The current conflicts in Iraq and Afghanistan have resulted in a large cohort of military personnel exposed to combat-related psychological trauma as well as biomechanical trauma, including proximity to blast events. Historically, the long-term effects of both types of trauma have been viewed as having different neural substrates, with some controversy over the proper attribution of such symptoms evident after each of the major conflicts of the last century. Recently, great effort has been directed toward distinguishing which neuropsychiatric sequelae are due to which type of trauma. Of interest, however, is that the chronic effects of exposure to either process are associated with a significant overlap in clinical symptoms. Furthermore, similar brain regions are vulnerable to the effects of either psychological or biomechanical trauma, raising the possibility that shared mechanisms may underlie the clinically observed overlap in symptom profile. This paper reviews the literature on the neural substrate of biomechanical and psychological injury and discusses the implications for evaluation and treatment of the neuropsychiatric sequelae of these processes.
Mild traumatic brain injury (mTBI) represents the great majority of traumatic brain injuries, and is a common medical problem affecting cognitive and vocational functioning as well as quality of life in some individuals. Functional MRI (fMRI) is an important research method for investigating the neuroanatomic substrates of cognitive disorders and their treatment. Surprisingly, however, relatively little research has utilized fMRI to examine alterations in brain functioning after mTBI. This article provides a critical overview of the published fMRI research on mTBI to date. These topics include examination of frontal lobe/ executive functions such as working memory, as well as episodic memory and resting state/functional connectivity. mTBI has also been investigated in military populations where studies have focused on effects of blast injury and comorbid conditions such as post-traumatic stress disorder and major depressive disorder. Finally, we address fMRI evaluations of response to behavioral or pharmacological challenges and interventions targeting cognitive and behavioral sequelae of mTBI. The review concludes with identification and discussion of gaps in current knowledge and future directions for fMRI studies of mTBI. The authors conclude that fMRI in combination with related methods can be expected to play an increasing role in research related to studies of pathophysiological mechanisms of the sequelae of mTBI as well as in diagnosis and treatment monitoring.
IMPORTANCE: Concussions are a common occurrence in young athletes. Hypobaric hypoxemia, such as that experienced during airplane travel, can potentially cause alterations to cerebral blood flow and increased neuroinflammatory response. It remains unknown whether flying early after a concussion may influence the clinical course of injury. OBJECTIVE: To determine whether there is an association between concussion recovery and airplane travel in collegiate athletes and military cadets. DESIGN, SETTING, AND PARTICIPANTS: This cohort study was conducted by the National Collegiate Athletic Association and US Department of Defense Concussion Assessment, Research, and Education Consortium from August 3, 2014, to September 13, 2018. Participant groups were categorized by those who flew within 72 hours of injury and those who did not fly. All participants included in the final analyses had complete data of interest and only 1 injury during the study. Data analysis was performed from September 2018 to March 2020. MAIN OUTCOMES AND MEASURES: Recovery outcome measures were defined as time (in days) from injury to return to activity, school, and baseline symptoms. Symptom and headache severity scores were derived from the Sports Concussion Assessment Tool—Third Edition. Scores for both groups were taken at baseline and a median of 2 days after injury. RESULTS: A total of 92 participants who flew (mean [SD] age, 19.1 [1.2] years; 55 male [59.8%]) and 1383 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 809 male [58.5%]) were included in the analysis of symptom recovery outcomes (analysis 1). Similarly, 100 participants who flew (mean [SD] age, 19.2 [1.2] years; 63 male [63.0%]) and 1577 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 916 male [58.1%]) were included in the analysis of symptom severity outcomes (analysis 2). No significant group differences were found regarding recovery outcome measures. Likewise, there were no group differences in symptom (estimated mean difference, 0.029; 95% CI, ...
Importance: Concussions are a common occurrence in young athletes. Hypobaric hypoxemia, such as that experienced during airplane travel, can potentially cause alterations to cerebral blood flow and increased neuroinflammatory response. It remains unknown whether flying early after a concussion may influence the clinical course of injury. Objective: To determine whether there is an association between concussion recovery and airplane travel in collegiate athletes and military cadets. Design, Setting, and Participants: This cohort study was conducted by the National Collegiate Athletic Association and US Department of Defense Concussion Assessment, Research, and Education Consortium from August 3, 2014, to September 13, 2018. Participant groups were categorized by those who flew within 72 hours of injury and those who did not fly. All participants included in the final analyses had complete data of interest and only 1 injury during the study. Data analysis was performed from September 2018 to March 2020. Main Outcomes and Measures: Recovery outcome measures were defined as time (in days) from injury to return to activity, school, and baseline symptoms. Symptom and headache severity scores were derived from the Sports Concussion Assessment Tool-Third Edition. Scores for both groups were taken at baseline and a median of 2 days after injury. Results: A total of 92 participants who flew (mean [SD] age, 19.1 [1.2] years; 55 male [59.8%]) and 1383 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 809 male [58.5%]) were included in the analysis of symptom recovery outcomes (analysis 1). Similarly, 100 participants who flew (mean [SD] age, 19.2 [1.2] years; 63 male [63.0%]) and 1577 participants who did not fly (mean [SD] age, 18.9 [1.3] years; 916 male [58.1%]) were included in the analysis of symptom severity outcomes (analysis 2). No significant group differences were found regarding recovery outcome measures. Likewise, there were no group differences in symptom (estimated mean difference, 0.029; 95% CI, -0.083 to 0.144; P = .67) or headache (estimated mean difference, -0.007; 95% CI, -0.094 to 0.081; P = .91) severity scores. Conclusions and Relevance: Airplane travel early after concussion was not associated with recovery or severity of concussion symptoms. These findings may help guide future recommendations on flight travel after concussion in athletes.
BACKGROUND: Timely removal from activity after concussion symptoms remains problematic despite heightened awareness. Previous studies indicated potential adverse effects of continuing to participate in physical activity immediately after sustaining a concussion. HYPOTHESIS/PURPOSE: The purpose was to determine the effect of timing of removal from play after concussion on clinical outcomes. It was hypothesized that immediate removal from activity after sport-related concussion (SRC) would be associated with less time missed from sport, a shorter symptomatic period, and better outcomes on acute clinical measures. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Data were reported from the National Collegiate Athletic Association and Department of Defense Grand Alliance: Concussion Awareness, Research, and Education (CARE) Consortium. Participants with 506 diagnosed SRCs from 18 sports and 25 institutions and military service academies were analyzed and classified as either immediate removal from activity (I-RFA) or delayed removal from activity (D-RFA). Outcomes of interest included time missed from sport attributed to their SRC, symptom duration, and clinical assessment scores. RESULTS: There were 322 participants (63.6%) characterized as D-RFA. I-RFA status was associated with significantly less time missed from sport (R(2) change = .022–.024, P < .001 to P = .001) and shorter symptom duration (R(2) change = .044–.046, P < .001 [all imputations]) while controlling for other SRC recovery modifiers. These athletes missed approximately 3 fewer days from sport participation. I-RFA athletes had significantly less severe acute SRC symptoms and were at lower risk of recovery taking ≥14 days (relative risk = .614, P < .001, small-medium effect size) and ≥21 days (relative risk = .534, P = .010, small effect size). CONCLUSION: I-RFA is a protective factor associated with less severe acute symptoms and shorter recovery after SRC. Conveying this message to athletes, coaches, and others involved in the ...
Despite the significant impact that concussion has on military service members, significant gaps remain in our understanding of the optimal diagnostic, management, and return to activity/duty criteria to mitigate the consequences of concussion. In response to these significant knowledge gaps, the US Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) partnered to form the NCAA-DoD Grand Alliance in 2014. The NCAA-DoD CARE Consortium was established with the aim of creating a national multisite research network to study the clinical and neurobiological natural history of concussion in NCAA athletes and military Service Academy cadets and midshipmen. In addition to the data collected for the larger CARE Consortium effort, the service academies have pursued military-specific lines of research relevant to operational and medical readiness associated with concussion. The purpose of this article is to describe the structure of the NCAA-DoD Grand Alliance efforts at the service academies, as well as discuss military-specific research objectives and provide an overview of progress to date. A secondary objective is to discuss the challenges associated with conducting large-scale studies in the Service Academy environment and highlight future directions for concussion research endeavors across the CARE Service Academy sites.
Despite the significant impact that concussion has on military service members, significant gaps remain in our understanding of the optimal diagnostic, management, and return to activity/duty criteria to mitigate the consequences of concussion. In response to these significant knowledge gaps, the US Department of Defense (DoD) and the National Collegiate Athletic Association (NCAA) partnered to form the NCAA-DoD Grand Alliance in 2014. The NCAA-DoD CARE Consortium was established with the aim of creating a national multisite research network to study the clinical and neurobiological natural history of concussion in NCAA athletes and military Service Academy cadets and midshipmen. In addition to the data collected for the larger CARE Consortium effort, the service academies have pursued military-specific lines of research relevant to operational and medical readiness associated with concussion. The purpose of this article is to describe the structure of the NCAA-DoD Grand Alliance efforts at the service academies, as well as discuss military-specific research objectives and provide an overview of progress to date. A secondary objective is to discuss the challenges associated with conducting large-scale studies in the Service Academy environment and highlight future directions for concussion research endeavors across the CARE Service Academy sites.
Importance Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure Concussion incurred during combative training. Main Outcomes and Measures Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and Relevance This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions. ; Grand Alliance Concussion Assessment, Research, and Education Consortium; National Collegiate Athletic Association; US Department of DefenseUnited States Department of Defense; Office of the Assistant Secretary of Defense for Health Affairs [W81XWH-14-2-0151] ; This study was supported by the Grand Alliance Concussion Assessment, Research, and Education Consortium, the National Collegiate Athletic Association, the US Department of Defense, and grant W81XWH-14-2-0151 from the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program.
Question Are plasma biomarkers associated with a return-to-sport period of less than 14 days vs 14 days or more in male and female collegiate athletes following a sport-related concussion? Findings This diagnostic study, which included 127 collegiate athletes who had sustained a sports-related concussion, found that higher total tau concentrations 24 to 48 hours after injury and at the time of symptom resolution as well as lower glial fibrillary acidic protein levels acutely postinjury were associated with return-to-sport decisions. Meaning In this study, total tau and glial fibrillary acidic protein levels were associated with return to sport in male and female collegiate athletes following a sports-related concussion. This diagnostic study examines whether plasma biomarkers can differentiate collegiate athletes who return to sport in less than 14 days vs 14 days or more following a sports-related concussion. Importance Identifying plasma biomarkers associated with the amount of time an athlete may need before they return to sport (RTS) following a sport-related concussion (SRC) is important because it may help to improve the health and safety of athletes. Objective To examine whether plasma biomarkers can differentiate collegiate athletes who RTS in less than 14 days or 14 days or more following SRC. Design, Setting, and Participants This multicenter prospective diagnostic study, conducted by the National Collegiate Athletics Association-Department of Defense Concussion Assessment, Research, and Education Consortium, included 127 male and female athletes who had sustained an SRC while enrolled at 6 Concussion Assessment, Research, and Education Consortium Advanced Research Core sites as well as 2 partial-Advanced Research Core military service academies. Data were collected between February 2015 and May 2018. Athletes with SRC completed clinical testing and blood collection at preseason (baseline), postinjury (0-21 hours), 24 to 48 hours postinjury, time of symptom resolution, and 7 days after unrestricted RTS. Main Outcomes and Measures A total of 3 plasma biomarkers (ie, total tau protein, glial fibrillary acidic protein [GFAP], and neurofilament light chain protein [Nf-L]) were measured using an ultrasensitive single molecule array technology and were included in the final analysis. RTS was examined between athletes who took less than 14 days vs those who took 14 days or more to RTS following SRC. Linear mixed models were used to identify significant interactions between period by RTS group. Area under the receiver operating characteristic curve analyses were conducted to examine whether these plasma biomarkers could discriminate between RTS groups. Results The 127 participants had a mean (SD) age of 18.9 (1.3) years, and 97 (76.4%) were men; 65 (51.2%) took less than 14 days to RTS, and 62 (48.8%) took 14 days or more to RTS. Linear mixed models identified significant associations for both mean (SE) plasma total tau (24-48 hours postinjury, = 14 days RTS: -0.65 [0.12] pg/mL vs -0.14 [0.14] pg/mL; P = .008) and GFAP (postinjury, 14 days RTS vs >= 14 days RTS: 4.72 [0.12] pg/mL vs 4.39 [0.11] pg/mL; P = .04). Total tau at the time of symptom resolution had acceptable discrimination power (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.63-0.86; P < .001). We also examined a combined plasma biomarker panel that incorporated Nf-L, GFAP, and total tau at each period to discriminate RTS groups. Although the analyses did reach significance at each time period when combined, results indicated that they were poor at distinguishing the groups (area under the receiver operating characteristic curve, <0.7). Conclusions and Relevance The findings of this study suggest that measures of total tau and GFAP may identify athletes who will require more time to RTS. However, further research is needed to improve our ability to determine recovery following an SRC. ; Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium; NCAA; Department of DefenseUnited States Department of Defense; Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program [W81XWH-14-2-0151] ; This publication was made possible with support from the Grand Alliance Concussion Assessment, Research, and Education (CARE) Consortium, funded, in part by the NCAA and the Department of Defense. The US Army Medical Research Acquisition Activity, 820 Chandler St, Ft Detrick, MD 21702, is the awarding and administering acquisition office. This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Psychological Health and Traumatic Brain Injury Program under award No. W81XWH-14-2-0151.
Importance: Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective: To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, setting, and participants: This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main outcomes and measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity ...
Mild Traumatic brain injury (mTBI) is a signature wound in military personnel, and repetitive mTBI has been linked to age‐related neurogenerative disorders that affect white matter (WM) in the brain. However, findings of injury to specific WM tracts have been variable and inconsistent. This may be due to the heterogeneity of mechanisms, etiology, and comorbid disorders related to mTBI. Non‐negative matrix factorization (NMF) is a data‐driven approach that detects covarying patterns (components) within high‐dimensional data. We applied NMF to diffusion imaging data from military Veterans with and without a self‐reported TBI history. NMF identified 12 independent components derived from fractional anisotropy (FA) in a large dataset (n = 1,475) gathered through the ENIGMA (Enhancing Neuroimaging Genetics through Meta‐Analysis) Military Brain Injury working group. Regressions were used to examine TBI‐ and mTBI‐related associations in NMF‐derived components while adjusting for age, sex, post‐traumatic stress disorder, depression, and data acquisition site/scanner. We found significantly stronger age‐dependent effects of lower FA in Veterans with TBI than Veterans without in four components (q < 0.05), which are spatially unconstrained by traditionally defined WM tracts. One component, occupying the most peripheral location, exhibited significantly stronger age‐dependent differences in Veterans with mTBI. We found NMF to be powerful and effective in detecting covarying patterns of FA associated with mTBI by applying standard parametric regression modeling. Our results highlight patterns of WM alteration that are differentially affected by TBI and mTBI in younger compared to older military Veterans.
OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.
OBJECTIVE: To develop evidence-informed, expert consensus research diagnostic criteria for traumatic encephalopathy syndrome (TES), the clinical disorder associated with neuropathologically diagnosed chronic traumatic encephalopathy (CTE). METHODS: A panel of 20 expert clinician-scientists in neurology, neuropsychology, psychiatry, neurosurgery, and physical medicine and rehabilitation, from 11 academic institutions, participated in a modified Delphi procedure to achieve consensus, initiated at the First National Institute of Neurological Disorders and Stroke Consensus Workshop to Define the Diagnostic Criteria for TES, April, 2019. Before consensus, panelists reviewed evidence from all published cases of CTE with neuropathologic confirmation, and they examined the predictive validity data on clinical features in relation to CTE pathology from a large clinicopathologic study (n = 298). RESULTS: Consensus was achieved in 4 rounds of the Delphi procedure. Diagnosis of TES requires (1) substantial exposure to repetitive head impacts (RHIs) from contact sports, military service, or other causes; (2) core clinical features of cognitive impairment (in episodic memory and/or executive functioning) and/or neurobehavioral dysregulation; (3) a progressive course; and (4) that the clinical features are not fully accounted for by any other neurologic, psychiatric, or medical conditions. For those meeting criteria for TES, functional dependence is graded on 5 levels, ranging from independent to severe dementia. A provisional level of certainty for CTE pathology is determined based on specific RHI exposure thresholds, core clinical features, functional status, and additional supportive features, including delayed onset, motor signs, and psychiatric features. CONCLUSIONS: New consensus diagnostic criteria for TES were developed with a primary goal of facilitating future CTE research. These criteria will be revised as updated clinical and pathologic information and in vivo biomarkers become available.
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.