RESUMO
Although the cerebellum contributes to higher-order cognitive and emotional functions relevant to posttraumatic stress disorder (PTSD), prior research on cerebellar volume in PTSD is scant, particularly when considering subregions that differentially map on to motor, cognitive, and affective functions. In a sample of 4215 adults (PTSD n = 1642; Control n = 2573) across 40 sites from the ENIGMA-PGC PTSD working group, we employed a new state-of-the-art deep-learning based approach for automatic cerebellar parcellation to obtain volumetric estimates for the total cerebellum and 28 subregions. Linear mixed effects models controlling for age, gender, intracranial volume, and site were used to compare cerebellum volumes in PTSD compared to healthy controls (88% trauma-exposed). PTSD was associated with significant grey and white matter reductions of the cerebellum. Compared to controls, people with PTSD demonstrated smaller total cerebellum volume, as well as reduced volume in subregions primarily within the posterior lobe (lobule VIIB, crus II), vermis (VI, VIII), flocculonodular lobe (lobule X), and corpus medullare (all p-FDR < 0.05). Effects of PTSD on volume were consistent, and generally more robust, when examining symptom severity rather than diagnostic status. These findings implicate regionally specific cerebellar volumetric differences in the pathophysiology of PTSD. The cerebellum appears to play an important role in higher-order cognitive and emotional processes, far beyond its historical association with vestibulomotor function. Further examination of the cerebellum in trauma-related psychopathology will help to clarify how cerebellar structure and function may disrupt cognitive and affective processes at the center of translational models for PTSD.
Assuntos
Cerebelo , Imageamento por Ressonância Magnética , Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/patologia , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Cerebelo/patologia , Cerebelo/diagnóstico por imagem , Feminino , Masculino , Adulto , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Substância Branca/patologia , Substância Branca/diagnóstico por imagem , Substância Cinzenta/patologia , Tamanho do Órgão , Aprendizado ProfundoRESUMO
BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Reprodutibilidade dos Testes , Big Data , Neuroimagem , Imageamento por Ressonância Magnética/métodos , Encéfalo/diagnóstico por imagemRESUMO
Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.
Assuntos
Imageamento por Ressonância Magnética , Transtornos de Estresse Pós-Traumáticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Feminino , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Neuroimagem , Adulto JovemRESUMO
A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Substância Branca , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anisotropia , Encéfalo/diagnóstico por imagem , Imagem de Tensor de Difusão , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Substância Branca/diagnóstico por imagem , Adulto JovemRESUMO
Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values < 0.039) and were significantly negatively correlated with PTSS severity. After adjusting for depression symptoms, the PTSD findings in left and right LOFG remained significant. These findings indicate that cortical volumes in PTSD patients are smaller in prefrontal regulatory regions, as well as in broader emotion and sensory processing cortical regions.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Córtex Cerebral/diagnóstico por imagem , Genômica , Humanos , Imageamento por Ressonância Magnética , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/genética , Lobo TemporalRESUMO
Posttraumatic stress disorder (PTSD) is associated with altered hypothalamic-pituitary-adrenal (HPA) axis function. Measurement of hair cortisol concentrations (HCC) allows retrospective assessment of HPA axis regulation over prolonged periods of time. Currently, research investigating HCC in PTSD remains sparse. Previous cross-sectional studies have included only civilian populations, although it is known that trauma type moderates associations between PTSD status and HPA axis function. We investigated differences in HCC between trauma-exposed female police officers with current PTSD (n = 13) and without current and lifetime PTSD (n = 15). To investigate whether HCC was associated with neural correlates of PTSD, we additionally performed exploratory correlational analyses between HCC and amygdala reactivity to negative affective stimuli. We observed significantly lower HCC in participants with PTSD than in participants without PTSD, d = 0.89. Additionally, within participants with PTSD, we observed positive correlations between HCC and right amygdala reactivity to negative affective (vs. happy/neutral) faces, r = .806 (n = 11) and left amygdala reactivity to negative affective (vs. neutral) pictures, r = .663 (n = 10). Additionally, left amygdala reactivity to negative faces was positively correlated with HCC in trauma-exposed controls, r = .582 (n = 13). This indicates that lower HCC is associated with diminished amygdala differentiation between negative affective and neutral stimuli. Thus, we observed lower HCC in trauma-exposed noncivilian women with PTSD compared to those without PTSD, which likely reflects prolonged HPA axis dysregulation. Additionally, HCC was associated with hallmark neurobiological correlates of PTSD, providing additional insights into pathophysiological processes in PTSD.
Spanish Abstracts by Asociación Chilena de Estrés Traumático (ACET) Concentraciones de cortisol en cabello se asocian con la condición de TEPT y la reactividad de la amígdala a estímulos emocionales negativos en oficiales de policía mujeres BAJO NIVEL DE CORTISOL EN CABELLO EN PACIENTES MUJERES CON TEPT El trastorno de estrés postraumático (TEPT) está asociado con la función alterada del eje hipotálamo-hipófisis-adrenal (HPA). La medición de las concentraciones de cortisol en cabello (HCC por sus siglas en inglés) permite evaluar en forma retrospectiva la regulación del eje HPA en periodos prolongados. Actualmente las investigaciones de HCC en TEPT son escasas. Los estudios transversales previos solo han incluido población civil, aunque se sabe que el tipo de trauma modera las asociaciones entre la condición del TEPT y la función del eje HPA. Investigamos las diferencias en el HCC entre oficiales de policía de sexo femenino expuestos a trauma con TEPT actual (n = 13) y sin TEPT actual o a lo largo de su vida (n = 15). Para investigar si la HCC se asociaba con correlatos neurales del TEPT, adicionalmente realizamos un análisis exploratorio correlacional entre la HCC y reactividad de la amígdala a estímulos emocionales negativos. Observamos niveles significativamente más bajos de HCC en las participantes con TEPT que en las sin TEPT, d = 0.89. Adicionalmente, entre las participantes con TEPT, observamos correlaciones positivas entre HCC y la reactividad de la amígdala derecha a caras con emociones negativas (vs. felicidad/neutral), r = .806 (n = 11) y la reactividad de la amígdala izquierda a fotografías con emociones negativas (vs. Neutral) r = .663 (n = 10). Adicionalmente, la reactividad de la amígdala izquierda a caras con emociones negativas estuvo correlacionada positivamente con HCC en controles expuestos a trauma, r = .582 (n = 13). Esto indica que HCC más bajos se asocian con capacidad de diferenciación disminuida de la amígdala entre estímulos emocionales negativos y neutrales. Así, observamos niveles más bajos de HCC en mujeres no civiles expuestas a trauma con TEPT comparadas con aquellas sin TEPT, lo que probablemente refleja una prolongada desregulación del eje HPA. Adicionalmente, HCC se asoció con correlatos neurobiológicos distintivos del TEPT, proveyendo información adicional de los procesos patofisiológicos en el TEPT.
Assuntos
Cabelo/química , Hidrocortisona/metabolismo , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/isolamento & purificação , Imageamento por Ressonância Magnética , Sistema Hipófise-Suprarrenal/fisiopatologia , Polícia/psicologia , Adulto JovemRESUMO
BACKGROUND: Posttraumatic stress disorder (PTSD) is a disabling psychiatric disorder that has been associated with lower white matter integrity of tracts connecting the prefrontal cortex with limbic regions. However, previous diffusion tensor imaging (DTI) findings have been inconsistent, showing high variability in the exact location and direction of effects. METHODS: We performed probabilistic tractography of the bilateral uncinate fasciculus, cingulum and superior longitudinal fasciculus (both temporal and parietal projections) in male and female police officers with and without PTSD. RESULTS: We included 38 (21 men) police officers with and 39 (20 men) without PTSD in our analyses. Compared with trauma-exposed controls, patients with PTSD showed significantly higher mean diffusivity of the right uncinate fasciculus, the major white matter tract connecting the amygdala to the prefrontal cortex (p = 0.012). No other significant between-group or group × sex differences were observed. Mean diffusivity of the right uncinate fasciculus was positively associated with anxiety symptoms (r = 0.410, p = 0.013) in patients with PTSD as well as with amygdala activity (r = 0.247, p = 0.038) and ventromedial prefrontal cortex (vmPFC) activity (r = 0.283, p = 0.016) in all participants in response to happy and neutral faces. LIMITATIONS: Our specific sample of trauma-exposed police officers limits the generalizability of our findings to other PTSD patient groups (e.g., civilian trauma). CONCLUSION: Patients with PTSD showed diminished structural connectivity between the amygdala and vmPFC, which was correlated with higher anxiety symptoms and increased functional activity of these brain regions. Our findings provide additional evidence for the prevailing neurocircuitry model of PTSD, postulating that ineffective communication between the amygdala and vmPFC underlies decreased top-down control over fear responses.
Assuntos
Encéfalo/diagnóstico por imagem , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Administração Intranasal , Adulto , Encéfalo/fisiopatologia , Mapeamento Encefálico , Estudos Cross-Over , Imagem de Tensor de Difusão , Método Duplo-Cego , Emoções/fisiologia , Reconhecimento Facial/fisiologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Vias Neurais/fisiopatologia , Testes Neuropsicológicos , Ocitocina/administração & dosagem , Polícia , Psicotrópicos/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Substância Branca/diagnóstico por imagem , Substância Branca/fisiopatologia , Violência no TrabalhoRESUMO
The neuropeptide oxytocin (OXT) facilitates prosocial behavior and selective sociality. In the context of stress, OXT also can down-regulate hypothalamic-pituitary-adrenal (HPA) axis activity, leading to consideration of OXT as a potential treatment for many socioaffective disorders. However, the mechanisms through which administration of exogenous OXT modulates social behavior in stressful environmental contexts are not fully understood. Here, we investigate the hypothesis that autonomic pathways are components of the mechanisms through which OXT aids the recruitment of social resources in stressful contexts that may elicit mobilized behavioral responses. Female prairie voles (Microtus ochrogaster) underwent a stressor (walking in shallow water) following pretreatment with intraperitoneal OXT (0.25mg/kg) or OXT antagonist (OXT-A, 20mg/kg), and were allowed to recover with or without their sibling cagemate. Administration of OXT resulted in elevated OXT concentrations in plasma, but did not dampen the HPA axis response to a stressor. However, OXT, but not OXT-A, pretreatment prevented the functional coupling, usually seen in the absence of OXT, between paraventricular nucleus (PVN) activity as measured by c-Fos immunoreactivity and HPA output (i.e. corticosterone release). Furthermore, OXT pretreatment resulted in functional coupling between PVN activity and brain regions regulating both sympathetic (i.e. rostral ventrolateral medulla) and parasympathetic (i.e. dorsal vagal complex and nucleus ambiguous) branches of the autonomic nervous system. These findings suggest that OXT increases central neural control of autonomic activity, rather than strictly dampening HPA axis activity, and provides a potential mechanism through which OXT may facilitate adaptive and context-dependent behavioral and physiological responses to stressors.
Assuntos
Nível de Alerta/fisiologia , Coração/inervação , Ocitocina/fisiologia , Sistema Nervoso Parassimpático/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Sistema Nervoso Simpático/fisiologia , Transmissão Sináptica/fisiologia , Animais , Arvicolinae , Feminino , Frequência Cardíaca/fisiologia , Sistema Hipotálamo-Hipofisário/fisiologia , Vias Neurais/fisiologia , Sistema Hipófise-Suprarrenal/fisiologiaRESUMO
BACKGROUND: About 10% of trauma-exposed individuals develop PTSD. Although a growing number of studies have investigated resting-state abnormalities in PTSD, inconsistent results suggest a need for a meta-analysis and a systematic review. METHODS: We conducted a systematic literature search in four online databases using keywords for PTSD, functional neuroimaging, and resting-state. In total, 23 studies matched our eligibility criteria. For the meta-analysis, we included 14 whole-brain resting-state studies, reporting data on 663 participants (298 PTSD patients and 365 controls). We used the activation likelihood estimation approach to identify concurrence of whole-brain hypo- and hyperactivations in PTSD patients during rest. Seed-based studies could not be included in the quantitative meta-analysis. Therefore, a separate qualitative systematic review was conducted on nine seed-based functional connectivity studies. RESULTS: The meta-analysis showed consistent hyperactivity in the ventral anterior cingulate cortex and the parahippocampus/amygdala, but hypoactivity in the (posterior) insula, cerebellar pyramis and middle frontal gyrus in PTSD patients, compared to healthy controls. Partly concordant with these findings, the systematic review on seed-based functional connectivity studies showed enhanced salience network (SN) connectivity, but decreased default mode network (DMN) connectivity in PTSD. CONCLUSIONS: Combined, these altered resting-state connectivity and activity patterns could represent neurobiological correlates of increased salience processing and hypervigilance (SN), at the cost of awareness of internal thoughts and autobiographical memory (DMN) in PTSD. However, several discrepancies between findings of the meta-analysis and systematic review were observed, stressing the need for future studies on resting-state abnormalities in PTSD patients.
Assuntos
Encéfalo/fisiopatologia , Diagnóstico por Imagem/métodos , Neuroimagem Funcional/métodos , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Humanos , DescansoRESUMO
BACKGROUND: Currently few evidence based interventions are available for the prevention of PTSD within the first weeks after trauma. Increased risk for PTSD development is associated with dysregulated fear and stress responses prior to and shortly after trauma, as well as with a lack of perceived social support early after trauma. Oxytocin is a potent regulator of these processes. Therefore, we propose that oxytocin may be important in reducing adverse consequences of trauma. The 'BONDS' study is conducted in order to assess the efficacy of an early intervention with intranasal oxytocin for the prevention of PTSD. METHODS/DESIGN: In this multicenter double-blind randomized placebo-controlled trial we will recruit 220 Emergency Department patients at increased risk of PTSD. Trauma-exposed patients are screened for increased PTSD risk with questionnaires assessing peri-traumatic distress and acute PTSD symptoms within 7 days after trauma. Baseline PTSD symptom severity scores and neuroendocrine and psychophysiological measures will be collected within 10 days after trauma. Participants will be randomized to 7.5 days of intranasal oxytocin (40 IU) or placebo twice a day. Follow-up measurements at 1.5, 3 and 6 months post-trauma are collected to assess PTSD symptom severity (the primary outcome measure). Other measures of symptoms of psychopathology, and neuroendocrine and psychophysiological disorders are secondary outcome measures. DISCUSSION: We hypothesize that intranasal oxytocin administered early after trauma is an effective pharmacological strategy to prevent PTSD in individuals at increased risk, which is both safe and easily applicable. Interindividual and contextual factors that may influence the effects of oxytocin treatment will be considered in the analysis of the results. TRIAL REGISTRATION: Netherlands Trial Registry: NTR3190.
Assuntos
Medo/efeitos dos fármacos , Ocitocina/administração & dosagem , Transtornos de Estresse Pós-Traumáticos/etiologia , Transtornos de Estresse Pós-Traumáticos/prevenção & controle , Administração Intranasal , Adolescente , Adulto , Idoso , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Adulto JovemRESUMO
Posttraumatic stress disorder (PTSD) is associated with lower cortical thickness (CT) in prefrontal, cingulate, and insular cortices in diverse trauma-affected samples. However, some studies have failed to detect differences between PTSD patients and healthy controls or reported that PTSD is associated with greater CT. Using data-driven dimensionality reduction, we sought to conduct a well-powered study to identify vulnerable networks without regard to neuroanatomic boundaries. Moreover, this approach enabled us to avoid the excessive burden of multiple comparison correction that plagues vertex-wise methods. We derived structural covariance networks (SCNs) by applying non-negative matrix factorization (NMF) to CT data from 961 PTSD patients and 1124 trauma-exposed controls without PTSD. We used regression analyses to investigate associations between CT within SCNs and PTSD diagnosis (with and without accounting for the potential confounding effect of trauma type) and symptom severity in the full sample. We performed additional regression analyses in subsets of the data to examine associations between SCNs and comorbid depression, childhood trauma severity, and alcohol abuse. NMF identified 20 unbiased SCNs, which aligned closely with functionally defined brain networks. PTSD diagnosis was most strongly associated with diminished CT in SCNs that encompassed the bilateral superior frontal cortex, motor cortex, insular cortex, orbitofrontal cortex, medial occipital cortex, anterior cingulate cortex, and posterior cingulate cortex. CT in these networks was significantly negatively correlated with PTSD symptom severity. Collectively, these findings suggest that PTSD diagnosis is associated with widespread reductions in CT, particularly within prefrontal regulatory regions and broader emotion and sensory processing cortical regions.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Imageamento por Ressonância Magnética , Encéfalo , Emoções , Córtex Pré-FrontalRESUMO
Background: Intrusive traumatic re-experiencing domain (ITRED) was recently introduced as a novel perspective on posttraumatic psychopathology, proposing to focus research of posttraumatic stress disorder (PTSD) on the unique symptoms of intrusive and involuntary re-experiencing of the trauma, namely, intrusive memories, nightmares, and flashbacks. The aim of the present study was to explore ITRED from a neural network connectivity perspective. Methods: Data were collected from 9 sites taking part in the ENIGMA (Enhancing Neuro Imaging Genetics through Meta Analysis) PTSD Consortium (n= 584) and included itemized PTSD symptom scores and resting-state functional connectivity (rsFC) data. We assessed the utility of rsFC in classifying PTSD, ITRED-only (no PTSD diagnosis), and trauma-exposed (TE)-only (no PTSD or ITRED) groups using a machine learning approach, examining well-known networks implicated in PTSD. A random forest classification model was built on a training set using cross-validation, and the averaged cross-validation model performance for classification was evaluated using the area under the curve. The model was tested using a fully independent portion of the data (test dataset), and the test area under the curve was evaluated. Results: rsFC signatures differentiated TE-only participants from PTSD and ITRED-only participants at about 60% accuracy. Conversely, rsFC signatures did not differentiate PTSD from ITRED-only individuals (45% accuracy). Common features differentiating TE-only participants from PTSD and ITRED-only participants mainly involved default mode network-related pathways. Some unique features, such as connectivity within the frontoparietal network, differentiated TE-only participants from one group (PTSD or ITRED-only) but to a lesser extent from the other group. Conclusions: Neural network connectivity supports ITRED as a novel neurobiologically based approach to classifying posttrauma psychopathology.
RESUMO
Background: Alexithymia, an inability to recognise one's emotions, has been associated with trauma-exposure and posttraumatic stress disorder (PTSD). Previous research suggests involvement of the oxytocin system, and socio-emotional neural processes. However, the paucity of neurobiological research on alexithymia, particularly in trauma-exposed populations, warrants further investigation.Objective: Explore associations between alexithymia, endogenous oxytocin levels, and socio-emotional brain function and morphometry in a trauma-exposed sample.Method: Dutch trauma-exposed police officers with (n = 38; 18 females) and without PTSD (n = 40; 20 females) were included. Alexithymia was assessed with the Toronto Alexithymia Scale (TAS-20). Endogenous salivary oxytocin was assessed during rest, using radioimmunoassay. Amygdala and insula reactivity to socio-emotional stimuli were assessed with functional MRI, amygdala and insula grey matter volume were derived using Freesurfer.Results: Alexithymia was higher in PTSD patients compared to trauma-exposed controls (F(1,70) = 54.031, p < .001). Within PTSD patients, alexithymia was positively associated with PTSD severity (ρ(36) = 0.497, p = .002). Alexithymia was not associated with childhood trauma exposure (ß = 0.076, p = .509), police work-related trauma exposure (ß = -0.107, p = .355), oxytocin levels (ß = -0.164, p = .161), insula (ß = -0.170, p = .158) or amygdala (ß = -0.175, p = .135) reactivity, or amygdala volume (ß = 0.146, p = .209). Insula volume was positively associated with alexithymia (ß = 0.222, p = .016), though not significant after multiple testing corrections. Bayesian analyses supported a lack of associations.Conclusions: No convincing neurobiological correlates of alexithymia were observed with any of the markers included in the current study. Yet, the current study confirmed high levels of alexithymia in PTSD patients, independent of trauma-exposure, substantiating alexithymia's relevance in the clinical phenotype of PTSD.
Little is known about neurobiological correlates of alexithymia in trauma-exposed and posttraumatic stress disorder (PTSD) populations.In this highly trauma-exposed sample, alexithymia was associated with PTSD symptoms, but not with childhood or adult trauma exposure, suggesting alexithymia is not a direct consequence of trauma.Alexithymia was not convincingly associated with salivary oxytocin, amygdala and insula reactivity to socio-emotional stimuli, amygdala or insula grey matter volume.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Feminino , Humanos , Transtornos de Estresse Pós-Traumáticos/psicologia , Sintomas Afetivos , Polícia/psicologia , Ocitocina , Teorema de Bayes , EmoçõesRESUMO
BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with markers of accelerated aging. Estimates of brain age, compared to chronological age, may clarify the effects of PTSD on the brain and may inform treatment approaches targeting the neurobiology of aging in the context of PTSD. METHOD: Adult subjects (N = 2229; 56.2% male) aged 18-69 years (mean = 35.6, SD = 11.0) from 21 ENIGMA-PGC PTSD sites underwent T1-weighted brain structural magnetic resonance imaging, and PTSD assessment (PTSD+, n = 884). Previously trained voxel-wise (brainageR) and region-of-interest (BARACUS and PHOTON) machine learning pipelines were compared in a subset of control subjects (n = 386). Linear mixed effects models were conducted in the full sample (those with and without PTSD) to examine the effect of PTSD on brain predicted age difference (brain PAD; brain age - chronological age) controlling for chronological age, sex, and scan site. RESULTS: BrainageR most accurately predicted brain age in a subset (n = 386) of controls (brainageR: ICC = 0.71, R = 0.72, MAE = 5.68; PHOTON: ICC = 0.61, R = 0.62, MAE = 6.37; BARACUS: ICC = 0.47, R = 0.64, MAE = 8.80). Using brainageR, a three-way interaction revealed that young males with PTSD exhibited higher brain PAD relative to male controls in young and old age groups; old males with PTSD exhibited lower brain PAD compared to male controls of all ages. DISCUSSION: Differential impact of PTSD on brain PAD in younger versus older males may indicate a critical window when PTSD impacts brain aging, followed by age-related brain changes that are consonant with individuals without PTSD. Future longitudinal research is warranted to understand how PTSD impacts brain aging across the lifespan.
Assuntos
Transtornos de Estresse Pós-Traumáticos , Adolescente , Adulto , Idoso , Envelhecimento , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Feminino , Humanos , Aprendizado de Máquina , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Adulto JovemRESUMO
BACKGROUND: Posttraumatic stress disorder (PTSD) is accompanied by disrupted cortical neuroanatomy. We investigated alteration in covariance of structural networks associated with PTSD in regions that demonstrate the case-control differences in cortical thickness (CT) and surface area (SA). METHODS: Neuroimaging and clinical data were aggregated from 29 research sites in >1300 PTSD cases and >2000 trauma-exposed control subjects (ages 6.2-85.2 years) by the ENIGMA-PGC (Enhancing Neuro Imaging Genetics through Meta Analysis-Psychiatric Genomics Consortium) PTSD working group. Cortical regions in the network were rank ordered by the effect size of PTSD-related cortical differences in CT and SA. The top-n (n = 2-148) regions with the largest effect size for PTSD > non-PTSD formed hypertrophic networks, the largest effect size for PTSD < non-PTSD formed atrophic networks, and the smallest effect size of between-group differences formed stable networks. The mean structural covariance (SC) of a given n-region network was the average of all positive pairwise correlations and was compared with the mean SC of 5000 randomly generated n-region networks. RESULTS: Patients with PTSD, relative to non-PTSD control subjects, exhibited lower mean SC in CT-based and SA-based atrophic networks. Comorbid depression, sex, and age modulated covariance differences of PTSD-related structural networks. CONCLUSIONS: Covariance of structural networks based on CT and cortical SA are affected by PTSD and further modulated by comorbid depression, sex, and age. The SC networks that are perturbed in PTSD comport with converging evidence from resting-state functional connectivity networks and networks affected by inflammatory processes and stress hormones in PTSD.
Assuntos
Conectoma , Transtornos de Estresse Pós-Traumáticos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Criança , Conectoma/métodos , Humanos , Imageamento por Ressonância Magnética/métodos , Pessoa de Meia-Idade , Neuroimagem , Adulto JovemRESUMO
BACKGROUND: Efficient prevention of posttraumatic stress disorder (PTSD) needs to target individuals with an increased risk for adverse outcome after trauma. Prognostic or prescriptive biological markers assessed early posttrauma may inform personalized treatment recommendations. OBJECTIVE: To test prognostic and prescriptive effects of early (posttraumatic) autonomic and endocrine markers on PTSD symptom development. METHOD: Autonomic and endocrine markers were assessed within 12 days posttrauma and before treatment initiation within a randomized placebo-controlled trial investigating repeated oxytocin administration as preventive intervention for PTSD. Linear mixed effects models were used to test the effects of heart rate (variability), resting cortisol, morning cortisol and cortisol awakening response (CAR), cortisol suppression by dexamethasone and resting oxytocin on PTSD symptoms 1.5, 3 and 6 months posttrauma in men (n = 54), women using hormonal contraception (n = 27) and cycling women (n = 19). RESULTS: We found significant prognostic effects of resting oxytocin and cortisol suppression. In women using hormonal contraception, higher oxytocin was associated with higher PTSD symptoms across follow-up. Stronger cortisol suppression by dexamethasone, reflecting increased glucocorticoid receptor feedback sensitivity, was associated with lower PTSD symptoms across follow-up in men, but with higher symptoms at 1.5 months in women using hormonal contraception. These effects were independent of treatment condition. No further significant prognostic or prescriptive effects were detected. CONCLUSION: Our exploratory study indicates that resting oxytocin and glucocorticoid receptor feedback sensitivity early posttrauma are associated with subsequent PTSD symptom severity. Notably, prognostic effects depended on sex and hormonal contraception use, emphasizing the necessity to consider these factors in biomedical PTSD research.
Antecedentes: La prevención eficiente del trastorno de estrés postraumático (TEPT) necesita dirigirse a personas con un mayor riesgo de consecuencias adversas después de un trauma. Los marcadores biológicos pronósticos o preceptivos evaluados tempranamente luego del trauma pueden informar recomendaciones de tratamiento personalizadas.Objetivo: Evaluar los efectos pronósticos y preceptivos de los marcadores tempranos (postraumáticos) autonómicos y endocrinos sobre el desarrollo de síntomas de TEPT.Método: Fueron evaluados marcadores autonómicos y endocrinos dentro de los 12 días postrauma y antes de la iniciación del tratamiento dentro de un estudio aleatorio placebo-control, investigando la administración repetida de oxitocina como intervención preventiva para TEPT. Se utilizaron modelos lineales de efectos mixtos para evaluar los efectos de la frecuencia cardiaca (variabilidad), cortisol en reposo, cortisol matutino y respuesta al despertar de cortisol (CAR por sus siglas en inglés), supresión del cortisol por dexametasona y oxitocina en reposo sobre los síntomas de TEPT a los 1.5, 3 y 6 meses postrauma en hombres (N=54), mujeres que usaban contracepción hormonal (N=27) y mujeres ciclantes (N=19).Resultados: Encontramos efectos pronósticos significativos de la oxitocina en reposo y de la supresión de cortisol. En las mujeres que usaban contracepción hormonal, los niveles de oxitocina más altos se asociaron con más síntomas de TEPT a lo largo del seguimiento. La supresión mayor del cortisol por dexametasona, que refleja una mayor sensibilidad a la retroalimentación del receptor de glucocorticoides, se asoció con menos síntomas de TEPT a lo largo del seguimiento en los hombres, pero con mayores síntomas a los 1.5 meses en las mujeres que usaban contracepción hormonal. Estos efectos fueron independientes de la condición de tratamiento. No se detectaron más efectos pronósticos o preceptivos significativos.Conclusión: Nuestro estudio exploratorio indica que la oxitocina en reposo y la sensibilidad a la retroalimentación del receptor de glucocorticoides tempranamente luego del trauma se asocian con la subsecuente severidad de los síntomas de TEPT. Notablemente, los efectos pronósticos dependen del sexo y del uso de contracepción hormonal, lo que enfatiza la necesidad de considerar estos factores en la investigación biomédica en TEPT.
RESUMO
Post-traumatic stress disorder (PTSD) is characterized by difficulty down-regulating emotional responses towards trauma-reminders. The neuropeptide oxytocin may enhance treatment response in PTSD, by dampening excessive fear and improving fear regulation. However, oxytocin effects on (neural correlates of) cognitive emotion regulation abilities have never been investigated in PTSD patients. Therefore, we investigated behavioral and neural effects of intranasal oxytocin administration (40IU) on distraction as emotion regulation strategy in male and female police officers with and without PTSD (nâ¯=â¯76), using a randomized placebo-controlled cross-over fMRI study. The distraction condition consisted of a working memory task while negative affective pictures were presented. Under placebo, male PTSD patients showed decreased right striatal activity during distraction compared to male trauma-exposed controls, which was unaffected by oxytocin. After oxytocin administration, left thalamus activity during distraction was enhanced in all participants, independent of PTSD status or sex. Although left thalamus activity during distraction did not differ between PTSD patients and controls under placebo, it was negatively correlated with error rates within PTSD patients. Furthermore, oxytocin administration increased functional connectivity between the left thalamus and amygdala in PTSD patients and male trauma-exposed controls. Upregulation of thalamus activity during distraction by oxytocin may enhance cognitive emotion regulation abilities during psychotherapy in PTSD, although this should still be investigated in a clinical setting. Our findings open an important research avenue into oxytocin effects on cognitive emotion regulation in PTSD and other psychiatric disorders characterized by deficient emotion regulation abilities. Registered in the Netherlands Trial Registry, registration number: NTR3516.
Assuntos
Emoções/efeitos dos fármacos , Ocitócicos/administração & dosagem , Ocitocina/administração & dosagem , Transtornos de Estresse Pós-Traumáticos/tratamento farmacológico , Administração Intranasal , Adolescente , Adulto , Idoso , Estudos Transversais , Método Duplo-Cego , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Pessoa de Meia-Idade , Oxigênio/sangue , Estatísticas não Paramétricas , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Adulto JovemRESUMO
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that may develop after a traumatic event. Here we aimed to identify epigenetic and genetic loci associated with PTSD. We included 73 traumatized police officers with extreme phenotypes regarding symptom severity despite similar trauma history: n = 34 had PTSD and n = 39 had minimal PTSD symptoms. Epigenetic and genetic profiles were based on the Illumina HumanMethylation450 BeadChip. We searched for differentially methylated probes (DMPs) and differentially methylated regions (DMRs). For genetic associations we analyzed the CpG-SNPs present on the array. We detected no genome-wide significant DMPs and we did not replicate previously reported DMPs associated with PTSD. However, GSE analysis of the top 100 DMPs showed enrichment of three genes involved in the dopaminergic neurogenesis pathway. Furthermore, we observed a suggestive association of one relatively large DMR between patients and controls, which was located at the PAX8 gene and previously associated with other psychiatric disorders. Finally, we validated five PTSD-associated CpG-SNPs identified with the array using sanger sequencing. We subsequently replicated the association of one common SNP (rs1990322) in the CACNA1C locus with PTSD in an independent cohort of traumatized children. The CACNA1C locus was previously associated with other psychiatric disorders, but not yet with PTSD. Thus, despite the small sample size, inclusion of extreme symptom severity phenotypes in a highly homogenous traumatized cohort enabled detection of epigenetic and genetic loci associated with PTSD. Moreover, here we showed that genetically confounded 450K probes are informative for genetic association analysis.
Assuntos
Canais de Cálcio Tipo L/genética , Polícia/psicologia , Polimorfismo de Nucleotídeo Único , Transtornos de Estresse Pós-Traumáticos/genética , Adulto , Idoso , Estudos de Casos e Controles , Ilhas de CpG , Metilação de DNA , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Many studies report smaller hippocampal and amygdala volumes in posttraumatic stress disorder (PTSD), but findings have not always been consistent. Here, we present the results of a large-scale neuroimaging consortium study on PTSD conducted by the Psychiatric Genomics Consortium (PGC)-Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) PTSD Working Group. METHODS: We analyzed neuroimaging and clinical data from 1868 subjects (794 PTSD patients) contributed by 16 cohorts, representing the largest neuroimaging study of PTSD to date. We assessed the volumes of eight subcortical structures (nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, thalamus, and lateral ventricle). We used a standardized image-analysis and quality-control pipeline established by the ENIGMA consortium. RESULTS: In a meta-analysis of all samples, we found significantly smaller hippocampi in subjects with current PTSD compared with trauma-exposed control subjects (Cohen's d = -0.17, p = .00054), and smaller amygdalae (d = -0.11, p = .025), although the amygdala finding did not survive a significance level that was Bonferroni corrected for multiple subcortical region comparisons (p < .0063). CONCLUSIONS: Our study is not subject to the biases of meta-analyses of published data, and it represents an important milestone in an ongoing collaborative effort to examine the neurobiological underpinnings of PTSD and the brain's response to trauma.
Assuntos
Adultos Sobreviventes de Eventos Adversos na Infância/estatística & dados numéricos , Hipocampo/patologia , Neuroimagem/estatística & dados numéricos , Caracteres Sexuais , Transtornos de Estresse Pós-Traumáticos/patologia , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/patologia , Estudos de Coortes , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/patologia , Feminino , Hipocampo/diagnóstico por imagem , Humanos , Ventrículos Laterais/diagnóstico por imagem , Ventrículos Laterais/patologia , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Metanálise como Assunto , Transtornos de Estresse Pós-Traumáticos/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Tálamo/patologiaRESUMO
Background: Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder which develops in approximately 10% of trauma-exposed individuals. Currently, there are few early preventive interventions available for PTSD. Intranasal oxytocin administration early posttrauma may prevent PTSD symptom development, as oxytocin administration was previously found to beneficially impact neurobiological (e.g. amygdala reactivity) and socio-emotional PTSD vulnerability factors. Objective: The overall aim of this dissertation was to investigate the potential of intranasal oxytocin administration as early preventive intervention for PTSD. Methods: We performed a functional magnetic resonance imaging (fMRI) study to assess the acute effects of a single administration of oxytocin on the functional fear neurocircuitry - consisting of the amygdala and (pre)frontal brain regions - in recently trauma-exposed emergency department patients (range n = 37-41). In addition, we performed a multicentre randomized double-blind placebo-controlled clinical trial (RCT) to assess the efficacy of repeated intranasal oxytocin administration early after trauma for preventing PTSD symptom development up to six months posttrauma (n = 107). Results: In our fMRI experiments we observed acutely increased amygdala reactivity to fearful faces and attenuated amygdala-ventromedial and ventrolateral prefrontal cortex functional connectivity after a single oxytocin administration in recently trauma-exposed individuals. However, in our RCT we found that repeated intranasal oxytocin administration early posttrauma reduced subsequent PTSD symptom development in recently trauma-exposed emergency department patients with high acute PTSD symptoms. Conclusions: These findings indicate that repeated intranasal oxytocin is a promising early preventive intervention for PTSD for individuals at increased risk for PTSD due to high acute symptom severity. Administration frequency dependent effects of oxytocin or the effects of oxytocin administration on salience processing may serve as explanatory frameworks for the contrasting oxytocin effects on anxiety-related measures in our clinical and neuroimaging studies.