The basis for different neural activations in response to male and female voices as well as the question, whether men and women perceive male and female voices differently, has not been thoroughly investigated. Therefore, the aim of the present study was to examine the behavioral and neural correlates of gender-related voice perception in healthy male and female volunteers. fMRI data were collected while 39 participants (19 female) were asked to indicate the gender of 240 voice stimuli. These stimuli included recordings of 3-syllable nouns as well as the same recordings pitch-shifted in 2, 4 and 6 semitone steps in the direction of the other gender. Data analysis revealed a) equal voice discrimination sensitivity in men and women but better performance in the categorization of opposite-sex stimuli at least in men, b) increased responses to increasing gender ambiguity in the mid cingulate cortex and bilateral inferior frontal gyri, and c) stronger activation in a fronto-temporal neural network in response to voices of the opposite sex. Our results indicate a gender specific processing for male and female voices on a behavioral and neuronal level. We suggest that our results reflect higher sensitivity probably due to the evolutionary relevance of voice perception in mate selection.

Borderline personality disorder (BPD) and major depressive disorder (MDD) are both associated with abnormalities in the regulation of emotion, with BPD being highly comorbid with MDD. Disorder-specific dysfunctions in BPD, however, have hardly been addressed, hence the lack of knowledge pertaining to the specificity of emotion processing deficits and their commonality with MDD. 24 healthy comparison subjects, 21 patients with MDD, and 13 patients with comorbid BPD and MDD (BPD + MDD group) were studied using functional MRI. The subjects were required to perform an emotional interference task that entailed categorizing facial affect while ignoring words that labeled the emotional contents of the external stimuli. Collapsing across emotional face types, we observed that participants with BPD + MDD uniquely displayed a greater involvement of the visual areas and the cerebellum. During emotional conflict processing, on the other hand, the lateral prefrontal cortex (LPFC) appeared to be affected in both patient groups. In comparison to the HC, the MDD group showed differences also in the posterior medial frontal cortex (pMFC) and the inferior parietal lobule (IPL). Thus, our data indicate dysfunctionality in the neural circuitry responsible for emotional conflict control in both disorders. The enhanced visual cortex activation in BPD + MDD suggests the visual system's hyperresponsiveness to faces at an early perceptual level. Not being associated with co-occurring depression, this effect in BPD + MDD appears to represent specific personality traits such as disturbed reactivity toward emotionally expressive facial stimuli.

Recent evidence suggests that humans can communicate emotion via chemosensory signals. Olfactory cues signaling anxiety can bias the perception of ambiguous stimuli, but the underlying neurobiological mechanisms of this effect are currently unknown. Here, we investigated the brain responses to subtle changes in facial expressions in response to anxiety chemosensory cues. Ten healthy individuals donated their sweat in two situations: while anticipating an important oral examination (anxiety condition) and during physical exercise (control condition). Subsequently, 24 participants completed a parametrically morphed (neutral to fearful) emotion recognition task under exposure to the olfactory cues of anxiety and sports, in the fMRI scanner. Behaviorally, the participants rated more discernible fearful faces as more fearful and neutral faces as more neutral under exposure to the anxiety cues. For brain response, under exposure to the anxiety cues, increased fearfulness of the face corresponded to increased activity in the left insula and the left middle occipital gyrus extending into fusiform gyrus. Moreover, with higher subjective ratings of facial fearfulness, participants additionally showed increased activity in the left hippocampus. These results suggest that chemosensory anxiety cues facilitate processing of socially relevant fearful stimuli and boost memory retrieval due to enhanced emotional context.

Temporolimbic circuits play a crucial role in the regulation of human emotion. A highly sensitive single-shot multiecho functional magnetic resonance imaging (fMRI) technique with gradient compensation of local magnetic field inhomogeneities and real-time data analysis were used to measure increases in amygdala activation during single 60-s trials of self-induced sadness. Six healthy male and female subjects performed a validated mood induction paradigm with randomized presentation of sad or neutral faces in 10 trials per scan. Subjects reported the intensity of experienced sadness after each trial. Immediate feedback of amygdala activation was given to the subjects during the ongoing scan to reinforce mood induction. Correspondence between increased intensity of predominantly left sided amygdala activation and self-rating of sadness was found in 78% of 120 sad trials, in contrast to only 14% of neutral trials. Amygdala activation was reproducible during repeated scanning sessions and displayed the strongest correlation with self-rating among all regions. These results suggest that amygdala activation may be closely associated with self-induced sadness. This novel real-time fMRI technology is applicable to a wide range of neuroscience studies, particularly those of the limbic system, and to neuropsychiatric conditions, such as depression, in which pathology of the amygdala has been implicated.

Subtle structural brain abnormalities are an established finding in first-episode psychosis. Nevertheless their relationship to the clinical course of schizophrenia is controversially discussed. In a multicentre study 45 first-episode schizophrenia patients (FE-SZ) underwent standardized MRI scanning and were followed up to 1 year. In 32 FE-SZ volumetric measurement of three regions of interests (ROIs) potentially associated with disease course, hippocampus, lateral ventricle and the anterior limb of the internal capsule (ALIC) could be performed. The subgroups of FE-SZ with good (12 patients) and poor outcome (11 patients), defined by a clinically relevant change of the PANSS score, were compared with regard to these volumetric measures. Multivariate analysis of covariance revealed a significant reduced maximal cross sectional area of the left ALIC in FE-SZ with clinically relevant deterioration compared to those with stable psychopathology. There were no differences in the other selected ROIs between the two subgroups. In conclusion, reduced maximal area of ALIC, which can be interpreted as a disturbance of fronto-thalamic connectivity, is associated with poor outcome during the 1 year course of first-episode schizophrenia.

ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p12. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable than generally perceived.

Tourette syndrome (TS) is a neuropsychiatric disorder with the core phenomenon of tics, whose origin and temporal pattern are unclear. We investigated the When and Where of tic generation and resting state networks (RSNs) via functional magnetic resonance imaging (fMRI).

Gender dysphoria (also known as "transsexualism") is characterized as a discrepancy between anatomical sex and gender identity. Research points towards neurobiological influences. Due to the sexually dimorphic characteristics of the human voice, voice gender perception provides a biologically relevant function, e.g. in the context of mating selection. There is evidence for a better recognition of voices of the opposite sex and a differentiation of the sexes in its underlying functional cerebral correlates, namely the prefrontal and middle temporal areas. This fMRI study investigated the neural correlates of voice gender perception in 32 male-to-female gender dysphoric individuals (MtFs) compared to 20 non-gender dysphoric men and 19 non-gender dysphoric women. Participants indicated the sex of 240 voice stimuli modified in semitone steps in the direction to the other gender. Compared to men and women, MtFs showed differences in a neural network including the medial prefrontal gyrus, the insula, and the precuneus when responding to male vs. female voices. With increased voice morphing men recruited more prefrontal areas compared to women and MtFs, while MtFs revealed a pattern more similar to women. On a behavioral and neuronal level, our results support the feeling of MtFs reporting they cannot identify with their assigned sex.

Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, resensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K/AKT and MAPK/ERK signaling in parental cells, but only GAS6 activated these pathways in OSI-resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naive and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.

Adequate emotional control is essential for mental health. Deficiencies in emotion regulation are evident in many psychiatric disorders, including depression. Patients with depression show, for instance, disrupted neural emotion regulation in cognitive regulation regions such as lateral and medial prefrontal cortices. Since depressed individuals tend to attribute positive events to external circumstances and negative events to themselves, modifying this non-self-serving attributional style may represent a promising regulation strategy. Spontaneous causal attributions are generally processed in medial brain structures, particularly the precuneus. However, so far no study has investigated neural correlates of instructed causal attributions (e.g. instructing a person to intentionally relate positive events to the self) and their potential to regulate emotions. The current study therefore aimed to examine how instructed causal attributions of positive and negative events affect the emotional experience of depressed individuals as well as its neural bases. For this purpose pictures of sad and happy faces were presented to 26 patients with a lifetime major depression (MDD) and 26 healthy controls (HC) during fMRI. Participants should respond naturally ("view") or imagine that the person on the picture was sad/happy because of them ("internal attribution") or because something else happened ("external attribution"). Trait attributional style and depressive symptoms were assessed with questionnaires to examine potential influential factors on emotion regulation ability. Results revealed that patients compared to controls show a non-self-serving trait attributional style (i.e. more external attributions of positive events and more internal attributions of negative events). Intriguingly, when instructed to apply specific causal attributions during the emotion regulation task, patients and controls were similarly able to regulate positive and negative emotions. Regulating emotions through instructed attributions (internal/external attribution>view) generally engaged the precuneus, which was correlated with patients' trait attributional style (i.e. more precuneus activation during external>view was linked to a general tendency to relate positive events to external sources). Up-regulating happiness through internal (compared to external) attributions recruited the parahippocampal gyrus only in controls. The down-regulation of sadness (external>internal attribution), in contrast, engaged the superior frontal gyrus only in patients. Superior frontal gyrus activation thereby correlated with depression severity, which implies a greater need of cognitive resources for a successful regulation in more severely depressed. Patients and controls did not differ in activation in brain regions related to cognitive emotion regulation or attribution. However, results point to a disturbed processing of positive emotions in depression. Interestingly, increased precuneus resting-state connectivity with emotion regulation brain regions (inferior parietal lobule, middle frontal gyrus) was linked to healthier attributions (i.e. external attributions of negative events) in patients and controls. Adequate neural communication between these regions therefore seem to facilitate an adaptive trait attributional style. Findings of this study emphasize that despite patients' dysfunctional trait attributional style, explicitly applying causal attributions effectively regulates emotions. Future research should examine the efficacy of instructed attributions in reducing negative affect and anhedonia in depressed patients, for instance by means of attribution trainings during psychotherapy.

Deutetrabenazine (Austedo) is indicated in adults for chorea associated with Huntington disease and tardive dyskinesia. Escalating deutetrabenazine doses were administered to healthy volunteers who were cytochrome P450 2D6 extensive/intermediate metabolizers (EMs) or poor metabolizers (PMs) to determine pharmacokinetic exposure of parent drug and active metabolites (α-dihydrotetrabenazine [α-HTBZ] and β-dihydrotetrabenazine [β-HTBZ]), and collect corresponding electrocardiograms (ECGs) for evaluation of the cardiodynamic effect using concentration-QTc (C-QTc) modeling. Participants (12 EMs, 24 PMs) received placebo or single doses of deutetrabenazine (24, 48, and 72 mg) to achieve plasma concentrations exceeding therapeutic range in both cohorts. Pharmacokinetic samples were obtained over 72 hours after dosing and were time matched with 12-lead ECGs extracted from continuous ECG recordings. C-QTc analysis, using linear mixed-effects modeling and model selection procedure, characterized the relationship between plasma concentrations of deutetrabenazine, deuterated α-HTBZ and β-HTBZ, and the change from baseline in QT interval corrected using Fridericia's formula. Deutetrabenazine exhibited linear kinetics, and a C-QTc model with deuterated α-HTBZ and β-HTBZ was selected to best describe the C-QTc relationship in pooled EM and PM data. This model predicted a placebo-corrected Fridericia corrected QT interval prolongation higher than 10 milliseconds can be excluded at concentrations associated with the maximum recommended doses in both populations. Adverse events increased with higher exposure as reflected by the higher event number in the PM cohort receiving 48 and 72 mg doses. No subject discontinued due to cardiac-related adverse events and no clinically relevant ECG findings were reported. Thus, this study found that deutetrabenazine does not have a clinically relevant effect on QT prolongation at maximum recommended doses in either cytochrome P450 2D6 EMs or PMs.

As many paths lead to aggression, understanding which situations and which person-specific traits facilitate or impede aggressive behavior is crucial. Provocation is among one of the most frequently reported predictors of aggressive behavior. However, it remains unclear whether the reaction to provocation is universal across different forms of aggression and whether individuals differ in their reactivity to such signals. Using the Taylor Aggression Paradigm (TAP), we investigated the influence of individual and contextual factors on physical and non-physical aggression in healthy men and women. The impact of trait aggression, sex, provocation, and the success of a competition against a fictitious opponent on aggressive behavior was examined in three different versions of the TAP. While equal provocation and punishment modalities were used in the first two versions, monetary deductions in the first and heat stimulus in the second study, the third experiment used non-physical provocation to trigger physical punishment. Trial-by-trial analyses revealed that provocation, independent of its specific nature, is a strong predictor for aggressive behavior, especially in highly aggressive participants. Although women initially showed less aggression than men, sex differences were diminished under prolonged, increasing provocation when provocation and punishment modality were identical. Only when modalities diverged, women, compared with men, were more hesitant to punish their opponent. These results, thus, extend evidence that women show lower levels of aggression under low provocation. However, high levels of provocation have similar effects on males' and females' reactive aggressive behavior across different forms of aggression. When competing for money, losing against the fictitious opponent was functioning as an additional provocative signal stimulating aggressive responses. Differences in aggressive responding have to be interpreted in the context of the specific type of provocation and aggression that is investigated since these modalities are shown to interact with individual characteristics.

The pathogenesis of multi-organ dysfunction associated with severe acute SARS-CoV-2 infection remains poorly understood. Endothelial damage and microvascular thrombosis have been identified as drivers of COVID-19 severity, yet the mechanisms underlying these processes remain elusive. Here we show alterations in fluid shear stress-responsive pathways in critically ill COVID-19 adults as compared to non-COVID critically ill adults using a multiomics approach. Mechanistic in-vitro studies, using microvasculature-on-chip devices, reveal that plasma from critically ill COVID-19 adults induces fibrinogen-dependent red blood cell aggregation that mechanically damages the microvascular glycocalyx. This mechanism appears unique to COVID-19, as plasma from non-COVID sepsis patients demonstrates greater red blood cell membrane stiffness but induces less significant alterations in overall blood rheology. Multiomics analyses in pediatric patients with acute COVID-19 or the post-infectious multi-inflammatory syndrome in children (MIS-C) demonstrate little overlap in plasma cytokine and metabolite changes compared to adult COVID-19 patients. Instead, pediatric acute COVID-19 and MIS-C patients show alterations strongly associated with cytokine upregulation. These findings link high fibrinogen and red blood cell aggregation with endotheliopathy in adult COVID-19 patients and highlight differences in the key mediators of pathogenesis between adult and pediatric populations.