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Recurrences of depressive episodes in major depressive disorder (MDD) can be explained by the diathesis-stress model, suggesting that stressful life events (SLEs) can trigger MDD episodes in individuals with pre-existing vulnerabilities. However, the longitudinal neurobiological impact of SLEs on gray matter volume (GMV) in MDD and its interaction with early-life adversity remains unresolved. In 754 participants aged 18-65 years (362 MDD patients; 392 healthy controls; HCs), we assessed longitudinal associations between SLEs (Life Events Questionnaire) and whole-brain GMV changes (3 Tesla MRI) during a 2-year interval, using voxel-based morphometry in SPM12/CAT12. We also explored the potential moderating role of childhood maltreatment (Childhood Trauma Questionnaire) on these associations. Over the 2-year interval, HCs demonstrated significant GMV reductions in the middle frontal, precentral, and postcentral gyri in response to higher levels of SLEs, while MDD patients showed no such GMV changes. Childhood maltreatment did not moderate these associations in either group. However, MDD patients who had at least one depressive episode during the 2-year interval, compared to those who did not, or HCs, showed GMV increases in the middle frontal, precentral, and postcentral gyri associated with an increase in SLEs and childhood maltreatment. Our findings indicate distinct GMV changes in response to SLEs between MDD patients and HCs. GMV decreases in HCs may represent adaptive responses to stress, whereas GMV increases in MDD patients with both childhood maltreatment and a depressive episode during the 2-year interval may indicate maladaptive changes, suggesting a neural foundation for the diathesis-stress model in MDD recurrences.
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Transtorno Depressivo Maior , Substância Cinzenta , Imageamento por Ressonância Magnética , Estresse Psicológico , Humanos , Transtorno Depressivo Maior/patologia , Transtorno Depressivo Maior/fisiopatologia , Feminino , Substância Cinzenta/patologia , Masculino , Adulto , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Adolescente , Idoso , Adulto Jovem , Estudos Longitudinais , Encéfalo/patologia , Acontecimentos que Mudam a Vida , Experiências Adversas da Infância , Maus-Tratos Infantis/psicologiaRESUMO
Reduced processing speed is a core deficit in major depressive disorder (MDD) and has been linked to altered structural brain network connectivity. Ample evidence highlights the involvement of genetic-immunological processes in MDD and specific depressive symptoms. Here, we extended these findings by examining associations between polygenic scores for tumor necrosis factor-α blood levels (TNF-α PGS), structural brain connectivity, and processing speed in a large sample of MDD patients. Processing speed performance of n = 284 acutely depressed, n = 177 partially and n = 198 fully remitted patients, and n = 743 healthy controls (HC) was estimated based on five neuropsychological tests. Network-based statistic was used to identify a brain network associated with processing speed. We employed general linear models to examine the association between TNF-α PGS and processing speed. We investigated whether network connectivity mediates the association between TNF-α PGS and processing speed. We identified a structural network positively associated with processing speed in the whole sample. We observed a significant negative association between TNF-α PGS and processing speed in acutely depressed patients, whereas no association was found in remitted patients and HC. The mediation analysis revealed that brain connectivity partially mediated the association between TNF-α PGS and processing speed in acute MDD. The present study provides evidence that TNF-α PGS is associated with decreased processing speed exclusively in patients with acute depression. This association was partially mediated by structural brain connectivity. Using multimodal data, the current findings advance our understanding of cognitive dysfunction in MDD and highlight the involvement of genetic-immunological processes in its pathomechanisms.
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Encéfalo , Transtorno Depressivo Maior , Imageamento por Ressonância Magnética , Testes Neuropsicológicos , Fator de Necrose Tumoral alfa , Humanos , Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/fisiopatologia , Transtorno Depressivo Maior/metabolismo , Masculino , Feminino , Adulto , Fator de Necrose Tumoral alfa/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Pessoa de Meia-Idade , Imageamento por Ressonância Magnética/métodos , Herança Multifatorial/genética , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia , Rede Nervosa/diagnóstico por imagem , Velocidade de ProcessamentoRESUMO
Multivariate techniques better fit the anatomy of complex neuropsychiatric disorders which are characterized not by alterations in a single region, but rather by variations across distributed brain networks. Here, we used principal component analysis (PCA) to identify patterns of covariance across brain regions and relate them to clinical and demographic variables in a large generalizable dataset of individuals with bipolar disorders and controls. We then compared performance of PCA and clustering on identical sample to identify which methodology was better in capturing links between brain and clinical measures. Using data from the ENIGMA-BD working group, we investigated T1-weighted structural MRI data from 2436 participants with BD and healthy controls, and applied PCA to cortical thickness and surface area measures. We then studied the association of principal components with clinical and demographic variables using mixed regression models. We compared the PCA model with our prior clustering analyses of the same data and also tested it in a replication sample of 327 participants with BD or schizophrenia and healthy controls. The first principal component, which indexed a greater cortical thickness across all 68 cortical regions, was negatively associated with BD, BMI, antipsychotic medications, and age and was positively associated with Li treatment. PCA demonstrated superior goodness of fit to clustering when predicting diagnosis and BMI. Moreover, applying the PCA model to the replication sample yielded significant differences in cortical thickness between healthy controls and individuals with BD or schizophrenia. Cortical thickness in the same widespread regional network as determined by PCA was negatively associated with different clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. PCA outperformed clustering and provided an easy-to-use and interpret method to study multivariate associations between brain structure and system-level variables. PRACTITIONER POINTS: In this study of 2770 Individuals, we confirmed that cortical thickness in widespread regional networks as determined by principal component analysis (PCA) was negatively associated with relevant clinical and demographic variables, including diagnosis, age, BMI, and treatment with antipsychotic medications or lithium. Significant associations of many different system-level variables with the same brain network suggest a lack of one-to-one mapping of individual clinical and demographic factors to specific patterns of brain changes. PCA outperformed clustering analysis in the same data set when predicting group or BMI, providing a superior method for studying multivariate associations between brain structure and system-level variables.
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Transtorno Bipolar , Imageamento por Ressonância Magnética , Obesidade , Análise de Componente Principal , Humanos , Transtorno Bipolar/diagnóstico por imagem , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/patologia , Adulto , Feminino , Masculino , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Obesidade/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/patologia , Esquizofrenia/tratamento farmacológico , Esquizofrenia/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Análise por Conglomerados , Adulto Jovem , Encéfalo/diagnóstico por imagem , Encéfalo/patologiaRESUMO
BACKGROUND: Schizotypy represents an index of psychosis-proneness in the general population, often associated with childhood trauma exposure. Both schizotypy and childhood trauma are linked to structural brain alterations, and it is possible that trauma exposure moderates the extent of brain morphological differences associated with schizotypy. METHODS: We addressed this question using data from a total of 1182 healthy adults (age range: 18-65 years old, 647 females/535 males), pooled from nine sites worldwide, contributing to the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Schizotypy working group. All participants completed both the Schizotypal Personality Questionnaire Brief version (SPQ-B), and the Childhood Trauma Questionnaire (CTQ), and underwent a 3D T1-weighted brain MRI scan from which regional indices of subcortical gray matter volume and cortical thickness were determined. RESULTS: A series of multiple linear regressions revealed that differences in cortical thickness in four regions-of-interest were significantly associated with interactions between schizotypy and trauma; subsequent moderation analyses indicated that increasing levels of schizotypy were associated with thicker left caudal anterior cingulate gyrus, right middle temporal gyrus and insula, and thinner left caudal middle frontal gyrus, in people exposed to higher (but not low or average) levels of childhood trauma. This was found in the context of morphological changes directly associated with increasing levels of schizotypy or increasing levels of childhood trauma exposure. CONCLUSIONS: These results suggest that alterations in brain regions critical for higher cognitive and integrative processes that are associated with schizotypy may be enhanced in individuals exposed to high levels of trauma.
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Experiências Adversas da Infância , Testes Psicológicos , Transtorno da Personalidade Esquizotípica , Autorrelato , Adulto , Masculino , Feminino , Humanos , Adolescente , Adulto Jovem , Pessoa de Meia-Idade , Idoso , Transtorno da Personalidade Esquizotípica/diagnóstico por imagem , Transtorno da Personalidade Esquizotípica/psicologia , Encéfalo/diagnóstico por imagem , Substância Cinzenta , Imageamento por Ressonância Magnética/métodosRESUMO
BACKGROUND: Individuals at risk for bipolar disorder (BD) have a wide range of genetic and non-genetic risk factors, like a positive family history of BD or (sub)threshold affective symptoms. Yet, it is unclear whether these individuals at risk and those diagnosed with BD share similar gray matter brain alterations. METHODS: In 410 male and female participants aged 17-35 years, we compared gray matter volume (3T MRI) between individuals at risk for BD (as assessed using the EPIbipolar scale; n = 208), patients with a DSM-IV-TR diagnosis of BD (n = 87), and healthy controls (n = 115) using voxel-based morphometry in SPM12/CAT12. We applied conjunction analyses to identify similarities in gray matter volume alterations in individuals at risk and BD patients, relative to healthy controls. We also performed exploratory whole-brain analyses to identify differences in gray matter volume among groups. ComBat was used to harmonize imaging data from seven sites. RESULTS: Both individuals at risk and BD patients showed larger volumes in the right putamen than healthy controls. Furthermore, individuals at risk had smaller volumes in the right inferior occipital gyrus, and BD patients had larger volumes in the left precuneus, compared to healthy controls. These findings were independent of course of illness (number of lifetime manic and depressive episodes, number of hospitalizations), comorbid diagnoses (major depressive disorder, attention-deficit hyperactivity disorder, anxiety disorder, eating disorder), familial risk, current disease severity (global functioning, remission status), and current medication intake. CONCLUSIONS: Our findings indicate that alterations in the right putamen might constitute a vulnerability marker for BD.
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BACKGROUND: Neuroinflammation affects brain tissue integrity in multiple sclerosis (MS) and may have a role in major depressive disorder (MDD). Whether advanced magnetic resonance imaging characteristics of the gray-to-white matter border serve as proxy of neuroinflammatory activity in MDD and MS remain unknown. METHODS: We included 684 participants (132 MDD patients with recurrent depressive episodes (RDE), 70 MDD patients with a single depressive episode (SDE), 222 MS patients without depressive symptoms (nMS), 58 MS patients with depressive symptoms (dMS), and 202 healthy controls (HC)). 3 T-T1w MRI-derived gray-to-white matter contrast (GWc) was used to reconstruct and characterize connectivity alterations of GWc-covariance networks by means of modularity, clustering coefficient, and degree. A cross-validated support vector machine was used to test the ability of GWc to stratify groups according to their depression symptoms, measured with BDI, at the single-subject level in MS and MDD independently. FINDINGS: MS and MDD patients showed increased modularity (ANOVA partial-η2 = 0.3) and clustering (partial-η2 = 0.1) compared to HC. In the subgroups, a linear trend analysis attested a gradient of modularity increases in the form: HC, dMS, nMS, SDE, and RDE (ANOVA partial-η2 = 0.28, p < 0.001) while this trend was less evident for clustering coefficient. Reduced morphological integrity (GWc) was seen in patients with increased depressive symptoms (partial-η2 = 0.42, P < 0.001) and was associated with depression scores across patient groups (r = -0.2, P < 0.001). Depressive symptoms in MS were robustly classified (88 %). CONCLUSIONS: Similar structural network alterations in MDD and MS exist, suggesting possible common inflammatory events like demyelination, neuroinflammation that are caught by GWc analyses. These alterations may vary depending on the severity of symptoms and in the case of MS may elucidate the occurrence of comorbid depression.
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Encéfalo , Depressão , Transtorno Depressivo Maior , Substância Cinzenta , Inflamação , Imageamento por Ressonância Magnética , Esclerose Múltipla , Substância Branca , Humanos , Feminino , Masculino , Adulto , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/patologia , Esclerose Múltipla/psicologia , Esclerose Múltipla/complicações , Esclerose Múltipla/fisiopatologia , Pessoa de Meia-Idade , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Depressão/fisiopatologia , Substância Cinzenta/patologia , Substância Cinzenta/diagnóstico por imagem , Doenças Neuroinflamatórias/diagnóstico por imagemRESUMO
Up to 70% of patients with major depressive disorder present with psychomotor disturbance (PmD), but at the present time understanding of its pathophysiology is limited. In this study, we capitalized on a large sample of patients to examine the neural correlates of PmD in depression. This study included 820 healthy participants and 699 patients with remitted (n = 402) or current (n = 297) depression. Patients were further categorized as having psychomotor retardation, agitation, or no PmD. We compared resting-state functional connectivity (ROI-to-ROI) between nodes of the cerebral motor network between the groups, including primary motor cortex, supplementary motor area, sensory cortex, superior parietal lobe, caudate, putamen, pallidum, thalamus, and cerebellum. Additionally, we examined network topology of the motor network using graph theory. Among the currently depressed 55% had PmD (15% agitation, 29% retardation, and 11% concurrent agitation and retardation), while 16% of the remitted patients had PmD (8% retardation and 8% agitation). When compared with controls, currently depressed patients with PmD showed higher thalamo-cortical and pallido-cortical connectivity, but no network topology alterations. Currently depressed patients with retardation only had higher thalamo-cortical connectivity, while those with agitation had predominant higher pallido-cortical connectivity. Currently depressed patients without PmD showed higher thalamo-cortical, pallido-cortical, and cortico-cortical connectivity, as well as altered network topology compared to healthy controls. Remitted patients with PmD showed no differences in single connections but altered network topology, while remitted patients without PmD did not differ from healthy controls in any measure. We found evidence for compensatory increased cortico-cortical resting-state functional connectivity that may prevent psychomotor disturbance in current depression, but may perturb network topology. Agitation and retardation show specific connectivity signatures. Motor network topology is slightly altered in remitted patients arguing for persistent changes in depression. These alterations in functional connectivity may be addressed with non-invasive brain stimulation.
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Childhood maltreatment (CM) has been associated with changes in structural brain connectivity even in the absence of mental illness. Social support, an important protective factor in the presence of childhood maltreatment, has been positively linked to white matter integrity. However, the shared effects of current social support and CM and their association with structural connectivity remain to be investigated. They might shed new light on the neurobiological basis of the protective mechanism of social support. Using connectome-based predictive modeling (CPM), we analyzed structural connectomes of N = 904 healthy adults derived from diffusion-weighted imaging. CPM predicts phenotypes from structural connectivity through a cross-validation scheme. Distinct and shared networks of white matter tracts predicting childhood trauma questionnaire scores and the social support questionnaire were identified. Additional analyses were applied to assess the stability of the results. CM and social support were predicted significantly from structural connectome data (all rs ≥ 0.119, all ps ≤ 0.016). Edges predicting CM and social support were inversely correlated, i.e., positively correlated with CM and negatively with social support, and vice versa, with a focus on frontal and temporal regions including the insula and superior temporal lobe. CPM reveals the predictive value of the structural connectome for CM and current social support. Both constructs are inversely associated with connectivity strength in several brain tracts. While this underlines the interconnectedness of these experiences, it suggests social support acts as a protective factor following adverse childhood experiences, compensating for brain network alterations. Future longitudinal studies should focus on putative moderating mechanisms buffering these adverse experiences.
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Maus-Tratos Infantis , Conectoma , Testes Psicológicos , Autorrelato , Substância Branca , Adulto , Humanos , Criança , Conectoma/métodos , Imageamento por Ressonância Magnética , EncéfaloRESUMO
While most people are right-handed, a minority are left-handed or mixed-handed. It has been suggested that mental and developmental disorders are associated with increased prevalence of left-handedness and mixed-handedness. However, substantial heterogeneity exists across disorders, indicating that not all disorders are associated with a considerable shift away from right-handedness. Increased frequencies in left- and mixed-handedness have also been associated with more severe clinical symptoms, indicating that symptom severity rather than diagnosis explains the high prevalence of non-right-handedness in mental disorders. To address this issue, the present study investigated the association between handedness and measures of stress reactivity, depression, mania, anxiety, and positive and negative symptoms in a large sample of 994 healthy controls and 1213 patients with DSM IV affective disorders, schizoaffective disorders, or schizophrenia. A series of complementary analyses revealed lower lateralization and a higher percentage of mixed-handedness in patients with major depression (14.9%) and schizophrenia (24.0%) compared to healthy controls (12%). For patients with schizophrenia, higher symptom severity was associated with an increasing tendency towards left-handedness. No associations were found for patients diagnosed with major depression, bipolar disorder, or schizoaffective disorder. In healthy controls, no association between hand preference and symptoms was evident. Taken together, these findings suggest that both diagnosis and symptom severity are relevant for the shift away from right-handedness in mental disorders like schizophrenia and major depression.
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In her target article, Burt revives a by now ancient debate on nature and nurture, and the ways to measure, disentangle, and ultimately trust one or the other of these forces. Unfortunately, she largely dismisses recent advances in behavior genetics and its huge potential in contributing to a better prediction and understanding of complex traits in social sciences.
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Frutas , Genética Comportamental , Humanos , Feminino , Ciências SociaisRESUMO
The ability to mentalize is central in the context of the parent-child relationship.The parental competence to see the child'smental state as an independent individual is an essential prerequisite for perceiving and interpreting child signals appropriately.These abilities are crucial but not always available under elevated stress levels when confronted with a child's affects and parenting challenges. Despite the clinical and conceptual relevance of mentalization with borderline personality disorder (BPD) and affective disorders, the subject has rarely been systematically addressed in parents.This review provides a systematic overview of parental mentalization in mothers with affective disorders or BPD and its impact on the quality of maternal interactive behaviour. The findings generally revealed a negative association between mothers' parental mentalization and depression or BPD, which varied greatly depending on the mentalization constructs. Both psychiatric diagnosis and current severity of symptoms were found to be relevant. However, some positive aspects of mentalization were not markedly impaired. Further, a lowermentalizing abilitywas associatedwith reduced sensitive behaviour in depressedmothers. The results contribute to a better understanding of the association between mentalization and maternal psychopathology and help refine early interventions in parent-child settings.
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Transtorno da Personalidade Borderline , Mentalização , Transtorno da Personalidade Borderline/diagnóstico , Transtorno da Personalidade Borderline/psicologia , Transtorno da Personalidade Borderline/terapia , Feminino , Humanos , Transtornos do Humor , Mães/psicologia , Relações Pais-Filho , Pais/psicologiaRESUMO
Background: Epigenetic variation in the serotonin transporter gene (SLC6A4) has been shown to modulate the functioning of brain circuitry associated with the salience network and may heighten the risk for mental illness. This study is, to our knowledge, the first to test this epigenomebrainbehaviour pathway in patients with anorexia nervosa. Methods: We obtained resting-state functional connectivity (rsFC) data and blood samples from 55 acutely underweight female patients with anorexia nervosa and 55 age-matched female healthy controls. We decomposed imaging data using independent component analysis. We used bisulfite pyrosequencing to analyze blood DNA methylation within the promoter region of SLC6A4. We then explored salience network rsFC patterns in the group × methylation interaction. Results: We identified a positive relationship between SLC6A4 methylation levels and rsFC between the dorsolateral prefrontal cortex and the salience network in patients with anorexia nervosa compared to healthy controls. Increased rsFC in the salience network mediated the link between SLC6A4 methylation and eating disorder symptoms in patients with anorexia nervosa. We confirmed findings of rsFC alterations for CpG-specific methylation at a locus with evidence of methylation correspondence between brain and blood tissue. Limitations: This study was cross-sectional in nature, the sample size was modest for the method and methylation levels were measured peripherally, so findings cannot be fully generalized to brain tissue. Conclusion: This study sheds light on the neurobiological process of how epigenetic variation in the SLC6A4 gene may relate to rsFC in the salience network that is linked to psychopathology in anorexia nervosa.
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Anorexia Nervosa/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adolescente , Adulto , Anorexia Nervosa/genética , Anorexia Nervosa/fisiopatologia , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Criança , Metilação de DNA/genética , Feminino , Neuroimagem Funcional , Humanos , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Adulto JovemRESUMO
Background: Epigenetic variation in the serotonin transporter gene (SLC6A4) has been shown to modulate the functioning of brain circuitry associated with the salience network and may heighten the risk for mental illness. This study is, to our knowledge, the first to test this epigenomebrainbehaviour pathway in patients with anorexia nervosa. Methods: We obtained resting-state functional connectivity (rsFC) data and blood samples from 55 acutely underweight female patients with anorexia nervosa and 55 age-matched female healthy controls. We decomposed imaging data using independent component analysis. We used bisulfite pyrosequencing to analyze blood DNA methylation within the promoter region of SLC6A4. We then explored salience network rsFC patterns in the group × methylation interaction. Results: We identified a positive relationship between SLC6A4 methylation levels and rsFC between the dorsolateral prefrontal cortex and the salience network in patients with anorexia nervosa compared to healthy controls. Increased rsFC in the salience network mediated the link between SLC6A4 methylation and eating disorder symptoms in patients with anorexia nervosa. We confirmed findings of rsFC alterations for CpG-specific methylation at a locus with evidence of methylation correspondence between brain and blood tissue. Limitations: This study was cross-sectional in nature, the sample size was modest for the method and methylation levels were measured peripherally, so findings cannot be fully generalized to brain tissue. Conclusion: This study sheds light on the neurobiological process of how epigenetic variation in the SLC6A4 gene may relate to rsFC in the salience network that is linked to psychopathology in anorexia nervosa.
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Transtornos Mentais , Saúde Mental , Feminino , Humanos , Transtornos Mentais/psicologia , Transtornos Mentais/terapia , Parto , GravidezRESUMO
The impact of acute stress on executive processes is commonly attributed to glucocorticoid-induced disruptions of the pFC. However, the occipital cortex seems to express a higher density of glucocorticoid receptors. Consequently, acute stress effects on executive processes could as well be mediated by glucocorticoid (e.g., cortisol)-induced alterations of visual sensory processes. To investigate this alternative route of stress action by demarcating the effects of acute stress and cortisol on executive from those on visual sensory processes, 40 healthy young men completed a standardized stress induction (i.e., the Trier Social Stress Test) and control protocol in two consecutive sessions. In addition, they received either a placebo or hydrocortisone (0.12-mg/kg bodyweight) pill and processed a dual and a partial report task to assess their executive and visual sensory processing abilities, respectively. Hydrocortisone administration improved both partial report and dual-task performance as indicated by increased response accuracies and/or decreased RTs. Intriguingly, the hydrocortisone-induced increase in dual-task performance was completely mediated by its impact on partial report performance (i.e., visual sensory processes). Moreover, RT measures in both tasks shared approximately 26% of variance, which was only in part attributable to hydrocortisone administration (ΔR2 = 8%). By contrast, acute stress selectively impaired dual-task performance (i.e., executive processes), presumably through an alternative route of action. In summary, the present results suggest that cortisol secretion (as mimicked by hydrocortisone administration) may counteract adverse residual stress effects on executive processes by improving visual sensory processes (e.g., the maintenance and amplification of task-relevant sensory information).
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Genetic variation in the serotonin transporter gene (SLC6A4) has been associated with psychopathology and aberrant brain functioning in a plethora of clinical and imaging studies. In contrast, the neurobiological correlates of epigenetic signatures in SLC6A4, such as DNA methylation profiles, have only recently been explored in human brain imaging research. The present study is the first to apply a resting state functional magnetic resonance imaging approach to identify changes in brain networks related to SLC6A4 promoter methylation (N=74 healthy individuals). The amygdalae were defined as seed regions given that resting state functional connectivity in this brain area is under serotonergic control and relates to a broad range of psychiatric phenotypes. We further used bisulfite pyrosequencing to analyze quantitative methylation at 83 CpG sites within a promoter-associated CpG island of SLC6A4 from blood-derived DNA samples. The major finding of this study indicates a positive relation of SLC6A4 promoter methylation and amygdaloid resting state functional coupling with key nodes of the salience network (SN) including the anterior insulae and the dorsal anterior cingulate cortices. Increased intra-network connectivity in the SN is thought to facilitate the detection and subsequent processing of potentially negative stimuli and reflects a core feature of psychopathology. As such, epigenetic changes within the SLC6A4 gene predict connectivity patterns in clinically and behaviorally relevant brain networks which may in turn convey increased disease susceptibility.
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Tonsila do Cerebelo/fisiologia , Córtex Cerebral/fisiologia , Conectoma/métodos , Epigênese Genética/genética , Rede Nervosa/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Adulto , Ilhas de CpG , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Regiões Promotoras Genéticas , Adulto JovemRESUMO
Empathy as one of the basic prerequisites for successful social interactions seems to be aberrant in individuals with major depressive disorder (MDD). Although understanding empathic impairments in MDD is crucial considering the frequently reported social skill deficits in patients, the current state of research is still inconclusive, pointing to both elevated and impaired levels of empathy. In this review, we extend previous reports of MDD-related aberrations in self-reported and behavioral empathy by shedding light on the neural correlates of empathy in MDD. Study findings indicate a complex and potentially state-dependent association, comprising both elevated and lower neural activity in empathy-related brain regions such as the inferior frontal gyri, bilateral anterior insulae, and cingulate areas. Predominantly, lower activity in these areas seems to be induced by antidepressant treatment or remission, with accompanying behavioral results indicating a reduced negativity-bias in empathic processing compared to acute states of MDD. We propose a preliminary model of empathy development throughout the course of the disorder, comprising initially elevated levels of empathy and a somewhat detached and lower empathic responding during the further progression of the disorder or post-treatment. The seemingly multifaceted nature of the association between empathy and MDD requires further exploration in future multimodal and longitudinal studies. The study of neural correlates of empathy in MDD should prospectively be enlarged by including further socio-affective and -cognitive capacities in MDD and related mental disorders.
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Acute stress is assumed to affect executive processing of stimulus information, although extant studies have yielded heterogeneous findings. The temporal flanker task, in which a target stimulus is preceded by a distractor of varying utility, offers a means of investigating various components involved in the adjustment of information processing and conflict control. Both behavioral and EEG data obtained with this task suggest stronger distractor-related response activation in conditions associated with higher predictivity of the distractor for the upcoming target. In two experiments we investigated distractor-related processing and conflict control after inducing acute stress (Trier Social Stress Test). Although the stressed groups did not differ significantly from unstressed control groups concerning behavioral markers of attentional adjustment (i.e., Proportion Congruent Effect), or event-related sensory components in the EEG (i.e., posterior P1 and N1), the lateralized readiness potential demonstrated reduced activation evoked by (predictive) distractor information under stress. Our results suggest flexible adjustment of attention under stress but hint at decreased usage of nominally irrelevant stimulus information for biasing response selection.
Assuntos
Atenção , Eletroencefalografia , Estresse Psicológico , Humanos , Masculino , Feminino , Atenção/fisiologia , Adulto Jovem , Adulto , Estresse Psicológico/fisiopatologia , Potenciais Evocados/fisiologia , Tempo de Reação/fisiologiaRESUMO
BACKGROUND: Cognitive deficits are a key source of disability in individuals with major depressive disorder (MDD) and worsen with disease progression. Despite their clinical relevance, the underlying mechanisms of cognitive deficits remain poorly elucidated, hampering effective treatment strategies. Emerging evidence suggests that alterations in white matter microstructure might contribute to cognitive dysfunction in MDD. We aimed to investigate the complex association between changes in white matter integrity, cognitive decline, and disease course in MDD in a comprehensive longitudinal dataset. METHODS: In the naturalistic, observational, prospective, case-control Marburg-Münster Affective Disorders Cohort Study, individuals aged 18-65 years and of Caucasian ancestry were recruited from local psychiatric hospitals in Münster and Marburg, Germany, and newspaper advertisements. Individuals diagnosed with MDD and individuals without any history of psychiatric disorder (ie, healthy controls) were included in this subsample analysis. Participants had diffusion-weighted imaging, a battery of neuropsychological tests, and detailed clinical data collected at baseline and at 2 years of follow-up. We used linear mixed-effect models to compare changes in cognitive performance and white matter integrity between participants with MDD and healthy controls. Diffusion-weighted imaging analyses were conducted using tract-based spatial statistics. To correct for multiple comparisons, threshold free cluster enhancement (TFCE) was used to correct α-values at the family-wise error rate (FWE; ptfce-FWE). Effect sizes were estimated by conditional, partial R2 values (sr2) following the Nakagawa and Schielzeth method to quantify explained variance. The association between changes in cognitive performance and changes in white matter integrity was analysed. Finally, we examined whether the depressive disease course between assessments predicted cognitive performance at follow-up and whether white matter integrity mediated this association. People with lived experience were not involved in the research and writing process. FINDINGS: 881 participants were selected for our study, of whom 418 (47%) had MDD (mean age 36·8 years [SD 13·4], 274 [66%] were female, and 144 [34%] were male) and 463 (53%) were healthy controls (mean age 35·6 years [13·5], 295 [64%] were female, and 168 [36%] were male). Baseline assessments were done between Sept 11, 2014, and June 3, 2019, and after a mean follow-up of 2·20 years (SD 0·19), follow-up assessments were done between Oct 6, 2016, and May 31, 2021. Participants with MDD had lower cognitive performance than did healthy controls (p<0·0001, sr2=0·056), regardless of timepoint. Analyses of diffusion-weighted imaging indicated a significant diagnosisâ×âtime interaction with a steeper decline in white matter integrity of the superior longitudinal fasciculus over time in participants with MDD than in healthy controls (ptfce-FWE=0·026, sr2=0·002). Furthermore, cognitive decline was robustly associated with the decline in white matter integrity over time across both groups (ptfce-FWE<0·0001, sr2=0·004). In participants with MDD, changes in white matter integrity (p=0·0040, ß=0·071) and adverse depressive disease course (p=0·0022, ß=-0·073) independently predicted lower cognitive performance at follow-up. INTERPRETATION: Alterations of white matter integrity occurred over time to a greater extent in participants with MDD than in healthy controls, and decline in white matter integrity was associated with a decline in cognitive performance across groups. Our findings emphasise the crucial role of white matter microstructure and disease progression in depression-related cognitive dysfunction, making both priority targets for future treatment development. FUNDING: German Research Foundation (DFG).