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Childhood maltreatment (CM) is associated with increased limbic activity, while social support is linked to decreased limbic activity towards negative stimuli. Our study aimed to explore the interaction of perceived social support with CM, and their combined impact on limbic activity in negative emotion processing. A total of 130 healthy individuals (HC) underwent a negative emotional face processing paradigm. They were divided into two groups based on the Childhood Trauma Questionnaire: n = 65 HC without CM matched with n = 65 HC with CM. In a region-of-interest approach of the bilateral amygdala-hippocampus-complex (AHC), regression analyses investigating the association of CM and perceived social support with limbic activity and a social support x CM ANCOVA were conducted. CM was associated with increased AHC activity, while perceived social support tended to be associated with decreased AHC activity during negative emotion processing. The ANCOVA showed a significant interaction in bilateral AHC activity (pFWE ≤ 0.024) driven by a negative association between perceived social support and bilateral AHC activity in HC without CM. No significant association was observed in HC with CM. Exploratory analyses using continuous CM scores support this finding. Our results suggest that CM moderates the link between perceived social support and limbic activity, with a protective effect of perceived social support only in HC without CM. The lack of this effect in HC with CM suggests that CM may alter the buffering effect of perceived social support on limbic functioning, highlighting the potential need for preventive interventions targeting social perception of HC with CM.
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Introduction: As a source of audio-visual stimulation, movies expose people to various emotions. Interestingly, several genres are characterized by negative emotional content. Albeit theoretical approaches exist, little is known about preferences for specific movie genres and the neuronal processing of negative emotions. Methods: We investigated associations between movie genre preference and limbic and reward-related brain reactivity to close this gap by employing an fMRI paradigm with negative emotional faces in 257 healthy participants. We compared the functional activity of the amygdala and the nucleus accumbens (NAcc) between individuals with a preference for a particular movie genre and those without such preference. Results and discussion: Amygdala activation was relatively higher in individuals with action movie preference (p TFCE-FWE = 0.013). Comedy genre preference was associated with increased amygdala (p TFCE-FWE = 0.038) and NAcc activity (p TFCE-FWE = 0.011). In contrast, crime/thriller preference (amygdala: p TFCE-FWE ≤ 0.010, NAcc: p TFCE-FWE = 0.036), as well as documentary preference, was linked to the decreased amygdala (p TFCE-FWE = 0.012) and NAcc activity (p TFCE-FWE = 0.015). The study revealed associations between participants' genre preferences and brain reactivity to negative affective stimuli. Interestingly, preferences for genres with similar emotion profiles (action, crime/thriller) were associated with oppositely directed neural activity. Potential links between brain reactivity and susceptibility to different movie-related gratifications are discussed.
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Thromboembolic events are common in patients with essential thrombocythemia (ET). However, the pathophysiological mechanisms underlying the increased thrombotic risk remain to be determined. Here, we perform the first phenotypical characterization of platelet expression using single-cell mass cytometry in six ET patients and six age- and sex-matched healthy individuals. A large panel of 18 transmembrane regulators of platelet function and activation were analyzed, at baseline and after ex-vivo stimulation with thrombin receptor-activating peptide (TRAP). We detected a significant overexpression of the activation marker CD62P (p-Selectin) (p = .049) and the collagen receptor GPVI (p = .044) in non-stimulated ET platelets. In contrast, ET platelets had a lower expression of the integrin subunits of the fibrinogen receptor GPIIb/IIIa CD41 (p = .036) and CD61 (p = .044) and of the von Willebrand factor receptor CD42b (p = .044). Using the FlowSOM algorithm, we identified 2 subclusters of ET platelets with a prothrombotic expression profile, one of them (cluster 3) significantly overrepresented in ET (22.13% of the total platelets in ET, 2.94% in controls, p = .035). Platelet counts were significantly increased in ET compared to controls (p = .0123). In ET, MPV inversely correlated with platelet count (r=-0.96). These data highlight the prothrombotic phenotype of ET and postulate GPVI as a potential target to prevent thrombosis in these patients.
Essential thrombocythemia (ET) is a rare disease characterized by an increased number of platelets in the blood. As a complication, many of these patients develop a blood clot, which can be life-threatening. So far, the reason behind the higher risk of blood clots is unclear. In this study, we analyzed platelet surface markers that play a critical role in platelet function and platelet activation using a modern technology called mass cytometry. For this purpose, blood samples from 6 patients with ET and 6 healthy control individuals were analyzed. We found significant differences between ET platelets and healthy platelets. ET platelets had higher expression levels of p-Selectin (CD62P), a key marker of platelet activation, and of the collagen receptor GPVI, which is important for clot formation. These results may be driven by a specific platelet subcluster overrepresented in ET. Other surface markers, such as the fibrinogen receptor GPIIb/IIIa CD41, CD61, and the von Willebrand factor receptor CD42b, were lower expressed in ET platelets. When ET platelets were treated with the clotting factor thrombin (thrombin receptor-activating peptide, TRAP), we found a differential response in platelet activation compared to healthy platelets. In conclusion, our results show an increased activation and clotting potential of ET platelets. The platelet surface protein GPVI may be a potential drug target to prevent abnormal blood clotting in ET patients.
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Plaquetas , Trombocitemia Essencial , Trombose , Humanos , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/complicações , Plaquetas/metabolismo , Masculino , Feminino , Trombose/metabolismo , Trombose/etiologia , Pessoa de Meia-Idade , Idoso , Citometria de Fluxo/métodos , Ativação Plaquetária , Estudos de Casos e Controles , AdultoRESUMO
Biased emotion processing has been suggested to underlie the etiology and maintenance of depression. Neuroimaging studies have shown mood-congruent alterations in amygdala activity in patients with acute depression, even during early, automatic stages of emotion processing. However, due to a lack of prospective studies over periods longer than 8 weeks, it is unclear whether these neurofunctional abnormalities represent a persistent correlate of depression even in remission. In this prospective case-control study, we aimed to examine brain functional correlates of automatic emotion processing in the long-term course of depression. In a naturalistic design, n = 57 patients with acute major depressive disorder (MDD) and n = 37 healthy controls (HC) were assessed with functional magnetic resonance imaging (fMRI) at baseline and after 2 years. Patients were divided into two subgroups according to their course of illness during the study period (n = 37 relapse, n = 20 no-relapse). During fMRI, participants underwent an affective priming task that assessed emotion processing of subliminally presented sad and happy compared to neutral face stimuli. A group × time × condition (3 × 2 × 2) ANOVA was performed for the amygdala as region-of-interest (ROI). At baseline, there was a significant group × condition interaction, resulting from amygdala hyperactivity to sad primes in patients with MDD compared to HC, whereas no difference between groups emerged for happy primes. In both patient subgroups, amygdala hyperactivity to sad primes persisted after 2 years, regardless of relapse or remission at follow-up. The results suggest that amygdala hyperactivity during automatic processing of negative stimuli persists during remission and represents a trait rather than a state marker of depression. Enduring neurofunctional abnormalities may reflect a consequence of or a vulnerability to depression.
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Tonsila do Cerebelo , Transtorno Depressivo Maior , Emoções , Imageamento por Ressonância Magnética , Humanos , Tonsila do Cerebelo/fisiopatologia , Masculino , Feminino , Adulto , Imageamento por Ressonância Magnética/métodos , Transtorno Depressivo Maior/fisiopatologia , Emoções/fisiologia , Estudos de Casos e Controles , Pessoa de Meia-Idade , Estudos Prospectivos , Expressão Facial , Depressão/fisiopatologia , Mapeamento Encefálico/métodos , Estimulação SubliminarRESUMO
BACKGROUND: Magnetic resonance imaging (MRI) studies on major depressive disorder (MDD) have predominantly found short-term electroconvulsive therapy (ECT)-related gray matter volume (GMV) increases, but research on the long-term stability of such changes is missing. Our aim was to investigate long-term GMV changes over a 2-year period after ECT administration and their associations with clinical outcome. METHODS: In this nonrandomized longitudinal study, patients with MDD undergoing ECT (n = 17) are assessed three times by structural MRI: Before ECT (t0), after ECT (t1) and 2 years later (t2). A healthy (n = 21) and MDD non-ECT (n = 33) control group are also measured three times within an equivalent time interval. A 3(group) × 3(time) ANOVA on whole-brain level and correlation analyses with clinical outcome variables is performed. RESULTS: Analyses yield a significant group × time interaction (pFWE < 0.001) resulting from significant volume increases from t0 to t1 and decreases from t1 to t2 in the ECT group, e.g., in limbic areas. There are no effects of time in both control groups. Volume increases from t0 to t1 correlate with immediate and delayed symptom increase, while volume decreases from t1 to t2 correlate with long-term depressive outcome (all p ⩽ 0.049). CONCLUSIONS: Volume increases induced by ECT appear to be a transient phenomenon as volume strongly decreased 2 years after ECT. Short-term volume increases are associated with less symptom improvement suggesting that the antidepressant effect of ECT is not due to volume changes. Larger volume decreases are associated with poorer long-term outcome highlighting the interplay between disease progression and structural changes.
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Transtorno Depressivo Maior , Eletroconvulsoterapia , Humanos , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/terapia , Transtorno Depressivo Maior/patologia , Eletroconvulsoterapia/métodos , Depressão , Estudos Longitudinais , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodosRESUMO
Electroconvulsive Therapy (ECT) is arguably the most effective intervention for treatment-resistant depression. While large interindividual variability exists, a theory capable of explaining individual response to ECT remains elusive. To address this, we posit a quantitative, mechanistic framework of ECT response based on Network Control Theory (NCT). Then, we empirically test our approach and employ it to predict ECT treatment response. To this end, we derive a formal association between Postictal Suppression Index (PSI)-an ECT seizure quality index-and whole-brain modal and average controllability, NCT metrics based on white-matter brain network architecture, respectively. Exploiting the known association of ECT response and PSI, we then hypothesized an association between our controllability metrics and ECT response mediated by PSI. We formally tested this conjecture in N = 50 depressive patients undergoing ECT. We show that whole-brain controllability metrics based on pre-ECT structural connectome data predict ECT response in accordance with our hypotheses. In addition, we show the expected mediation effects via PSI. Importantly, our theoretically motivated metrics are at least on par with extensive machine learning models based on pre-ECT connectome data. In summary, we derived and tested a control-theoretic framework capable of predicting ECT response based on individual brain network architecture. It makes testable, quantitative predictions regarding individual therapeutic response, which are corroborated by strong empirical evidence. Our work might constitute a starting point for a comprehensive, quantitative theory of personalized ECT interventions rooted in control theory.
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BACKGROUND: Cognitive dysfunction and brain structural connectivity alterations have been observed in major depressive disorder (MDD). However, little is known about their interrelation. The present study follows a network approach to evaluate alterations in cognition-related brain structural networks. METHODS: Cognitive performance of n = 805 healthy and n = 679 acutely depressed or remitted individuals was assessed using 14 cognitive tests aggregated into cognitive factors. The structural connectome was reconstructed from structural and diffusion-weighted magnetic resonance imaging. Associations between global connectivity strength and cognitive factors were established using linear regressions. Network-based statistics were applied to identify subnetworks of connections underlying these global-level associations. In exploratory analyses, effects of depression were assessed by evaluating remission status-related group differences in subnetwork-specific connectivity. Partial correlations were employed to directly test the complete triad of cognitive factors, depressive symptom severity, and subnetwork-specific connectivity strength. RESULTS: All cognitive factors were associated with global connectivity strength. For each cognitive factor, network-based statistics identified a subnetwork of connections, revealing, for example, a subnetwork positively associated with processing speed. Within that subnetwork, acutely depressed patients showed significantly reduced connectivity strength compared to healthy controls. Moreover, connectivity strength in that subnetwork was associated to current depressive symptom severity independent of the previous disease course. CONCLUSIONS: Our study is the first to identify cognition-related structural brain networks in MDD patients, thereby revealing associations between cognitive deficits, depressive symptoms, and reduced structural connectivity. This supports the hypothesis that structural connectome alterations may mediate the association of cognitive deficits and depression severity.
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BACKGROUND: The second-generation antipsychotic (SGA) quetiapine is an essential option for antidepressant augmentation therapy in major depressive disorder (MDD), yet neurobiological mechanisms behind its antidepressant properties remain unclear. As SGAs interfere with activity in reward-related brain areas, including the anterior cingulate cortex (ACC) - a key brain region in antidepressant interventions, this study examined whether quetiapine treatment affects ACC activity during reward processing in MDD patients. METHODS: Using the ACC as region of interest, an independent t-test comparing reward-related BOLD response of 51 quetiapine-taking and 51 antipsychotic-free MDD patients was conducted. Monetary reward outcome feedback was measured in a card-guessing paradigm using pseudorandom blocks. Participants were matched for age, sex, and depression severity and analyses were controlled for confounding variables, including total antidepressant medication load, illness chronicity and acute depression severity. Potential dosage effects were examined in a 3 × 1 ANOVA. Differences in ACC-related functional connectivity were assessed in psycho-physiological interaction (PPI) analyses. RESULTS: Left subgenual ACC activity was significantly higher in the quetiapine group compared to antipsychotic-free participants and dependent on high-dose quetiapine intake. Results remained significant after controlling for confounding variables. The PPI analysis did not yield significant group differences in ACC-related functional connectivity. LIMITATIONS: Causal interpretation is limited due to cross-sectional findings. CONCLUSION: Elevated subgenual ACC activity to rewarding stimuli may represent a neurobiological marker and potential key interface of quetiapine's antidepressant effects in MDD. These results underline ACC activity during reward processing as an investigative avenue for future research and therapeutic interventions to improve MDD treatment outcomes.
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Antipsicóticos , Transtorno Depressivo Maior , Humanos , Antipsicóticos/efeitos adversos , Fumarato de Quetiapina/uso terapêutico , Giro do Cíngulo , Estudos Transversais , Antidepressivos/uso terapêutico , Antidepressivos/farmacologia , Recompensa , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Altered brain structural connectivity has been implicated in the pathophysiology of psychiatric disorders including schizophrenia (SZ), bipolar disorder (BD), and major depressive disorder (MDD). However, it is unknown which part of these connectivity abnormalities are disorder specific and which are shared across the spectrum of psychotic and affective disorders. We investigated common and distinct brain connectivity alterations in a large sample (N = 1743) of patients with SZ, BD, or MDD and healthy control (HC) subjects. METHODS: This study examined diffusion-weighted imaging-based structural connectome topology in 720 patients with MDD, 112 patients with BD, 69 patients with SZ, and 842 HC subjects (mean age of all subjects: 35.7 years). Graph theory-based network analysis was used to investigate connectome organization. Machine learning algorithms were trained to classify groups based on their structural connectivity matrices. RESULTS: Groups differed significantly in the network metrics global efficiency, clustering, present edges, and global connectivity strength with a converging pattern of alterations between diagnoses (e.g., efficiency: HC > MDD > BD > SZ, false discovery rate-corrected p = .028). Subnetwork analysis revealed a common core of edges that were affected across all 3 disorders, but also revealed differences between disorders. Machine learning algorithms could not discriminate between disorders but could discriminate each diagnosis from HC. Furthermore, dysconnectivity patterns were found most pronounced in patients with an early disease onset irrespective of diagnosis. CONCLUSIONS: We found shared and specific signatures of structural white matter dysconnectivity in SZ, BD, and MDD, leading to commonly reduced network efficiency. These results showed a compromised brain communication across a spectrum of major psychiatric disorders.
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Transtorno Bipolar , Transtorno Depressivo Maior , Transtornos Psicóticos , Humanos , Adulto , Transtorno Depressivo Maior/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Transtornos Psicóticos/diagnóstico por imagemRESUMO
Identifying brain alterations associated with suicidal thoughts and behaviors (STBs) in young people is critical to understanding their development and improving early intervention and prevention. The ENIGMA Suicidal Thoughts and Behaviours (ENIGMA-STB) consortium analyzed neuroimaging data harmonized across sites to examine brain morphology associated with STBs in youth. We performed analyses in three separate stages, in samples ranging from most to least homogeneous in terms of suicide assessment instrument and mental disorder. First, in a sample of 577 young people with mood disorders, in which STBs were assessed with the Columbia Suicide Severity Rating Scale (C-SSRS). Second, in a sample of young people with mood disorders, in which STB were assessed using different instruments, MRI metrics were compared among healthy controls without STBs (HC; N = 519), clinical controls with a mood disorder but without STBs (CC; N = 246) and young people with current suicidal ideation (N = 223). In separate analyses, MRI metrics were compared among HCs (N = 253), CCs (N = 217), and suicide attempters (N = 64). Third, in a larger transdiagnostic sample with various assessment instruments (HC = 606; CC = 419; Ideation = 289; HC = 253; CC = 432; Attempt=91). In the homogeneous C-SSRS sample, surface area of the frontal pole was lower in young people with mood disorders and a history of actual suicide attempts (N = 163) than those without a lifetime suicide attempt (N = 323; FDR-p = 0.035, Cohen's d = 0.34). No associations with suicidal ideation were found. When examining more heterogeneous samples, we did not observe significant associations. Lower frontal pole surface area may represent a vulnerability for a (non-interrupted and non-aborted) suicide attempt; however, more research is needed to understand the nature of its relationship to suicide risk.
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Ideação Suicida , Tentativa de Suicídio , Adolescente , Humanos , Encéfalo , Neuroimagem/métodos , Transtornos do HumorRESUMO
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.
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Transtorno Depressivo Maior , Encéfalo , Estudos Transversais , Progressão da Doença , Humanos , Estudos Longitudinais , Imageamento por Ressonância Magnética , Córtex Pré-Frontal , Estudos ProspectivosRESUMO
Human platelets differ considerably with regard to their size, RNA content and thrombogenicity. Reticulated platelets (RPs) are young, hyper-reactive platelets that are newly released from the bone marrow. They are larger and contain more RNA compared to older platelets. In comparison to more mature platelets, they exhibit a significantly higher thrombogenicity and are known to be elevated in patients with an increased platelet turnover such as, diabetics and after acute myocardial infarction. Several studies have shown that RPs correlate with an insufficient antiplatelet response to aspirin and specific P2Y12 receptor inhibitors. In addition, RPs are promising novel biomarkers for the prediction of adverse cardiovascular events in cardiovascular disease. However, the reason for RPs intrinsic hyper-reactivity and their association with ischemic events is not completely understood and the biology of RPs is still under investigation. We here present a structured review of preclinical and clinical findings concerning the role of RPs in cardiovascular disease.
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Plaquetas , Doenças Cardiovasculares , Aspirina/uso terapêutico , Plaquetas/fisiologia , Humanos , Inibidores da Agregação Plaquetária/uso terapêutico , Contagem de Plaquetas , RNARESUMO
Previous neuroimaging studies in body dysmorphic disorder (BDD) have focused on discordances in visual processing systems. However, little is known about brain functional aberrations in individuals with BDD during emotional face processing. An fMRI paradigm with negative emotional faces was employed in 20 individuals with BDD and 43 mentally healthy controls (HC). We compared functional activity and whole-brain connectivity patterns of the amygdala and the fusiform gyrus (FFG) between both groups. Regression analyses were performed for associations of body dysmorphic symptoms with brain activity and connectivity. Individuals with BDD exhibited higher activity in the left amygdala compared to HC (pFWE = .04) as well as increased functional connectivity of the left amygdala with a network including frontostriatal and temporal regions (pFWE < .05). The FFG revealed increased functional connectivity in individuals with BDD, mapping to brain areas such as the cingulate cortex and temporo-limbic regions (pFWE < .05). In HC, higher levels of body dysmorphic symptoms were associated with higher functional amygdala and FFG activity (pFWE < .05). Individuals with BDD show aberrant functional activity and connectivity patterns within the amygdala and the FFG for negative emotional face processing. Body dysmorphic symptoms in HC are associated with a mild pattern of brain functional alterations, which could emphasize the relevance of a dimensional approach in addition to diagnosis. Treatments for BDD could benefit from targeting visual misperception and evaluation processes upon confrontation with emotional information.
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Transtornos Dismórficos Corporais , Reconhecimento Facial , Transtornos Dismórficos Corporais/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Emoções , Humanos , Imageamento por Ressonância MagnéticaRESUMO
BACKGROUND: Relapses in major depression are frequent and are associated with a high burden of disease. Although short-term studies suggest a normalisation of depression-associated brain functional alterations directly after treatment, long-term investigations are sparse. AIMS: To examine brain function during negative emotion processing in association with course of illness over a 2-year span. METHOD: In this prospective case-control study, 72 in-patients with current depression and 42 healthy controls were investigated during a negative emotional face processing paradigm, at baseline and after 2 years. According to their course of illness during the study interval, patients were divided into subgroups (n = 25 no-relapse, n = 47 relapse). The differential changes in brain activity were investigated by a group × time analysis of covariance for the amygdala, hippocampus, insula and at whole-brain level. RESULTS: A significant relapse × time interaction emerged within the amygdala (PTFCE-FWE = 0.011), insula (PTFCE-FWE = 0.001) and at the whole-brain level mainly in the temporal and prefrontal cortex (PTFCE-FWE = 0.027), resulting from activity increases within the no-relapse group, whereas in the relapse group, activity decreased during the study interval. At baseline, the no-relapse group showed amygdala, hippocampus and insula hypoactivity compared with healthy controls and the relapse group. CONCLUSIONS: This study reveals course of illness-associated activity changes in emotion processing areas. Patients in full remission show a normalisation of their baseline hypo-responsiveness to the activation level of healthy controls after 2 years. Brain function during emotion processing could further serve as a potential predictive marker for future relapse.
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Depressão , Transtorno Depressivo Maior , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico , Estudos de Casos e Controles , Transtorno Depressivo Maior/psicologia , Emoções/fisiologia , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Cytometry techniques are widely used to discover cellular characteristics at single-cell resolution. Many data analysis methods for cytometry data focus solely on identifying subpopulations via clustering and testing for differential cell abundance. For differential expression analysis of markers between conditions, only few tools exist. These tools either reduce the data distribution to medians, discarding valuable information, or have underlying assumptions that may not hold for all expression patterns. Here, we systematically evaluated existing and novel approaches for differential expression analysis on real and simulated CyTOF data. We found that methods using median marker expressions compute fast and reliable results when the data are not strongly zero-inflated. Methods using all data detect changes in strongly zero-inflated markers, but partially suffer from overprediction or cannot handle big datasets. We present a new method, CyEMD, based on calculating the earth mover's distance between expression distributions that can handle strong zero-inflation without being too sensitive. Additionally, we developed CYANUS - CYtometry ANalysis Using Shiny - a user-friendly R Shiny App allowing the user to analyze cytometry data with state-of-the-art tools, including well-performing methods from our comparison. A public web interface is available at https://exbio.wzw.tum.de/cyanus/.
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Análise por Conglomerados , BiomarcadoresRESUMO
Mass cytometry (CyTOF) is a new technology that allows the investigation of protein expression at single cell level with high resolution. While several protocols are available to investigate leukocyte expression, platelet staining and analysis with CyTOF have been described only from whole blood. Moreover, available protocols do not allow sample storage but require fresh samples to be obtained, processed, and measured immediately. We provide a structured and reproducible method to stain platelets from platelet-rich plasma to study thrombocyte protein expression and reactivity using mass cytometry. With our method, it is possible to acquire a large number of events allowing deep bioinformatic investigation of platelet expression heterogeneity. Integrated in our protocol is also a previously established freezing protocol that allows the storage of stained samples and to delay their measurement. Finally, we provide a structured workflow using different platelet stimulators and a freely available bioinformatic pipeline to analyze platelet expression. Our protocol unlocks the potential of CyTOF analysis for studying platelet biology in health and disease.
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Plaquetas , Plasma Rico em Plaquetas , Plaquetas/metabolismo , Citometria de Fluxo/métodos , Humanos , Leucócitos , Plasma Rico em Plaquetas/metabolismoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces a coagulopathy characterized by platelet activation and a hypercoagulable state with an increased incidence of cardiovascular events. The viral spike protein S has been reported to enhance thrombosis formation, stimulate platelets to release procoagulant factors, and promote the formation of platelet-leukocyte aggregates even in absence of the virus. Although SARS-CoV-2 vaccines induce spike protein overexpression to trigger SARS-CoV-2-specific immune protection, thrombocyte activity has not been investigated in this context. Here, we provide the first phenotypic platelet characterization of healthy human subjects undergoing BNT162b2 vaccination. Using mass cytometry, we analyzed the expression of constitutive transmembrane receptors, adhesion proteins, and platelet activation markers in 12 healthy donors before and at five different time points within 4 weeks after the first BNT162b2 administration. We measured platelet reactivity by stimulating thrombocyte activation with thrombin receptor-activating peptide. Activation marker expression (P-selectin, LAMP-3, LAMP-1, CD40L, and PAC-1) did not change after vaccination. All investigated constitutive transmembrane proteins showed similar expressions over time. Platelet reactivity was not altered after BNT162b2 administration. Activation marker expression was significantly lower compared with an independent cohort of mild symptomatic COVID-19 patients analyzed with the same platform. This study reveals that BNT162b2 administration does not alter platelet protein expression and reactivity.
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Vacina BNT162 , Plaquetas , COVID-19 , Anticorpos Antivirais , Vacina BNT162/efeitos adversos , Plaquetas/metabolismo , Ligante de CD40 , COVID-19/prevenção & controle , Vacinas contra COVID-19/efeitos adversos , Humanos , Proteínas de Membrana/metabolismo , Selectina-P/metabolismo , Receptores de Trombina/metabolismo , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
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.
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Transtorno Bipolar , Transtornos Psicóticos , Esquizofrenia , Transtorno da Personalidade Esquizotípica , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Transtornos Psicóticos/diagnóstico por imagem , Transtorno da Personalidade Esquizotípica/diagnóstico por imagemRESUMO
BACKGROUND: Brain functional alterations during emotion processing in patients with major depressive disorder (MDD) compared with healthy control subjects (HCs) are frequently reported. However, evidence for functional correlates of emotion processing with regard to MDD trajectories is scarce. This study investigates the role of lifetime disease course for limbic brain activation during negative emotional face processing in patients with MDD. METHODS: In a large sample of patients with MDD (n = 333; 58.55% female) and HCs (n = 333; 60.06% female), brain activation was investigated during a negative emotional face-processing task within a cross-sectional design. Differences between HC and MDD groups were analyzed. Previous disease course, characterized by 2 components, namely hospitalization and duration of illness, was regressed on brain activation of the amygdala, (para-)hippocampus, and insula in patients with MDD. RESULTS: Patients with MDD showed increased activation in the amygdala, insula, and hippocampus compared with HCs (all p values corrected for familywise error [pFWE] < .045). The hospitalization component showed negative associations with brain activation in the bilateral insula (right: pFWE = .026, left: pFWE = .019) and (para-)hippocampus (right: pFWE = .038, left: pFWE = .031). No significant association was found for the duration of illness component (all pFWE > .057). CONCLUSIONS: This study investigated negative emotion processing in a large sample of patients with MDD and HCs. Our results confirm limbic hyperactivation in patients with MDD during negative emotion processing; however, this hyperactivation may resolve with a more severe lifetime disease course in the insula and (para-)hippocampus-brain regions involved in emotion processing and regulation. These findings need further replication in longitudinal studies.