Combat-related mild traumatic brain injury (cmTBI) is a leading cause of sustained physical, cognitive, emotional, and behavioral disabilities in Veterans and active-duty military personnel. Accurate diagnosis of cmTBI is challenging since the symptom spectrum is broad and conventional neuroimaging techniques are insensitive to the underlying neuropathology. The present study developed a novel deep-learning neural network method, 3D-MEGNET, and applied it to resting-state magnetoencephalography (rs-MEG) source-magnitude imaging data from 59 symptomatic cmTBI individuals and 42 combat-deployed healthy controls (HCs). Analytic models of individual frequency bands and all bands together were tested. The All-frequency model, which combined delta-theta (1-7 Hz), alpha (8-12 Hz), beta (15-30 Hz), and gamma (30-80 Hz) frequency bands, outperformed models based on individual bands. The optimized 3D-MEGNET method distinguished cmTBI individuals from HCs with excellent sensitivity (99.9 ± 0.38%) and specificity (98.9 ± 1.54%). Receiver-operator-characteristic curve analysis showed that diagnostic accuracy was 0.99. The gamma and delta-theta band models outperformed alpha and beta band models. Among cmTBI individuals, but not controls, hyper delta-theta and gamma-band activity correlated with lower performance on neuropsychological tests, whereas hypo alpha and beta-band activity also correlated with lower neuropsychological test performance. This study provides an integrated framework for condensing large source-imaging variable sets into optimal combinations of regions and frequencies with high diagnostic accuracy and cognitive relevance in cmTBI. The all-frequency model offered more discriminative power than each frequency-band model alone. This approach offers an effective path for optimal characterization of behaviorally relevant neuroimaging features in neurological and psychiatric disorders.
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
In: Smith , A K , Ratanatharathorn , A , Maihofer , A X , Naviaux , R K , Aiello , A E , Amstadter , A B , Ashley-Koch , A E , Baker , D G , Beckham , J C , Boks , M P , Bromet , E , Dennis , M , Galea , S , Garrett , M E , Geuze , E , Guffanti , G , Hauser , M A , Katrinli , S , Kilaru , V , Kessler , R C , Kimbrel , N A , Koenen , K C , Kuan , P-F , Li , K , Logue , M W , Lori , A , Luft , B J , Miller , M W , Naviaux , J C , Nugent , N R , Qin , X , Ressler , K J , Risbrough , V B , Rutten , B P F , Stein , M B , Ursano , R J , Vermetten , E , Vinkers , C H , Wang , L , Youssef , N A , Uddin , M , Nievergelt , C M , INTRuST Clinical Consortium , VA Mid-Atlantic MIRECC Workgroup & PGC PTSD Epigenetics Workgroup 2020 , ' Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR ' , Nature Communications , vol. 11 , no. 1 , 5965 . https://doi.org/10.1038/s41467-020-19615-x
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD. PTSD has been associated with DNA methylation of specific loci in the genome, but studies have been limited by small sample sizes. Here, the authors perform a meta-analysis of DNA methylation data from 10 different cohorts and identify CpGs in AHRR that are associated with PTSD.
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.
In: Smith , A K , Ratanatharathorn , A , Maihofer , A X , Naviaux , R K , Aiello , A E , Amstadter , A B , Ashley-Koch , A E , Baker , D G , Beckham , J C , Boks , M P , Bromet , E , Dennis , M , Galea , S , Garrett , M E , Geuze , E , Guffanti , G , Hauser , M A , Katrinli , S , Kilaru , V , Kessler , R C , Kimbrel , N A , Koenen , K C , Kuan , P F , Li , K , Logue , M W , Lori , A , Luft , B J , Miller , M W , Naviaux , J C , Nugent , N R , Qin , X , Ressler , K J , Risbrough , V B , Rutten , B P F , Stein , M B , Ursano , R J , Vermetten , E , Vinkers , C H , Wang , L , Youssef , N A , Marx , C , Grant , G , Stein , M , Qin , X J , Jain , S , McAllister , T W , Zafonte , R , Lang , A , Coimbra , R , Andaluz , N , Shutter , L , George , M S , Brancu , M , Calhoun , P S , Dedert , E , Elbogen , E B , Fairbank , J A , Hurley , R A , Kilts , J D , Kirby , A , Marx , C E , McDonald , S D , Moore , S D , Morey , R A , Naylor , J C , Rowland , J A , Swinkels , C , Szabo , S T , Taber , K H , Tupler , L A , Van Voorhees , E E , Yoash-Gantz , R E , Basu , A , Brick , L A , Dalvie , S , Daskalakis , N P , Ensink , J B M , Hemmings , S M J , Herringa , R , Ikiyo , S , Koen , N , Kuan , P F , Montalvo-Ortiz , J , Nispeling , D , Pfeiffer , J , Qin , X J , Ressler , K J , Schijven , D , Seedat , S , Shinozaki , G , Sumner , J A , Swart , P , Tyrka , A , Van Zuiden , M , Wani , A , Wolf , E J , Zannas , A , Uddin , M , Nievergelt , C M , INTRuST Clinical Consortium , VA Mid-Atlantic MIRECC Workgroup & PGC PTSD Epigenetics Workgroup 2020 , ' Epigenome-wide meta-analysis of PTSD across 10 military and civilian cohorts identifies methylation changes in AHRR ' , Nature Communications , vol. 11 , no. 1 , 5965 . https://doi.org/10.1038/s41467-020-19615-x
Epigenetic differences may help to distinguish between PTSD cases and trauma-exposed controls. Here, we describe the results of the largest DNA methylation meta-analysis of PTSD to date. Ten cohorts, military and civilian, contribute blood-derived DNA methylation data from 1,896 PTSD cases and trauma-exposed controls. Four CpG sites within the aryl-hydrocarbon receptor repressor (AHRR) associate with PTSD after adjustment for multiple comparisons, with lower DNA methylation in PTSD cases relative to controls. Although AHRR methylation is known to associate with smoking, the AHRR association with PTSD is most pronounced in non-smokers, suggesting the result was independent of smoking status. Evaluation of metabolomics data reveals that AHRR methylation associated with kynurenine levels, which are lower among subjects with PTSD. This study supports epigenetic differences in those with PTSD and suggests a role for decreased kynurenine as a contributor to immune dysregulation in PTSD.