In functional magnetic resonance imaging (fMRI) studies that apply a "subsequent memory" approach, successful encoding is indicated by increased fMRI activity during the encoding phase for hits vs. misses, in areas underlying memory encoding such as the hippocampal formation. Signal-detection theory (SDT) can be used to analyze memory-related fMRI activity as a function of the participant's memory trace strength (d(')). The goal of the present study was to use SDT to examine the relationship between fMRI activity during incidental encoding and participants' recognition performance. To implement a new approach, post-experimental group assignment into High- or Low Performers (HP or LP) was based on 29 healthy participants' recognition performance, assessed with SDT. The analyses focused on the interaction between the factors group (HP vs. LP) and recognition performance (hits vs. misses). A whole-brain analysis revealed increased activation for HP vs. LP during incidental encoding for remembered vs. forgotten items (hits > misses) in the insula/temporo-parietal junction (TPJ) and the fusiform gyrus (FFG). Parameter estimates in these regions exhibited a significant positive correlation with d('). As these brain regions are highly relevant for salience detection (insula), stimulus-driven attention (TPJ), and content-specific processing of mnemonic stimuli (FFG), we suggest that HPs' elevated memory performance was associated with enhanced attentional and content-specific sensory processing during the encoding phase. We provide first correlative evidence that encoding-related activity in content-specific sensory areas and content-independent attention and salience detection areas influences memory performance in a task with incidental encoding of facial stimuli. Based on our findings, we discuss whether the aforementioned group differences in brain activity during incidental encoding might constitute the basis of general differences in memory performance between HP and LP.

Recent evidence suggests that the experience of stress can be communicated between individuals via chemosensory cues. Little is known, however, about the impact of these cues on neurophysiological responses during a socially threatening situation. In the current investigation we implemented a widely used paradigm to study social exclusion-Cyberball-to examine whether chemosensory cues signaling anxiety modulate the neuronal effects of ostracism. In a double-blind, within-subjects design, 24 healthy, normosmic participants were presented with chemosensory cues of anxiety (or control samples) and completed the Cyberball task while in a 3T fMRI scanner. Axillary sweat collected from male students awaiting an oral examination served as the anxiety cues while the chemosensory control stimuli consisted of sweat collected from the same individuals participating in an ergometer training session. The neuroimaging data revealed that under the control chemosensory condition, exclusion from Cyberball was associated with significantly higher orbitofrontal cortex and anterior cingulate cortex activity, which is consistent with previous studies in the field. However, when participants were primed with the anxiety sweat, the activity in these regions was not observed. Further, under exposure to anxiety cues during ostracism the participants showed deactivations in brain regions involved in memory (hippocampus), social cognition (middle temporal gyrus, superior temporal gyrus) and processing of salience (inferior frontal gyrus). These results suggest that successful communication of anxiety via the chemosensory domain may moderate the experience of social exclusion. It is possible that the anxiety signals make it easier for the individuals to detach from the group, pointing to the communicative role of chemosensory anxiety cues in enhancing adjustment mechanisms in light of a distressing situation.

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive administration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200 mg/kg) and 10-day HAB treatment resulted in severe and progressive obliterative PH and formation of PXL (Day 26, right ventricular peak systolic pressure (mmHg): 26.1 ± 1.1, 41.5 ± 0.5 and 85.1 ± 5.9 in untreated, HAB treated and SU+HAB treated rats, respectively). In rats, repetitive administration of HAB increased plasma ADA activity and reduced urinary adenosine levels. Similarly, SCD patients had higher plasma ADA and PNP activity and accelerated adenosine, inosine, and guanosine metabolism than healthy controls. Our study provides evidence that hemolysis per se leads to the development of angioproliferative PH. We also report the development of a rat model of HA-PH that closely mimics pulmonary vasculopathy seen in patients with HA-PH. Finally, this study suggests that in hemolytic diseases released ADA and PNP may increase the risk of PH, likely by abolishing the vasoprotective effects of adenosine, inosine and guanosine. Further characterization of this new rat model of hemolysis-induced angioproliferative PH and additional studies of the role of purines metabolism in HA-PH are warranted.

SD-1077, a selectively deuterated precursor of dopamine (DA) structurally related to L-3,4-dihydroxyphenylalanine (L-DOPA), is under development for treatment of motor symptoms of Parkinson's disease. Preclinical models have shown slower metabolism of central deuterated DA. The present study investigated the peripheral pharmacokinetics (PK), metabolism and safety of SD-1077.

Animal studies suggest a causal link between testosterone and aggression. However, in human research the exact role of this hormone is still unclear, having been linked to dominance and approach behavior rather than to aggression per se. In a social context, the induction of aggression might be confounded with dominance or status changes, which potentially influence the association between aggression and testosterone. The objective of the current study was to investigate the influence of testosterone on non-social aggression in a double-blind, placebo-controlled experiment including 90 healthy male participants. To this end, we developed an innovative paradigm in which participants were provoked by a malfunctioning joystick restraining them from a promised reward. As measures for aggression throughout the task the joystick amplitude was recorded and anger was assessed via emotional self-ratings. Participants reacted to the provocation with a significant shift to more negative emotions and increased implicit aggressive behavior, reflected in the force exerted to pull the joystick following provocation. Importantly, the study demonstrated first evidence for a modulating influence of testosterone on non-social aggression in males: Self-rated anger was significantly elevated in the testosterone group compared to the placebo group as a function of provocation. Testosterone administration did not significantly influence the implicit aggressive response. These findings demonstrate a potentiating effect of testosterone on provocation-related anger in a non-social context. Furthermore, the results highlight the importance of disentangling different components of aggression and characterizing different influencing factors when inferring on hormonal effects.

Schizophrenia is a severe neuropsychiatric disorder with high heritability, though its exact etiopathogenesis is yet unknown. An increasing number of studies point to the importance of white matter anomalies in the pathophysiology of schizophrenia. While several studies have identified the impact of schizophrenia susceptibility gene variants on gray matter anatomy in both schizophrenia patients and healthy risk variant carriers, studies dealing with the impact of these gene variants on white matter integrity are still scarce. We here present a study on the effects of a Dysbindin schizophrenia susceptibility gene variant on fiber tract integrity in healthy young subjects. 101 subjects genotyped for Dysbindin-gene variant rs1018381, though without personal or first degree relative history of psychiatric disorders underwent diffusion tensor imaging (DTI), 83 of them were included in the final analysis. We used Tract-Based Spatial Statistics (TBSS) analysis to delineate the major fiber tracts. Carriers of the minor allele T of the rs1018381 in the Dysbindin gene showed two clusters of reduced fractional anisotropy (FA) values in the perihippocampal region of the right temporal lobe compared to homozygote carriers of the major allele C. Clusters of increased FA values in T-allele carriers were found in the left prefrontal white matter, the right fornix, the right midbrain area, the left callosal body, the left cerebellum and in proximity of the right superior medial gyrus. Dysbindin has been implicated in neurite outgrowth and morphology. Impairments in anatomic connectivity as found associated with the minor Dysbindin allele in our study may result in increased risk for schizophrenia due to altered fiber tracts.

Emotions are often encountered in a multimodal fashion. Consequently, contextual framing by other modalities can alter the way that an emotional facial expression is perceived and lead to emotional conflict. Whole brain fMRI data was collected when 35 healthy subjects judged emotional expressions in faces while concurrently being exposed to emotional (scream, laughter) or neutral (yawning) sounds. The behavioral results showed that subjects rated fearful and neutral faces as being more fearful when accompanied by screams than compared to yawns (and laughs for fearful faces). Moreover, the imaging data revealed that incongruence of emotional valence between faces and sounds led to increased activation in the middle cingulate cortex, right superior frontal cortex, right supplementary motor area as well as the right temporoparietal junction. Against expectations no incongruence effects could be found in the amygdala. Further analyses revealed that, independent of emotional valence congruency, the left amygdala was consistently activated when the information from both modalities was emotional. If a neutral stimulus was present in one modality and emotional in the other, activation in the left amygdala was significantly attenuated. These results indicate that incongruence of emotional valence in audiovisual integration activates a cingulate-fronto-parietal network involved in conflict monitoring and resolution. Furthermore in audiovisual pairing amygdala responses seem to signal also the absence of any neutral feature rather than only the presence of an emotionally charged one.

Echo time dependence of the BOLD sensitivity is an important topic in fMRI whenever brain regions are considered where the EPI data quality suffers from susceptibility gradients. Here, an fMRI study is presented showing that a reduced echo time EPI sequence significantly enhances the statistical inference in subcortical (limbic) brain regions, with special focus on the amygdala. As a consequence, to facilitate whole-brain fMRI with optimal echo times, a sequence with slice-dependent echo time is demonstrated with a focus on structures suffering from susceptibility changes. The applicability of this method is shown in a second fMRI study aimed at both, cortical, and limbic brain regions. The results are in good agreement with theoretical descriptions of the BOLD sensitivity under the influence of susceptibility gradients.

Tourette syndrome is a neuropsychiatric disorder with the cardinal symptoms of motor and vocal tics. Often tics are accompanied by comorbidities such as obsessive-compulsive disorder, attention-deficit-hyperactivity disorder or depression. Research has mainly focused on the cortico-striato-thalamo circuit, but clinical symptoms and recent neuroimaging studies reporting altered resting network connectivity have suggested abnormalities in Tourette syndrome beyond the major motor circuits. We acquired diffusion-weighted data at 1.5T in nineteen adult patients fulfilling the DSM-IV-TR criteria for Tourette syndrome and in a healthy control group. Diffusion tensor imaging (DTI) analysis in our adult TS sample shows a decrease of FA and increase in radial diffusivity in the corticospinal tract. There are widespread changes (reduced FA and increased radial diffusivity) in the anterior and posterior limb of the internal capsule. Furthermore, it confirms prior findings of altered interhemispheric connectivity as indicated by a FA-decrease in the corpus callosum. In addition, our results indicate that TS is not restricted to motor pathways alone but affects association fibres such as the inferior fronto-occipitalis fascicle, the superior longitudinal fascicle and fascicle uncinatus as well. Tics are the hallmark of Tourette syndrome, so the involvement of the corticospinal tract fits in well with clinical symptoms. Cortical regions as well as limbic structures take part in the modulation of tics. Our findings of alterations in long association fibre tracts and the corpus callosum are a potential source for hindered interhemispheric and transhemispheric interaction. The change in radial diffusivity points toward a deficit in myelination as one pathophysiological factor in Tourette syndrome.

The tumor necrosis factor (TNF)-receptor 1-associated death domain protein (TRADD) mediates induction of apoptosis as well as activation of NF-kappaB by cellular TNF-receptor 1 (TNFR1). TRADD is also recruited by the latent membrane protein 1 (LMP1) oncoprotein of Epstein-Barr virus, but its role in LMP1 signaling has remained enigmatic. In human B lymphocytes, we have generated, to our knowledge, the first genetic knockout of TRADD to investigate TRADD's role in LMP1 signal transduction. Our data from TRADD-deficient cells demonstrate that TRADD is a critical signaling mediator of LMP1 that is required for LMP1 to recruit and activate I-kappaB kinase beta (IKKbeta). However, in contrast to TNFR1, LMP1-induced TRADD signaling does not induce apoptosis. Searching for the molecular basis for this observation, we characterized the 16 C-terminal amino acids of LMP1 as an autonomous and unique virus-derived TRADD-binding domain. Replacing the death domain of TNFR1 by LMP1's TRADD-binding domain converts TNFR1 into a nonapoptotic receptor that activates NF-kappaB through a TRAF6-dependent pathway, like LMP1 but unlike wild-type TNFR1. Thus, the unique interaction of LMP1 with TRADD encodes the transforming phenotype of viral TRADD signaling and masks TRADD's pro-apoptotic function.

Deutetrabenazine (Austedo, Teva), an approved treatment of chorea in Huntington's disease and tardive dyskinesia in adult patients, is a rationally designed deuterated form of tetrabenazine. Two studies assessed the pharmacokinetics and safety of deutetrabenazine compared with tetrabenazine, and the effects of food on absorption of the deuterated active metabolites, α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ). One study was an open-label 2-part study in healthy volunteers; the first part included a crossover single dose of two 15 mg candidate deutetrabenazine formulations in fed and fasted states compared with tetrabenazine 25 mg in the fasted state, and the second part included single and repeated dosing of the commercial formulation of deutetrabenazine (7.5, 15, and 22.5 mg) compared with tetrabenazine 25 mg. The second study was an open-label 5-way crossover study in healthy volunteers (n = 32) to evaluate relative bioavailability of 4 dose levels of the commercial formulation of deutetrabenazine (6, 12, 18, and 24 mg) with a standard meal and 18 mg with a high-fat meal. Both studies confirmed longer half-lives for active metabolites and lower peak-to-trough fluctuations for the sum of the metabolites (total [α+β]-HTBZ) following deutetrabenazine compared with tetrabenazine (3- to 4-fold and 11-fold, respectively) in steady-state conditions. Deutetrabenazine doses estimated to provide total (α+β)-HTBZ exposure comparable to tetrabenazine 25 mg were 11.4-13.2 mg. Food had no effect on exposure to total (α+β)-HTBZ, as measured by AUC. Although the total (α+β)-HTBZ Cmax of deutetrabenazine was increased by ≈50% in the presence of food, it remained lower than that of tetrabenazine.

Deutetrabenazine (Austedo, Teva Pharmaceuticals) is a deuterated form of tetrabenazine. It is the first deuterated drug to receive US regulatory approval and is approved for treatment of chorea in Huntington's disease and tardive dyskinesia. Two oral single dose studies comparing deutetrabenazine (25 mg) with tetrabenazine (25 mg) in healthy volunteers evaluated the impact of deuteration on pharmacokinetics of the active metabolites, alpha-dihydrotetrabenazine (α-HTBZ) and beta-dihydrotetrabenazine (β-HTBZ), metabolite profile, safety, and tolerability. In the two-way, cross-over study, the mean elimination half-life of deuterated total (α + β)-HTBZ was doubled compared with nondeuterated total (α + β)-HTBZ, with a twofold increase in overall mean exposure (area under the concentration-time curve from zero to infinity (AUC0-inf )) and a marginal increase in mean peak plasma concentration (Cmax ). In the mass balance and metabolite profiling study, there were no novel plasma or urinary metabolites of [14 C]-deutetrabenazine relative to [14 C]-tetrabenazine. Specific deuteration in deutetrabenazine resulted in a superior pharmacokinetic profile and an increased ratio of active-to-inactive metabolites, attributes considered to provide significant benefits to patients.

Advanced paternal age (APA) is a risk factor for several neurodevelopmental disorders, including autism and schizophrenia. The potential mechanisms conferring this risk are poorly understood. Here, we show that the personality traits schizotypy and neuroticism correlated with paternal age in healthy subjects (N = 677). Paternal age was further positively associated with gray matter volume (VBM, N = 342) in the right prefrontal and the right medial temporal cortex. The integrity of fiber tracts (DTI, N = 222) connecting these two areas correlated positively with paternal age. Genome-wide methylation analysis in humans showed differential methylation in APA individuals, linking APA to epigenetic mechanisms. A corresponding phenotype was obtained in our rat model. APA rats displayed social-communication deficits and emitted fewer pro-social ultrasonic vocalizations compared to controls. They further showed repetitive and stereotyped patterns of behavior, together with higher anxiety during early development. At the neurobiological level, microRNAs miR-132 and miR-134 were both differentially regulated in rats and humans depending on APA. This study demonstrates associations between APA and social behaviors across species. They might be driven by changes in the expression of microRNAs and/or epigenetic changes regulating neuronal plasticity, leading to brain morphological changes and fronto-hippocampal connectivity, a network which has been implicated in social interaction.

The pathogenesis of severe COVID-19 remains poorly understood. While several studies suggest that immune dysregulation plays a central role, the key mediators of this process are yet to be defined. Here, we demonstrate that plasma from a high proportion (77%) of critically ill COVID-19 patients, but not healthy controls, contains broadly auto-reactive immunoglobulin M (IgM), and only infrequently auto-reactive IgG or IgA. Importantly, these auto-IgM preferentially recognize primary human lung cells in vitro, including pulmonary endothelial and epithelial cells. By using a combination of flow cytometry, LDH-release assays, and analytical proteome microarray technology, we identified high-affinity, complement-fixing, auto-reactive IgM directed against 263 candidate auto-antigens, including numerous molecules preferentially expressed on cellular membranes in pulmonary, vascular, gastrointestinal, and renal tissues. These findings suggest that broad IgM-mediated autoimmune reactivity may be involved in the pathogenesis of severe COVID-19, thereby identifying a potential target for novel therapeutic interventions.

Expression of polysialic acid (polySia) in the adult brain is enriched in areas of continuous neurogenesis and plasticity such as the hippocampus. Genome-wide association studies identified variants of glycosylation enzyme-encoding genes, required for the generation of polySia, to be associated with the development of schizophrenia and bipolar disorder. Here, we report that serum levels of polySia are increased in patients with schizophrenia spectrum disorder compared to patients with major depressive disorders or demographically matched healthy controls. Furthermore, elevated polySia serum levels are associated with structural hippocampal gray matter decline in schizophrenia spectrum and bipolar disorder. In patients with schizophrenia spectrum disorder, polySia serum levels correlate with the number, duration of disease-related hospitalizations, early retirement and medical leave as estimators of detrimental long-term disease trajectories. Our data show that polySia serum levels are linked to structural hippocampal brain changes in schizophrenia spectrum and bipolar disorders, and suggest a contribution of polySia to the pathophysiology of these diseases.

We currently observe a disconcerting phenomenon in machine learning studies in psychiatry: While we would expect larger samples to yield better results due to the availability of more data, larger machine learning studies consistently show much weaker performance than the numerous small-scale studies. Here, we systematically investigated this effect focusing on one of the most heavily studied questions in the field, namely the classification of patients suffering from Major Depressive Disorder (MDD) and healthy controls based on neuroimaging data. Drawing upon structural MRI data from a balanced sample of N = 1868 MDD patients and healthy controls from our recent international Predictive Analytics Competition (PAC), we first trained and tested a classification model on the full dataset which yielded an accuracy of 61%. Next, we mimicked the process by which researchers would draw samples of various sizes (N = 4 to N = 150) from the population and showed a strong risk of misestimation. Specifically, for small sample sizes (N = 20), we observe accuracies of up to 95%. For medium sample sizes (N = 100) accuracies up to 75% were found. Importantly, further investigation showed that sufficiently large test sets effectively protect against performance misestimation whereas larger datasets per se do not. While these results question the validity of a substantial part of the current literature, we outline the relatively low-cost remedy of larger test sets, which is readily available in most cases.

In this study, we determined the potential of polyethylene glycol-encapsulated iron oxide nanoparticles (IONPCO) for the intracellular delivery of the chemotherapeutic doxorubicin (IONPDOX) to enhance the cytotoxic effects of ionizing radiation. The biological effects of IONP and X-ray irradiation (50 kV and 6 MV) were determined in HeLa cells using the colony formation assay (CFA) and detection of γH2AX foci. Data are presented as mean ± SEM. IONP were efficiently internalized by HeLa cells. IONPCO radiomodulating effect was dependent on nanoparticle concentration and photon energy. IONPCO did not radiosensitize HeLa cells with 6 MV X-rays, yet moderately enhanced cellular radiosensitivity to 50 kV X-rays (DMFSF0.1 = 1.13 ± 0.05 (p = 0.01)). IONPDOX did enhance the cytotoxicity of 6 MV X-rays (DMFSF0.1 = 1.3 ± 0.1; p = 0.0005). IONP treatment significantly increased γH2AX foci induction without irradiation. Treatment of HeLa cells with IONPCO resulted in a radiosensitizing effect for low-energy X-rays, while exposure to IONPDOX induced radiosensitization compared to IONPCO in cells irradiated with 6 MV X-rays. The effect did not correlate with the induction of γH2AX foci. Given these results, IONP are promising candidates for the controlled delivery of DOX to enhance the cytotoxic effects of ionizing radiation.

Protein-protein interaction networks are altered in multi-gene dysregulations in many disorders. Image-based protein multiplexing sheds light on signaling pathways to dissect cell-to-cell heterogeneity, previously masked by the bulk assays. Herein, we present a rapid multiplexed immunofluorescence (RapMIF) method measuring up to 25-plex spatial protein maps from cultures and tissues at subcellular resolution, providing combinatorial 272 pairwise and 1,360 tri-protein signaling states across 33 multiplexed pixel-level clusters. The RapMIF pipeline automated staining, bleaching, and imaging of the biospecimens in a single platform. RapMIF showed that WNT/β-catenin signaling upregulated upon the inhibition of the AKT/mTOR pathway. Subcellular protein images demonstrated translocation patterns, spatial receptor discontinuity, and subcellular signaling clusters in single cells. Signaling networks exhibited spatial redistribution of signaling proteins in drug-responsive cultures. Machine learning analysis predicted the phosphorylated β-catenin expression from interconnected signaling protein images. RapMIF is an ideal signaling discovery approach for precision therapy design.

Cognitive deficits are central attendant symptoms of major depressive disorder (MDD) with a crucial impact in patients' everyday life. Thus, it is of particular clinical importance to understand their pathophysiology. The aim of this study was to investigate a possible relationship between brain structure and cognitive performance in MDD patients in a well-characterized sample. N = 1007 participants (NMDD = 482, healthy controls (HC): NHC = 525) were selected from the FOR2107 cohort for this diffusion-tensor imaging study employing tract-based spatial statistics. We conducted a principal component analysis (PCA) to reduce neuropsychological test results, and to discover underlying factors of cognitive performance in MDD patients. We tested the association between fractional anisotropy (FA) and diagnosis (MDD vs. HC) and cognitive performance factors. The PCA yielded a single general cognitive performance factor that differed significantly between MDD patients and HC (P < 0.001). We found a significant main effect of the general cognitive performance factor in FA (Ptfce-FWE = 0.002) in a large bilateral cluster consisting of widespread frontotemporal-association fibers. In MDD patients this effect was independent of medication intake, the presence of comorbid diagnoses, the number of previous hospitalizations, and depressive symptomatology. This study provides robust evidence that white matter disturbances and cognitive performance seem to be associated. This association was independent of diagnosis, though MDD patients show more pronounced deficits and lower FA values in the global white matter fiber structure. This suggests a more general, rather than the depression-specific neurological basis for cognitive deficits.

Neuroanatomical abnormalities have been reported along a continuum from at-risk stages, including high schizotypy, to early and chronic psychosis. However, a comprehensive neuroanatomical mapping of schizotypy remains to be established. The authors conducted the first large-scale meta-analyses of cortical and subcortical morphometric patterns of schizotypy in healthy individuals, and compared these patterns with neuroanatomical abnormalities observed in major psychiatric disorders. The sample comprised 3004 unmedicated healthy individuals (12-68 years, 46.5% male) from 29 cohorts of the worldwide ENIGMA Schizotypy working group. Cortical and subcortical effect size maps with schizotypy scores were generated using standardized methods. Pattern similarities were assessed between the schizotypy-related cortical and subcortical maps and effect size maps from comparisons of schizophrenia (SZ), bipolar disorder (BD) and major depression (MDD) patients with controls. Thicker right medial orbitofrontal/ventromedial prefrontal cortex (mOFC/vmPFC) was associated with higher schizotypy scores (r = 0.067, pFDR = 0.02). The cortical thickness profile in schizotypy was positively correlated with cortical abnormalities in SZ (r = 0.285, pspin = 0.024), but not BD (r = 0.166, pspin = 0.205) or MDD (r = -0.274, pspin = 0.073). The schizotypy-related subcortical volume pattern was negatively correlated with subcortical abnormalities in SZ (rho = -0.690, pspin = 0.006), BD (rho = -0.672, pspin = 0.009), and MDD (rho = -0.692, pspin = 0.004). Comprehensive mapping of schizotypy-related brain morphometry in the general population revealed a significant relationship between higher schizotypy and thicker mOFC/vmPFC, in the absence of confounding effects due to antipsychotic medication or disease chronicity. The cortical pattern similarity between schizotypy and schizophrenia yields new insights into a dimensional neurobiological continuity across the extended psychosis phenotype.