Neuroimaging studies of suicidal behavior have so far been conducted in small samples, prone to biases and false-positive associations, yielding inconsistent results. The ENIGMA-MDD Working Group aims to address the issues of poor replicability and comparability by coordinating harmonized analyses across neuroimaging studies of major depressive disorder and related phenotypes, including suicidal behavior.

MRI-derived cortical folding measures are an indicator of largely genetically driven early developmental processes. However, the effects of genetic risk for major mental disorders on early brain development are not well understood.

Syntax, the grammatical structure of sentences, is a fundamental aspect of language. It remains debated whether reduced syntactic complexity is unique to schizophrenia spectrum disorder (SSD) or whether it is also present in major depressive disorder (MDD). Furthermore, the association of syntax (including syntactic complexity and diversity) with language-related neuropsychology and psychopathological symptoms across disorders remains unclear. Thirty-four SSD patients and thirty-eight MDD patients diagnosed according to DSM-IV-TR as well as forty healthy controls (HC) were included and tasked with describing four pictures from the Thematic Apperception Test. We analyzed the produced speech regarding its syntax delineating measures for syntactic complexity (the total number of main clauses embedding subordinate clauses) and diversity (number of different types of complex sentences). We performed cluster analysis to identify clusters based on syntax and investigated associations of syntactic, to language-related neuropsychological (verbal fluency and verbal episodic memory), and psychopathological measures (positive and negative formal thought disorder) using network analyses. Syntax in SSD was significantly reduced in comparison to MDD and HC, whereas the comparison of HC and MDD revealed no significant differences. No associations were present between speech measures and current medication, duration and severity of illness, age or sex; the single association accounted for was education. A cluster analysis resulted in four clusters with different degrees of syntax across diagnoses. Subjects with less syntax exhibited pronounced positive and negative symptoms and displayed poorer performance in executive functioning, global functioning, and verbal episodic memory. All cluster-based networks indicated varying degrees of domain-specific and cross-domain connections. Measures of syntactic complexity were closely related while syntactic diversity appeared to be a separate node outside of the syntactic network. Cross-domain associations were more salient in more complex syntactic production.

One well-investigated division of attentional processes focuses on alerting, orienting and executive control, which can be assessed applying the attentional network test (ANT). The goal of the present study was to add further knowledge about the temporal dynamics of relevant neural correlates. As a right hemispheric dominance for alerting and orienting has previously been reported for intrinsic but not for phasic alertness, we additionally addressed a potential impact of this lateralization of attention by employing a lateralized version of the ANT, capturing phasic alertness processes. Sixteen healthy subjects underwent event-related functional magnetic resonance imaging (fMRI) while performing the ANT. Analyses of BOLD magnitude replicated the engagement of a fronto-parietal network in the attentional subsystems. The amplitudes of the attentional contrasts interacted with visual field presentation in the sense that the thalamus revealed a greater involvement for spatially cued items presented in the left visual field. Comparisons of BOLD latencies in visual cortices, first, verified faster BOLD responses following contra-lateral stimulus presentation. Second and more importantly, we identified attention-modulated activation in secondary visual and anterior cingulate cortices. Results are discussed in terms of bottom-up and lateralization processes. Although intrinsic and phasic alertness are distinct cognitive processes, we propose that neural substrates of intrinsic alertness may be accessed by phasic alertness provided that the attention-dominant (i.e., the right) hemisphere is activated directly by a warning stimulus.

Neuregulin 1 (NRG1) has been found to be associated with schizophrenia. Impaired performance in episodic memory tasks is an often replicated finding in this disorder. In functional neuroimaging studies, this dysfunction has been linked to signal changes in prefrontal and medial temporal areas. Therefore, it is of interest whether genes associated with the disorder, such as NRG1, modulate episodic memory performance and its neural correlates. Ninety-four healthy individuals performed an episodic memory encoding and a retrieval task while brain activation was measured with functional MRI. All subjects were genotyped for the single nucleotide polymorphism (SNP) rs35753505 in the NRG1 gene. The effect of genotype on brain activation was assessed with fMRI during the two tasks. While there were no differences in performance, brain activation in the cingulate gyrus (BA 24), the left middle frontal gyrus (BA 9), the bilateral fusiform gyrus and the left middle occipital gyrus (BA 19) was positively correlated with the number of risk alleles in NRG1 during encoding. During retrieval brain activation was positively correlated with the number of risk alleles in the left middle occipital gyrus (BA 19). NRG1 genotype does modulate brain activation during episodic memory processing in key areas for memory encoding and retrieval. The results suggest that subjects with risk alleles show hyperactivations in areas associated with elaborate encoding strategies.

Working memory dysfunctions are a prominent feature in schizophrenia. These impairments have been linked to alterations in prefrontal brain activation with studies reporting hypo- and hyperactivations. Since schizophrenia has a high heritability, it is of interest whether susceptibility genes modulate working memory and its neural correlates. The aim of the present study was to test the influence of the NRG1 schizophrenia susceptibility gene on working memory and its neural correlates in healthy subjects. 429 healthy individuals performed a verbal and a spatial working memory task. A subsample of 85 subjects performed a 2-back version of the Continuous Performance Test (CPT) in a functional MRI study. The NRG1 SNP8NRG221533 (rs35753505) carrier status was determined and correlated with working memory performance and brain activation. There were no effects of genetic status on behavioural performance in the working memory tasks in the 429 subjects and in the fMRI task (n=85). A linear effect of NRG1 SNP8NRG221533 carrier status on neuronal activation emerged in the fMRI experiment. Hyperactivation of the superior frontal gyrus (BA 10) was correlated with the number of risk alleles. The fMRI data suggest that performance measures between groups did not differ due to a compensational activation of BA 10 in risk-allele carriers. Our results are in line with functional imaging studies in patients with schizophrenia, which also showed a differential activation in lateral prefrontal areas.

The interleukin (IL)-1 family of cytokines is strongly associated with systemic sclerosis (SSc) and pulmonary involvement, but the molecular mechanisms are poorly understood. The aim of this study was to assess the role of IL-1α and IL-1β in pulmonary vascular and interstitial remodelling in a mouse model of SSc.IL-1α and IL-1β were localised in lungs of SSc patients and in the fos-related antigen-2 (Fra-2) transgenic (TG) mouse model of SSc. Lung function, haemodynamic parameters and pulmonary inflammation were measured in Fra-2 TG mice with or without 8 weeks of treatment with the IL-1 receptor antagonist anakinra (25 mg·kg-1·day-1). Direct effects of IL-1 on pulmonary arterial smooth muscle cells (PASMCs) and parenchymal fibroblasts were investigated in vitroFra-2 TG mice exhibited increased collagen deposition in the lung, restrictive lung function and enhanced muscularisation of the vasculature with concomitant pulmonary hypertension reminiscent of the changes in SSc patients. Immunoreactivity of IL-1α and IL-1β was increased in Fra-2 TG mice and in patients with SSc. IL-1 stimulation reduced collagen expression in PASMCs and parenchymal fibroblasts via distinct signalling pathways. Blocking IL-1 signalling in Fra-2 TG worsened pulmonary fibrosis and restriction, enhanced T-helper cell type 2 (Th2) inflammation, and increased the number of pro-fibrotic, alternatively activated macrophages.Our data suggest that blocking IL-1 signalling as currently investigated in several clinical studies might aggravate pulmonary fibrosis in specific patient subsets due to Th2 skewing of immune responses and formation of alternatively activated pro-fibrogenic macrophages.

Individual differences in traits such as impulsivity and processing of risk and reward have been linked to decision making and may underlie divergent decision making strategies. It is, however, unclear whether and how far individual differences in these characteristics jointly influence decision making. Here, we aimed to investigate the roles of skin conductance responses, a psychophysiological marker of risk processing and impulsivity, as assessed by the Barratt Impulsiveness Scale 11 on decision making. Forty-six healthy participants performed a modified version of the Balloon Analog Risk Task (BART), where reward and explosion risk are manipulated separately. Participants are informed about whether they play a high versus low reward and high versus low explosion risk condition. The exact risk and reward contingencies are, however, unknown to participants. Participants were less risk-taking under high, compared to low explosion risk and under high reward, compared to low reward on the modified BART, which served as a validation of the paradigm. Risk-taking was negatively related to skin conductance responses under high explosion risk. This relationship was primarily driven by individuals with relatively high levels of impulsivity. However, impulsivity alone was not found to be related to decision making on the modified BART. These results extend evidence that skin conductance responses may guide decision making in situations, where participants are informed about risk level (high vs. low), which might be differentially moderated by different levels of impulsivity.

This paper presents an fMRI study on healthy adult understanding of metaphors in multimodal communication. We investigated metaphors expressed either only in coverbal gestures ("monomodal metaphors") or in speech with accompanying gestures ("multimodal metaphors"). Monomodal metaphoric gestures convey metaphoric information not expressed in the accompanying speech (e.g. saying the non-metaphoric utterance, "She felt bad" while dropping down the hand with palm facing up; here, the gesture alone indicates metaphoricity), whereas coverbal gestures in multimodal metaphors indicate metaphoricity redundant to the speech (e.g. saying the metaphoric utterance, "Her spirits fell" while dropping the hand with palm facing up). In other words, in monomodal metaphors, gestures add information not spoken, whereas the gestures in multimodal metaphors can be redundant to the spoken content. Understanding and integrating the information in each modality, here spoken and visual, is important in multimodal communication, but most prior studies have only considered multimodal metaphors where the gesture is redundant to what is spoken. Our participants watched audiovisual clips of an actor speaking while gesturing. We found that abstract metaphor comprehension recruited the lateral superior/middle temporal cortices, regardless of the modality in which the conceptual metaphor is expressed. These results suggest that abstract metaphors, regardless of modality, involve resources implicated in general semantic processing and are consistent with the role of these areas in supramodal semantic processing as well as the theory of embodied cognition.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.

It has been difficult to find robust brain structural correlates of the overall severity of major depressive disorder (MDD). We hypothesized that specific symptoms may better reveal correlates and investigated this for the severity of insomnia, both a key symptom and a modifiable major risk factor of MDD. Cortical thickness, surface area and subcortical volumes were assessed from T1-weighted brain magnetic resonance imaging (MRI) scans of 1053 MDD patients (age range 13-79 years) from 15 cohorts within the ENIGMA MDD Working Group. Insomnia severity was measured by summing the insomnia items of the Hamilton Depression Rating Scale (HDRS). Symptom specificity was evaluated with correlates of overall depression severity. Disease specificity was evaluated in two independent samples comprising 2108 healthy controls, and in 260 clinical controls with bipolar disorder. Results showed that MDD patients with more severe insomnia had a smaller cortical surface area, mostly driven by the right insula, left inferior frontal gyrus pars triangularis, left frontal pole, right superior parietal cortex, right medial orbitofrontal cortex, and right supramarginal gyrus. Associations were specific for insomnia severity, and were not found for overall depression severity. Associations were also specific to MDD; healthy controls and clinical controls showed differential insomnia severity association profiles. The findings indicate that MDD patients with more severe insomnia show smaller surfaces in several frontoparietal cortical areas. While explained variance remains small, symptom-specific associations could bring us closer to clues on underlying biological phenomena of MDD.

Both, pharmacological and genome-wide association studies suggest N-methyl-D-aspartate receptor (NMDAR) dysfunction and excitatory/inhibitory (E/I)-imbalance as a major pathophysiological mechanism of schizophrenia. The identification of shared fMRI brain signatures of genetically and pharmacologically induced NMDAR dysfunction may help to define biomarkers for patient stratification. NMDAR-related genetic and pharmacological effects on functional connectivity were investigated by integrating three different datasets: (A) resting state fMRI data from 146 patients with schizophrenia genotyped for the disease-associated genetic variant rs7191183 of GRIN2A (encoding the NMDAR 2 A subunit) as well as 142 healthy controls. (B) Pharmacological effects of the NMDAR antagonist ketamine and the GABA-A receptor agonist midazolam were obtained from a double-blind, crossover pharmaco-fMRI study in 28 healthy participants. (C) Regional gene expression profiles were estimated using a postmortem whole-brain microarray dataset from six healthy donors. A strong resemblance was observed between the effect of the genetic variant in schizophrenia and the ketamine versus midazolam contrast of connectivity suggestive for an associated E/I-imbalance. This similarity became more pronounced for regions with high density of NMDARs, glutamatergic neurons, and parvalbumin-positive interneurons. From a functional perspective, increased connectivity emerged between striato-pallido-thalamic regions and cortical regions of the auditory-sensory-motor network, while decreased connectivity was observed between auditory (superior temporal gyrus) and visual processing regions (lateral occipital cortex, fusiform gyrus, cuneus). Importantly, these imaging phenotypes were associated with the genetic variant, the differential effect of ketamine versus midazolam and schizophrenia (as compared to healthy controls). Moreover, the genetic variant was associated with language-related negative symptomatology which correlated with disturbed connectivity between the left posterior superior temporal gyrus and the superior lateral occipital cortex. Shared genetic and pharmacological functional connectivity profiles were suggestive of E/I-imbalance and associated with schizophrenia. The identified brain signatures may help to stratify patients with a common molecular disease pathway providing a basis for personalized psychiatry.

Emotion regulation (ER) is crucial in terms of mental health and social functioning. Attention deployment (AD) and cognitive reappraisal (CR) are both efficient cognitive ER strategies, which are based on partially dissociated neural effects. Our understanding of the neural underpinnings of ER is based on laboratory paradigms that study changes of the brain activation related to isolated emotional stimuli. To track the neural response to ER in the changing and dynamic environment of daily life, we extended the common existing paradigms by applying a sequence of emotionally provocative stimuli involving three aversive images. Eighteen participants completed an ER paradigm, in which they had to either shift their attention away from the emotionally negative images by counting backwards (AD strategy) or reinterpret the meaning of stimuli (CR strategy) to attain a down-regulation of affective responses. An increased recruitment of left-sided lateral and medial PFC was shown upon regulation of negative emotions with CR as compared to AD. Remarkably, the amygdala activation showed an increasing pattern of activation during CR. The inverse relationship between PFC and amygdala was compromised during elongated blocks of reappraisal, reflecting a reduction in engagement of the top-down prefrontal regulatory circuitry upon repeated exposure to negative stimuli. These results highlight that temporal dynamic of amygdala response and its functional connectivity differentiates AD and CR strategies in regulating emotions. Findings of the current study underscore the importance of adopting temporally variant approaches for investigating the neural effects of ER. Identifying neural systems that subserve down-regulation of negative emotions is of importance in developing treatment strategies for various forms of psychopathology.

Intraoperative radiotherapy (IORT) after surgical resection using a low-kV-X-ray source is a proven method used in cancer treatment. However, the shape and size of the targeted surface area are limited to the size of the available applicators. This can lead to nonconformal and therefore suboptimal treatment for many patients.

A high frequency of outgroup contact-as experienced by urban dwellers and migrants-possibly increases schizophrenia risk. This risk might be further amplified by genetic and environmental risk factors, such as the A-allele of rs1006737 within the calcium voltage-gated channel subunit alpha1 C gene and childhood interpersonal trauma (CIT). Both have been related to ventral anterior cingulate cortex (vACC) functioning. We investigated vACC functioning, during ingroup and outgroup emotion perception in relation to rs1006737 and CIT. Group membership was manipulated through a minimal group paradigm. Thus, in our functional magnetic resonance imaging study, a group of healthy Caucasian participants (n = 178) viewed video-recorded facial emotions (happy vs angry) of actors artificially assigned to represent the ingroup or the outgroup. Rs1006737 and CIT were related to brain activation for group and emotion specific processing. The group-emotion interaction in the vACC showed reduced sensitivity to emotional valence for outgroup member processing. Specifically for the angry outgroup condition, we found a gene by environment interaction in vACC activity. We speculate that the increased schizophrenia risk in migrants and urban dwellers could therefore be facilitated via this pathophysiological pathway.

Former prospective studies showed that the occurrence of relapse in Major Depressive Disorder (MDD) is associated with volume loss in the insula, hippocampus and dorsolateral prefrontal cortex (DLPFC). However, these studies were confounded by the patient's lifetime disease history, as the number of previous episodes predict future recurrence. In order to analyze neural correlates of recurrence irrespective of prior disease course, this study prospectively examined changes in brain structure in patients with first-episode depression (FED) over 2 years. N = 63 FED patients and n = 63 healthy controls (HC) underwent structural magnetic resonance imaging at baseline and after 2 years. According to their disease course during the follow-up interval, patients were grouped into n = 21 FED patients with recurrence (FEDrec) during follow-up and n = 42 FED patients with stable remission (FEDrem). Gray matter volume changes were analysed using group by time interaction analyses of covariance for the DLPFC, hippocampus and insula. Significant group by time interactions in the DLPFC and insula emerged. Pairwise comparisons showed that FEDrec had greater volume decline in the DLPFC and insula from baseline to follow-up compared with FEDrem and HC. No group by time interactions in the hippocampus were found. Cross-sectional analyses at baseline and follow-up revealed no differences between groups. This longitudinal study provides evidence for neural alterations in the DLPFC and insula related to a detrimental course in MDD. These effects of recurrence are already detectable at initial stages of MDD and seem to occur without any prior disease history, emphasizing the importance of early interventions preventing depressive recurrence.

Major depressive disorder (MDD) has been associated with alterations in brain white matter (WM) microstructure. However, diffusion tensor imaging studies in biological relatives have presented contradicting results on WM alterations and their potential as biomarkers for vulnerability or resilience. To shed more light on associations between WM microstructure and resilience to familial risk, analyses including both healthy and depressed relatives of MDD patients are needed.

Formal thought disorder (FTD) is a key clinical factor in schizophrenia, but the neurobiological underpinnings remain unclear. In particular, relationship between FTD symptom dimensions and patterns of regional brain volume deficiencies in schizophrenia remain to be established in large cohorts. Even less is known about the cellular basis of FTD. Our study addresses these major obstacles based on a large multi-site cohort through the ENIGMA Schizophrenia Working Group (752 individuals with schizophrenia and 1256 controls), to unravel the neuroanatomy of positive, negative and total FTD in schizophrenia and their cellular bases. We used virtual histology tools to relate brain structural changes associated with FTD to cellular distributions in cortical regions. We identified distinct neural networks for positive and negative FTD. Both networks encompassed fronto-occipito-amygdalar brain regions, but negative FTD showed a relative sparing of orbitofrontal cortical thickness, while positive FTD also affected lateral temporal cortices. Virtual histology identified distinct transcriptomic fingerprints associated for both symptom dimensions. Negative FTD was linked to neuronal and astrocyte fingerprints, while positive FTD was also linked to microglial cell types. These findings relate different dimensions of FTD to distinct brain structural changes and their cellular underpinnings, improve our mechanistic understanding of these key psychotic symptoms.

Rupture of the anterior cruciate ligament (ACL) is a high incidence injury usually treated surgically. According to common knowledge, it does not heal spontaneously, although some claim the opposite. Regeneration therapy by Khalifa was developed for injuries of the musculoskeletal system by using specific pressure to the skin. This randomized, controlled, observer-blinded, multicentre study was performed to validate this assumption. Thirty patients with complete ACL rupture, magnetic resonance imaging (MRI) verified, were included. Study examinations (e.g., international knee documentation committee (IKDC) score) were performed at inclusion (t 0). Patients were randomized to receive either standardised physiotherapy (ST) or additionally 1 hour of Khalifa therapy at the first session (STK). Twenty-four hours later, study examinations were performed again (t 1). Three months later control MRI and follow-up examinations were performed (t 2). Initial status was comparable between both groups. There was a highly significant difference of mean IKDC score results at t 1 and t 2. After 3 months, 47% of the STK patients, but no ST patient, demonstrated an end-to-end homogeneous ACL in MRI. Clinical and physical examinations were significantly different in t 1 and t 2. ACL healing can be improved with manual therapy. Physical activity can be performed without pain and nearly normal range of motion after one treatment of specific pressure.

Social rewards are processed by the same dopaminergic-mediated brain networks as non-social rewards, suggesting a common representation of subjective value. Individual differences in personality and motivation influence the reinforcing value of social incentives, but it remains open whether the pursuit of social incentives is analogously supported by the neural reward system when positive social stimuli are connected to approach behavior. To test for a modulation of neural activation by approach motivation, individuals with high and low approach motivation (BAS) completed implicit and explicit social approach-avoidance paradigms during fMRI. High approach motivation was associated with faster implicit approach reactions as well as a trend for higher approach ratings, indicating increased approach tendencies. Implicit and explicit positive social approach was accompanied by stronger recruitment of the nucleus accumbens, middle cingulate cortex, and (pre-)cuneus for individuals with high compared to low approach motivation. These results support and extend prior research on social reward processing, self-other distinctions and affective judgments by linking approach motivation to the engagement of reward-related circuits during motivational reactions to social incentives. This interplay between motivational preferences and motivational contexts might underlie the rewarding experience during social interactions.