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.

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.

Self-Reported Sleep Quality Modulates Amygdala Resting-State Functional Connectivity in Anxiety and Depression.

Sufficient sleep plays an important role in neurocognitive function, yet, problematic sleep is ubiquitous in the general population. It is also frequently predictive of, and concurrent with, internalizing psychopathologies (IPs) such as anxiety and depression suggesting sleep quality is dimensional and transdiagnostic. Along with problematic sleep, IPs are characterized by negative affectivity, therefore, prominent neurobiological models of internalizing conditions involve the amygdala, a region central to emotion. In resting-state studies (independent of sleep considerations), abnormalities in amygdala-frontal functional connectivity are commonly observed suggesting emotion dysregulation may contribute to clinically-relevant phenotypes. In a separate line of research, studies of sleep deprivation, and insomnia disorder suggest sleep loss may alter amygdala-frontal connectivity. Taken together, findings point to shared neurobiology between sleep and emotion systems, however, the impact of sleep quality on the amygdala circuit in anxiety or depression is unclear. Therefore, we evaluated variance in naturalistic sleep quality on amygdala-based circuity in individuals with and without psychiatric illness. Resting-state fMRI data was collected in 87 un-medicated, treatment-seeking adults diagnosed with a primary anxiety disorder (n = 68) or primary depressive disorder (n = 19) in addition to healthy individuals (n = 40). Regression analysis was conducted with bilateral anatomical amygdala as seed regions and self-reported sleep quality was indexed with a validated self-report measure, the Pittsburgh Sleep Quality Index (PSQI). Post-hoc analysis was performed to evaluate whether diagnostic status (primary anxiety, primary depression, healthy) significantly explained functional connectivity results. Whole-brain regression analysis, controlling for anxiety and depression symptoms, revealed worse sleep quality (i.e., higher PSQI total scores) predicted increased left amygdala-subgenual anterior cingulate functional connectivity and reduced connectivity with posterior cerebellar lobe and superior temporal gyrus. For right amygdala, increased coupling with postcentral gyrus corresponded with worse sleep. Post-hoc analysis did not detect a significant relationship between diagnostic status and whole-brain findings. Results expand on previous studies and indicate variance in sleep quality tracks brain pathways involved in cognitive-emotion functions implicated in the neurobiology of IPs that may extend to individuals at risk for clinical anxiety or depression. Altogether, the clinical relevance of identifying phenotypes to improve our understanding of psychopathology may be improved by incorporating sleep quality.

Ventrolateral prefrontal cortex activation during social exclusion mediates the relation between intolerance of uncertainty and trait aggression.

Intolerance of uncertainty (IU) is an important individual difference factor that may contribute to trait-like aggression. Deficient engagement of the ventrolateral PFC (vlPFC) during social situations may also be a mechanism that links these two constructs. The aim of the current study was to test a proposed mediation model whereby IU is associated with trait aggression through neural activation of the vlPFC during a social exclusion task. Fifty-three adults with a range of impulsive-aggressive traits completed validated assessments of IU and trait aggression, and the 'Cyberball' social exclusion task during functional magnetic resonance imaging (fMRI). Results supported the mediation model such that greater levels of IU were associated with greater trait aggression through hypoactivation of the vlPFC during social exclusion. This study is the first to provide evidence suggesting that individuals higher in IU have difficulties engaging regulatory neural processes, which in-turn may increase the propensity for aggression.