view. Our results rather indicate that these regions constitute a supramodal semantic processing network.

Inferring causality is a fundamental feature of human cognition that allows us to theorize about and predict future states of the world. Michotte suggested that humans automatically perceive causality based on certain perceptual features of events. However, individual differences in judgments of perceptual causality cast doubt on Michotte’s view. To gain insights in the neural basis of individual difference in the perception of causality, our participants judged causal relationships in animations of a blue ball colliding with a red ball (a launching event) while fMRI-data were acquired. Spatial continuity and temporal contiguity were varied parametrically in these stimuli. We did not find consistent brain activation differences between trials judged as caused and those judged as non-caused, making it unlikely that humans have universal instantiation of perceptual causality in the brain. However, participants were slower to respond to and showed greater neural activity for violations of causality, suggesting that humans are biased to expect causal relationships when moving objects appear to interact. Our participants demonstrated considerable individual differences in their sensitivity to spatial and temporal characteristics in perceiving causality. These qualitative differences in sensitivity to time or space in perceiving causality were instantiated in individual differences in activation of the left basal ganglia or right parietal lobe, respectively. Thus, the perception that the movement of one object causes the movement of another is triggered by elemental spatial and temporal sensitivities, which themselves are instantiated in specific distinct neural networks.