Smaller total and subregional cerebellar volumes in posttraumatic stress disorder: a mega-analysis by the ENIGMA-PGC PTSD workgroup.

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.

Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

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.

A comparison of methods to harmonize cortical thickness measurements across scanners and sites.

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.

Cortical volume abnormalities in posttraumatic stress disorder: an ENIGMA-psychiatric genomics consortium PTSD workgroup mega-analysis.

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.

Neuroanatomy of transgender persons in a Non-Western population and improving reliability in clinical neuroimaging.

Although the neuroanatomy of transgender persons is slowly being charted, findings are presently discrepant. Moreover, the major body of work has focused on Western populations. One important factor is the issue of power and low signal-to-noise (SNR) ratio in neuroimaging studies of rare study populations including endocrine or neurological patient groups. The present study focused on the structural neuroanatomy of a Non-Western (Iranian) sample of 40 transgender men (TM), 40 transgender women (TW), 30 cisgender men (CM), and 30 cisgender women (CW), while assessing whether the reliability of findings across structural anatomical measures including gray matter volume (GMV), cortical surface area (CSA), and cortical thickness (CTh) could be increased by using two back-to-back within-session structural MRI scans. Overall, findings in transgender persons were more consistent with sex assigned at birth in GMV and CSA, while no group differences emerged for CTh. Repeated measures analysis also indicated that having a second scan increased SNR in all regions of interest, most notably bilateral frontal poles, pre- and postcentral gyri and putamina. The results suggest that a simple time and cost-effective measure to improve SNR in rare clinical populations with low prevalence rates is a second anatomical scan when structural MRI is of interest.

Defining the neural correlates of spontaneous theory of mind (ToM): An fMRI multi-study investigation.

There is a major debate in the theory of mind (ToM) field, concerning whether spontaneous and explicit ToM are based on the same or two distinct cognitive systems. While extensive research on the neural correlates of explicit ToM has demonstrated involvement of the temporo-parietal junction (TPJ) and the medial prefrontal cortex (mPFC), few studies investigated spontaneous ToM, leaving some open questions. Here, we implemented a multi-study approach by pooling data from three fMRI studies to obtain a larger sample to increase power and sensitivity to better define the neurocognitive mechanisms underlying spontaneous ToM. Participants watched videos in which an agent acquires a true or false belief about the location of a ball. Thus, the belief of the agent and that of the participant could either match or differ. Importantly, participants were never asked to consider the belief of the agent and were only instructed to press a button when they detected the presence of the ball after an occluder fell at the end of each video. By analysing the blood-oxygen level dependent signal during the belief formation phase for false versus true beliefs, we found a cluster of activation in the right, and to a lesser extent, left posterior parietal cortex spanning the TPJ, but no mPFC activation. Region of interest (ROI) analysis on bilateral TPJ and mPFC confirmed these results and added evidence to the asymmetry in laterality of the TPJ in spontaneous ToM. Interestingly, the whole brain analysis, supported by an overlap with brain maps, revealed maximum activation in areas involved in visuospatial working memory and attention switching functions, such as the supramarginal gyrus, the middle temporal gyrus, and the inferior frontal gyrus. By contrast, evidence for the presence of brain-behaviour correlations was mixed and there was no evidence for functional connectivity between the TPJ and mPFC. Taken together, these findings help clarifying the brain system supporting spontaneous ToM.

Examining the association between posttraumatic stress disorder and disruptions in cortical networks identified using data-driven methods.

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.

Remodeling of the Cortical Structural Connectome in Posttraumatic Stress Disorder: Results From the ENIGMA-PGC Posttraumatic Stress Disorder Consortium.

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.

Childhood Abuse and Adult Sociocognitive Skills: Distinguishing Between Self and Other Following Early Trauma.

Experience of childhood abuse (CA) impairs complex social functioning in children; however, much less is known about its effects on basic sociocognitive processes and even fewer studies have investigated these in adult survivors. Using two behavioral tasks, this study investigated spontaneous theory of mind (ToM) and imitative behavior in 41 women with CA and 26 unaffected comparison (UC) women. In the spontaneous ToM task, UCs showed a larger ToM index than CAs, indicating more facilitation by knowledge of another's false belief. In the imitation-inhibition task, CAs experienced less interference than UCs when observing another's incongruent movements. After controlling for depression, differences in ToM became marginally significant, yet remained highly significant for inhibiting imitative behavior. The findings suggest CA survivors have altered perspective-taking and are less influenced by others' perspectives, potentially due to changes in self-other distinction. Clinical implications regarding therapeutic practice with survivors of CA are discussed.

Do pictures really say more than a thousand words? A network approach to early traumatic experience and empathic responding.

Background: Empathy is essential for interpersonal relationships, yet remains difficult to measure. Some evidence suggests that early traumatic experiences leads to alterations in empathic responding. Objective: This study sought to differentiate connections between subtypes of childhood maltreatment, a pictorial test of affective empathy (PET), and self-reported empathy (Interpersonal Reactivity Index; IRI) by using network analysis approach to investigate the structure of relationships between childhood maltreatment and later empathic responding. Method: 301 participants completed the PET, the Early Trauma Inventory Self Report-Short Form (ETISR-SF), the IRI, and questionnaires assessing current mood and perceived stress levels. Results: The PET showed a strong positive association with the IRI subscale empathic concern (EC), after conditioning on all other nodes in the network. EC proved to be a highly central node and was positively related to severity of childhood sexual abuse (CSA), yet not to childhood physical abuse or emotional maltreatment. Pathways between emotional maltreatment and physical abuse and the PET were indirect, passing through self-reported EC and CSA. Conclusions: Our study suggests that CSA more so than other childhood maltreatment experiences is associated with increased self-reported affective empathy, but is not captured directly through a pictorial test of affective empathy.

Antecedentes: La empatía es esencial para las relaciones interpersonales, pero sigue siendo difícil de medir. Alguna evidencia sugiere que las experiencias traumáticas tempranas conducen a alteraciones en la respuesta empática.Objetivo: Este estudio buscó diferenciar las conexiones entre los subtipos de maltrato infantil, una prueba pictórica de empatía afectiva (PET) y la empatía auto-reportada (Índice de reactividad interpersonal; IRI) mediante el uso de un enfoque de análisis de red para investigar la estructura de las relaciones entre el maltrato infantil y la respuesta empática posterior.Método: 301 participantes completaron el PET, el Formulario abreviado del inventario de trauma temprano auto-reportado (ETISR-SF), el IRI y cuestionarios para evaluar el estado de ánimo actual y los niveles de estrés percibidos.Resultados: Después del acondicionamiento en todos los demás nodos de la red, el PET mostró una fuerte asociación positiva con la preocupación empática (CE) de la sub-escala IRI. La CE demostró ser un nodo altamente central y se relacionó positivamente con la gravedad del abuso sexual infantil (CSA), pero no con el abuso físico infantil o el maltrato emocional. Las conexiones entre el maltrato emocional y el abuso físico con la PET fueron indirectas, pasando a través de CE y CSA auto-reportados.Conclusiones: Nuestro estudio sugiere que el Abuso Sexual Infantil, más que otras experiencias de maltrato infantil, se asocia con una mayor empatía afectiva auto-reportada, pero no se observa directamente a través de una prueba pictórica de empatía afectiva.

Depression, trauma and mentalizing: No influence of depressive symptoms on spontaneous theory of mind in a subclinical sample.

BACKGROUND: Depressive symptoms are associated with impaired social functioning, arguably because of reduced mentalizing abilities. However, findings in persons with depressive symptoms and/or major depressive disorder (MDD) are presently mixed, finding evidence both for and against the hypothesis of reduced mentalizing abilities. AIMS: This study investigated spontaneous cognitive mentalizing in 36 age-, sex- and education-matched students with depressive symptoms and 45 comparisons with minimal depressive symptoms. METHOD: To assess spontaneous mentalizing, we used the implicit theory of mind (ToM) task, which looks specifically at spontaneous computation of false belief. RESULTS: Bayesian analysis did not support the hypothesis of impaired mentalizing; in fact, it suggested that the results were 3.90 times more likely to have occurred under the null hypothesis. Results remained stable when comparing depressed and non-depressed individuals without maltreatment exposure but were inconclusive in the maltreatment-exposed groups. CONCLUSION: The findings suggest no effect of spontaneous mentalizing in a high-functioning depressed sample. Moreover, the findings also emphasize the need to control for childhood maltreatment experiences in future ToM and social functioning research, as these may constitute subgroups within depressed samples. Tailored therapy for maltreated depression individuals may be beneficial.

Early interpersonal trauma reduces temporoparietal junction activity during spontaneous mentalising.

Experience of interpersonal trauma and violence alters self-other distinction and mentalising abilities (also known as theory of mind, or ToM), yet little is known about their neural correlates. This fMRI study assessed temporoparietal junction (TPJ) activation, an area strongly implicated in interpersonal processing, during spontaneous mentalising in 35 adult women with histories of childhood physical, sexual, and/or emotional abuse (childhood abuse; CA) and 31 women without such experiences (unaffected comparisons; UC). Participants watched movies during which an agent formed true or false beliefs about the location of a ball, while participants always knew the true location of the ball. As hypothesised, right TPJ activation was greater for UCs compared to CAs for false vs true belief conditions. In addition, CAs showed increased functional connectivity relative to UCs between the rTPJ and dorsomedial prefrontal cortex. Finally, the agent's belief about the presence of the ball influenced participants' responses (ToM index), but without group differences. These findings highlight that experiencing early interpersonal trauma can alter brain areas involved in the neural processing of ToM and perspective-taking during adulthood.

Women with early maltreatment experience show increased resting-state functional connectivity in the theory of mind (ToM) network.

Background: Experience of childhood maltreatment significantly increases the risk for the development of psychopathology and is associated with impairments in socio-cognitive skills including theory-of-mind (ToM). In turn, neural alterations in ToM processing might then influence future interpersonal interaction and social-emotional understanding. Objective: To assess resting-state activity in the theory-of-mind network in traumatized and non-traumatized persons. Methods: Thirty-five women with a history of childhood maltreatment and 31 unaffected women completed a resting-state scan and a ToM localizer task. The peak coordinates from the localizer were used as the seed regions for the resting-state functional connectivity (RSFC) analyses (temporo-parietal junction, dorsomedial prefrontal cortex, middle temporal gyrus and precuneus). Results: Child abuse was associated with increased RSFC between various ToM regions including the precuneus and the brainstem suggesting altered hierarchical processing in ToM regions. Number of types of abuse was driving the effect for the temporo-parietal junction and the brainstem, while the severity of abuse was linked to increased RSFC between the middle temporal gyrus and the frontal cortex. Post-hoc analyses of brainstem regions indicated the involvement of the serotonergic system (dorsal raphe). Conclusions: The data indicate a lasting impact of childhood maltreatment on the neural networks involved in social information processing that are integral to understanding others' emotional states. Indeed, such altered neural networks may account for some of the interpersonal difficulties victims of childhood maltreatment experience.

Antecedentes: La experiencia de maltrato infantil aumenta significativamente el riesgo del desarrollo de psicopatología y se encuentra asociado con deficiencia en las habilidades sociocognitivas, incluyendo la teoría-de-la-mente (ToM en su sigla en inglés). A su vez, las alteraciones neuronales en el procesamiento de la ToM podrían así influenciar las interacciones interpersonales futuras y el entendimiento socioemocional.Objetivo: Evaluar la actividad del estado de reposo en la red de la teoría-de-la-mente en personas traumatizadas y no traumatizadas.Métodos: Treinta y cinco mujeres con una historia de maltrato infantil y 31 mujeres no afectadas completaron un escáner en estado de reposo y una tarea localizadora de la ToM. Las coordenadas más altas del localizador fueron usadas como las regiones de origen para los análisis de la conectividad funcional del estado de descanso (RSFC en su sigla en inglés; incluyendo la unión temporoparietal, corteza prefrontal dorsomedial, giros cerebrales temporales medios, y precúneo).Resultados: El abuso infantil fue asociado con un incremento en la RSFC entre varias regiones de la ToM, incluyendo el precúneo y el tronco encefálico, sugiriendo una alteración en el procesamiento jerárquico en las regiones de la ToM. El número de los tipos de abuso estuvo dirigiendo el efecto de la unión temporoparietal y el tronco encefálico, mientras que la severidad del abuso se relacionó a una aumentada RSFC entre los giros cerebrales temporales medios y la corteza frontal. Los análisis post hoc de las regiones del tronco encefálico indicaron el rol del sistema serotoninérgico (rafe dorsal).Conclusiones: Los datos indican un impacto de largo plazo del maltrato infantil en las redes neuronales involucradas en el procesamiento de la información social que son fundamentales para el entendimiento de los estados emocionales de otros. De hecho, tales redes neuronales alteradas podrían ser responsables de algunas de las dificultades interpersonales que las víctimas de maltrato infantil experimentan.